HIV and AIDS

Contents
1

Retrovirus

1.1

Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.2

Multiplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.3

Transmission

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.4

Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.5

Provirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.6

Early evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.7

Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.8

Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.9

Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.9.1

Exogenous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.9.2

Endogenous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.10 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.11 Treatment of veterinary retroviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.12 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.13 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lentivirus

2.1

Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2

Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3

Genome organization and replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.4

Proteome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5

Antigenic properties

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.6

Biological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.7

Physicochemical and physical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.8

Practical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.9

Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.11 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.12 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Simian immunodeciency virus

3.1

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
i

ii

CONTENTS
3.2

Tropism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.3

Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.4

See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10

3.5

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10

3.6

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

HIV
4.1

12
Virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12

4.1.1

Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12

4.1.2

Structure and genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12

4.1.3

Tropism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

4.1.4

Replication cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14

4.1.5

Spread within the body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17

4.1.6

Genetic variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17

4.2

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18

4.3

Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19

4.4

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19

4.4.1

Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19

4.4.2

Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20

4.5

See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20

4.6

References

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21

4.7

Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26

4.8

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26

History of HIV/AIDS

27

5.1

Transmission from non-humans to humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27

5.1.1

HIV-1 from chimpanzees and gorillas to humans

. . . . . . . . . . . . . . . . . . . . . .

27

5.1.2

HIV-2 from sooty mangabeys to humans . . . . . . . . . . . . . . . . . . . . . . . . . . .

28

5.1.3

Bushmeat practice

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29

5.2.1

Unresolved questions about HIV origins and emergence . . . . . . . . . . . . . . . . . . .

29

5.2.2

Origin and epidemic emergence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29

5.3

Pathogenicity of SIV in non-human primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

5.4

History of spread . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

5.4.1

1959: David Carr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

5.4.2

1959: Congolese man . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

5.4.3

1960: Congolese woman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

5.4.4

1969: Robert Rayford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33

5.4.5

1969: Arvid Noe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

5.4.6

1973: Ugandan children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

5.4.7

Spread to the western hemisphere . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

5.4.8

Canadian ight attendant theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

5.2

Emergence

CONTENTS
5.4.9

1981: From GRID to AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34

Identication of the virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.5.1

May 1983: LAV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.5.2

May 1984: HTLV-III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.5.3

January 1985: both found to be the same . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.5.4

May 1986: the name HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.5.5

Nobel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.6

Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.7

Genetic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.8

Discredited hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35

5.9

See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36

5.10 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36

HIV/AIDS denialism

40

6.1

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40

6.1.1

U.S. courts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

6.1.2

South Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41

6.2

HIV/AIDS denialists claims and scientic evidence . . . . . . . . . . . . . . . . . . . . . . . . .

42

6.3

The HIV/AIDS denialist community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

6.3.1

Former denialists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43

6.3.2

Death of HIV-positive denialists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44

Impact beyond the scientic community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44

6.4.1

Impact in North America and Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . .

44

6.4.2

Impact in South Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46

6.5

See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47

6.6

Footnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47

6.7

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51

6.8

Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51

6.9

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51

5.5

6.4

Subtypes of HIV

52

7.1

Major types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52

7.1.1

HIV-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52

7.1.2

HIV-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53

Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54

7.2.1

Drug resistance mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54

7.3

See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54

7.4

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54

7.5

External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55

7.2

iii

HIV/AIDS
8.1

Signs and symptoms

56
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

56

iv

CONTENTS

8.2

8.1.1

Acute infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

56

8.1.2

Clinical latency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

57

8.1.3

Acquired immunodeciency syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . .

57

Transmission

58

8.2.1

Sexual

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58

8.2.2

Body uids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58

8.2.3

Mother-to-child

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59

8.3

Virology

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59

8.4

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60

8.5

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60

8.5.1

HIV testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61

8.5.2

Classications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61

Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62

8.6.1

Sexual contact

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62

8.6.2

Pre-exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62

8.6.3

Post-exposure

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62

8.6.4

Mother-to-child

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

8.6.5

Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

8.7.1

Antiviral therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

8.7.2

Opportunistic infections

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64

8.7.3

Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64

8.7.4

Alternative medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64

8.8

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64

8.9

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65

8.6

8.7

8.10 History

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66

8.10.1 Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66

8.10.2 Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66

8.11 Society and culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

8.11.1 Stigma

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

67

8.11.2 Economic impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68

8.11.3 Religion and AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

68

8.11.4 Media portrayal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

69

8.11.5 Criminal transmission

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69

8.11.6 Misconceptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

69

8.12 Research

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69

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

70

8.14 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

80

8.15 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81

Pathophysiology of HIV/AIDS

82

9.1

82

8.13 References

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Immunology

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CONTENTS

9.2

Cells aected . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

9.3

The eect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

9.4

Molecular basis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

9.5

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

83

10 Diagnosis of HIV/AIDS

84

10.1 AIDS diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

10.2 Terminology

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

10.3 Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84

10.3.1 Screening donor blood and cellular products . . . . . . . . . . . . . . . . . . . . . . . . .

84

10.3.2 Diagnosis of HIV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

10.3.3 Human rights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

10.3.4 Condentiality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

10.3.5 Anonymous testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

10.3.6 Routine testing recommendation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

10.4 Antibody tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

10.4.1 Window period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85

10.4.2 ELISA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

10.4.3 ELISA dongle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

10.4.4 Western blot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

86

10.4.5 Rapid or point-of-care tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

10.4.6 Interpreting antibody tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

10.4.7 Accuracy of HIV testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

10.5 Antigen tests

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

10.6 Nucleic acid-based tests (NAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88

10.7 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.8 Other tests used in HIV treatment

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.9 Criticisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.9.1 Oral tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

89

10.9.2 AIDS denialism

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90

10.10Fraudulent testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90

10.11References

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90

10.12External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

92

11 Prevention of HIV/AIDS

93

11.1 Prevention strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93

11.1.1 Pharmaceutical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

93

11.1.2 Social strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

11.1.3 Advertising and campaigns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

11.1.4 Sexual contact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

11.1.5 Pre exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.1.6 Post exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

vi

CONTENTS
11.1.7 Follow-up care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.1.8 Mother-to-child

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.1.9 Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.1.10 Legal system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

95

11.1.11 Quality in Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96

11.2 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96

11.2.1 1980s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96

11.2.2 From 2003 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96

11.2.3 From 2011 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

97

11.5 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

12 Management of HIV/AIDS
12.1 History

102

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

12.2 Classes of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

12.3 Combination therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
12.3.1 Fixed-dose combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
12.4 Treatment guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
12.4.1 Initiation of antiretroviral therapy
12.4.2 Guideline Sources

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

12.4.3 Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

12.4.4 Special populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
12.5 Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
12.6 Response to therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
12.6.1 Virologic response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
12.6.2 Immunologic response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
12.7 Salvage therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
12.8 Structured treatment interruptions

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

12.9 Adverse eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

12.9.1 NRTIs
12.9.2 NNRTIs

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

12.9.3 Protease inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

12.9.4 Integrase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
12.10HIV Postexposure Prophylaxis (PEP)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

12.11Pregnancy planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

12.12Towards a cure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
12.12.1 Berlin patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
12.12.2 Viral reservoirs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
12.12.3 Immune activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
12.13See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
12.14References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

CONTENTS

vii

12.15External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

13 Epidemiology of HIV/AIDS

114

13.1 By region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

13.1.1 Sub-Saharan Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
13.1.2 Middle East and North Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
13.1.3 South and South-East Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
13.1.4 East Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
13.1.5 Americas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
13.1.6 Eastern Europe and Central Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
13.1.7 Western Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
13.1.8 Oceania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
13.2 AIDS and society . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
13.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
13.4 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
13.5 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
14 HIV/AIDS research

121

14.1 Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

14.1.1 Pre- and post-exposure prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
14.2 Within-host dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
14.3 Virus characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
14.4 Management of HIV/AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
14.5 Age acceleration eects due to HIV-1 infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
14.6 Long-term nonprogressor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
14.7 HIV vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
14.8 Microbicides for sexually transmitted diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
14.9 Stem cell transplantation

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

14.10Immunomodulatory agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

14.11New developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
14.12See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
14.13References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
14.14External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
14.15Text and image sources, contributors, and licenses . . . . . . . . . . . . . . . . . . . . . . . . . . 126
14.15.1 Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
14.15.2 Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
14.15.3 Content license . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Chapter 1

Retrovirus
Retrovirology redirects here. For the journal, see 1.1 Structure
Retrovirology (journal).
For a more accessible and less technical introduction to Virions of retroviruses consist of enveloped particles
this topic, see Introduction to viruses.
about 100 nm in diameter. The virions also contain two
identical single-stranded RNA molecules 710 kilobases
Retroviridae is a family of enveloped viruses that repli- in length. Although virions of dierent retroviruses do
cate in a host cell through the process of reverse tran- not have the same morphology or biology, all the virion
[2]
scription. A retrovirus is a single-stranded positive- components are very similar.
sense RNA virus with a DNA intermediate and, as an The main virion components are:
obligate parasite, targets a host cell. Once inside the host
cell cytoplasm, the virus uses its own reverse transcrip Envelope: composed of lipids (obtained from the
tase enzyme to produce DNA from its RNA genome
host plasma membrane during budding process) as
the reverse of the usual pattern, thus retro (backwards).
well
as glycoprotein encoded by the env gene. The
This new DNA is then incorporated into the host cell
retroviral
envelope serves three distinct functions:
genome by an integrase enzyme, at which point the retroprotection
from the extracellular environment via
viral DNA is referred to as a provirus. The host cell then
the
lipid
bilayer,
enabling the retrovirus to enter/exit
treats the viral DNA as part of its own genome, translathost
cells
through
endosomal membrane tracking,
ing and transcribing the viral genes along with the cells
and
the
ability
to
directly
enter cells by fusing with
own genes, producing the proteins required to assemble
their
membranes.
new copies of the virus. It is dicult to detect the virus
until it has infected the host. At that point, the infection
RNA: consists of a dimer RNA. It has a cap at the
will persist indenitely.
5' end and a poly(A) tail at the 3' end. The RNA
In most viruses, DNA is transcribed into RNA, and then
genome also has terminal noncoding regions, which
RNA is translated into protein. However, retroviruses
are important in replication, and internal regions
function dierently their RNA is reverse-transcribed
that encode virion proteins for gene expression. The
into DNA, which is integrated into the host cells genome
5' end includes four regions, which are R, U5, PBS,
(when it becomes a provirus), and then undergoes the
and L. The R region is a short repeated sequence
usual transcription and translational processes to express
at each end of the genome used during the reverse
the genes carried by the virus. So, the information contranscription to ensure correct end-to-end transfer in
tained in a retroviral gene is used to generate the corthe growing chain. U5, on the other hand, is a short
responding protein via the sequence: RNA DNA
unique sequence between R and PBS. PBS (primer
RNA polypeptide. This extends the fundamental probinding site) consists of 18 bases complementary to
cess identied by Francis Crick (one gene-one peptide)
3' end of tRNA primer. L region is an untranslated
in which the sequence is: DNA RNA peptide (proleader region that gives the signal for packaging of
teins are made of one or more polypeptide chain; e.g.
the genome RNA. The 3' end includes 3 regions,
haemoglobin is a four-chain peptide).
which are PPT (polypurine tract), U3, and R. The
Retroviruses are valuable research tools in molecular biPPT is a primer for plus-strand DNA synthesis durology, and have been used successfully in gene delivery
ing reverse transcription. U3 is a sequence between
systems.[1]
PPT and R, which serves as a signal that the provirus
can use in transcription. R is the terminal repeated
sequence at 3' end.
Proteins: consisting of gag proteins, protease (PR),
pol proteins, and env proteins.
1

CHAPTER 1. RETROVIRUS
Group-specic antigen (gag) proteins are major components of the viral capsid, which are
about 20004000 copies per virion.
Protease is expressed dierently in dierent
viruses. It functions in proteolytic cleavages
during virion maturation to make mature gag
and pol proteins.
Pol proteins are responsible for synthesis of viral DNA and integration into host DNA after
infection.
Env proteins play a role in association and entry of virions into the host cell.[3] Possessing a
functional copy of an env gene is what makes
retroviruses distinct from retroelements.[4]
The ability of the retrovirus to bind to its target host cell using specic cell-surface receptors is given by the surface component (SU)
of the Env protein, while the ability of the
retrovirus to enter the cell via membrane fusion is imparted by the membrane-anchored
trans-membrane component (TM). Thus the
Env protein is what enables the retrovirus to
be infectious.

1.2 Multiplication

A retrovirus has a membrane containing glycoproteins, which are

able to bind to a receptor protein on a host cell. There are two
strands of RNA within the cell that have three enzymes; protease,
reverse transcriptase, and integrase (1). The rst step of replication is the binding of the glycoprotein to the receptor protein
(2). Once these have been bound, the cell membrane degrades,
becoming part of the host cell, and the RNA strands and enzymes
go into the cell (3). Within the cell, reverse transcriptase creates
a complementary strand of DNA from the retrovirus RNA and
the RNA is degraded; this strand of DNA is known as cDNA (4).
The cDNA is then replicated, and the two strands form a weak
bond and go into the nucleus (5). Once in the nucleus, the DNA is
integrated into the host cells DNA with the help of integrase (6).
This cell can either stay dormant, or RNA may be synthesized
from the DNA and used to create the proteins for a new retrovirus (7). Ribosome units are used to transcribe the mRNA of
the virus into the amino acid sequences which can be made into
proteins in the Rough Endoplasmic Reticulum. This step will also
make viral enzymes and capsid proteins (8). Viral RNA will be
made in the nucleus. These pieces are then gathered together and
are pinched o of the cell membrane as a new retrovirus (9).

generation. These endogenous retroviruses (ERVs), contrasted with exogenous ones, now make up 5-8% of the
human genome.[5] Most insertions have no known function and are often referred to as "junk DNA". However, many endogenous retroviruses play important roles
in host biology, such as control of gene transcription, cell
fusion during placental development in the course of the
germination of an embryo, and resistance to exogenous
retroviral infection. Endogenous retroviruses have also
received special attention in the research of immunologyrelated pathologies, such as autoimmune diseases like
multiple sclerosis, although endogenous retroviruses have
not yet been proven to play any causal role in this class of
disease.[6]
While transcription was classically thought to occur only
from DNA to RNA, reverse transcriptase transcribes
RNA into DNA. The term retro in retrovirus refers to
this reversal (making DNA from RNA) of the central
dogma of molecular biology. Reverse transcriptase activity outside of retroviruses has been found in almost
all eukaryotes, enabling the generation and insertion of
new copies of retrotransposons into the host genome.
These inserts are transcribed by enzymes of the host
into new RNA molecules that enter the cytosol. Next,
some of these RNA molecules are translated into viral
proteins. For example, the gag gene is translated into
molecules of the capsid protein, the pol gene is translated
into molecules of reverse transcriptase, and the env gene
is translated into molecules of the envelope protein. It is
important to note that a retrovirus must bring its own
reverse transcriptase in its capsid, otherwise it is unable
to utilize the enzymes of the infected cell to carry out the
task, due to the unusual nature of producing DNA from
RNA.
Industrial drugs that are designed as protease and reverse
transcriptase inhibitors are made such that they target
specic sites and sequences within their respective enzymes. However these drugs can quickly become ineffective due to the fact that the gene sequences that code
for the protease and the reverse transcriptase quickly mutate. These changes in bases cause specic codons and
sites with the enzymes to change and thereby avoid drug
targeting by losing the sites that the drug actually targets.
Because reverse transcription lacks the usual
proofreading of DNA replication, a retrovirus mutates
very often. This enables the virus to grow resistant
to antiviral pharmaceuticals quickly, and impedes the
development of eective vaccines and inhibitors for the
retrovirus.[7]

One diculty faced with some retroviruses, such as the

Moloney retrovirus, involves the requirement for cells to
be actively dividing for transduction. As a result, cells
such as neurons are very resistant to infection and transduction by retroviruses. This gives rise to a concern that
insertional mutagenesis due to integration into the host
When retroviruses have integrated their own genome into genome might lead to cancer or leukemia. This is unlike
the germ line, their genome is passed on to a following

1.7. GENE THERAPY

Lentivirus, a genus of Retroviridae, which are able to integrate their RNA into the genome of non-dividing host
cells.

1.3 Transmission
Cell-to-cell[8]
Fluids
Airborne, like the Jaagsiekte sheep retrovirus.

1.4 Genes
Retrovirus genomes commonly contain these three open
reading frames that encode for proteins that can be found
in the mature virus:

1.7 Gene therapy

Gammaretroviral and lentiviral vectors for gene therapy
have been developed that mediate stable genetic modication of treated cells by chromosomal integration of the
transferred vector genomes. This technology is of use,
not only for research purposes, but also for clinical gene
therapy aiming at the long-term correction of genetic defects, e.g., in stem and progenitor cells. Retroviral vector
particles with tropism for various target cells have been
designed. Gammaretroviral and lentiviral vectors have
so far been used in more than 300 clinical trials, addressing treatment options for various diseases.[1][9] Retro viral mutations can be developed to make transgenic mouse
models to study various cancers and their metastatic models.

1.8 Cancer

group-specic antigen (gag) codes for core and struc- Retroviruses that cause tumor growth include Rous sarcoma virus and Mouse mammary tumor virus. Cancer
tural proteins of the virus;
can be triggered by proto-oncogenes that were mistak polymerase (pol) codes for reverse transcriptase, enly incorporated into proviral DNA or by the disruption
of cellular proto-oncogenes. Rous sarcoma virus contains
protease and integrase;
the src gene that triggers tumor formation. Later it was
found that a similar gene in cells is involved in cell sig envelope (env) codes for the retroviral coat proteins.
naling, which was most likely excised with the proviral
DNA. Nontransforming viruses can randomly insert their
DNA into proto-oncogenes, disrupting the expression of
proteins that regulate the cell cycle. The promoter of the
1.5 Provirus
provirus DNA can also cause over expression of regulatory genes.
This DNA can be incorporated into host genome as a
provirus that can be passed on to progeny cells. The retrovirus DNA is inserted at random into the host genome.
Because of this, it can be inserted into oncogenes. In this
way some retroviruses can convert normal cells into can- 1.9 Classication
cer cells. Some provirus remains latent in the cell for a
long period of time before it is activated by the change in
cell environment.
Delta-retroviruses
*
Epsilon-retroviruses
(simple)
SnRV

1.6 Early evolution

HERV-W
Gammaretroviruses*
PERV
(simple) GALV

(complex)

BLV
HTLV-II

WDSV

Lentiviruses
EIAV (complex)
FIV
HIV-2
SIVmac

HTLV-I

MLV

Studies of retroviruses led to the rst demonstrated synFeLV

thesis of DNA from RNA templates, a fundamental
mode for transferring genetic material that occurs in both
eukaryotes and prokaryotes. It has been speculated that
FFV
SFVcpz
BFV
the RNA to DNA transcription processes used by retroSFVagm
Spumaviruses
viruses may have rst caused DNA to be used as genetic
(complex)
material. In this model, the RNA world hypothesis, cellular organisms adopted the more chemically stable DNA
when retroviruses evolved to create DNA from the RNA Phylogeny of Retroviruses
templates.

HIV-1
MVV
AlphaALV retroviruses*
RSV (simple)
JRSV
HERV-K
SRV
MMTV

Beta-retroviruses*
(simple)

CHAPTER 1. RETROVIRUS

1.9.1

Exogenous

as the template during genome replication. Virally encoded reverse transcriptase uses the pre-genomic RNA
These are infectious RNA-containing viruses which are as a template for the creation of genomic DNA.
transmitted from human to human.
Group VII includes:
The following genera are included here:
Family Hepadnaviridae e.g. Hepatitis B virus
Genus Alpharetrovirus; type species: Avian leukosis
Family Caulimoviridae e.g. Cauliower mosaic
virus; others include Rous sarcoma virus
virus
Genus Betaretrovirus; type species: Mouse mammary tumour virus

1.9.2 Endogenous

Genus Gammaretrovirus; type species: Murine

leukemia virus; others include Feline leukemia virus Main article: Endogenous retrovirus
Genus Deltaretrovirus; type species: Bovine
leukemia virus; others include the cancer-causing Endogenous retroviruses are not formally included in this
classication system, and are broadly classied into three
Human T-lymphotropic virus
classes, on the basis of relatedness to exogenous genera:
Genus Epsilonretrovirus; type species: Walleye dermal sarcoma virus
Class I are most similar to the gammaretroviruses
Genus Lentivirus; type species: Human immunodeciency virus 1; others include Simian, Feline immunodeciency viruses
Genus Spumavirus; type species: Simian foamy virus

Class II are most similar to the betaretroviruses and

alpharetroviruses
Class III are most similar to the spumaviruses.

These were previously divided into three subfamilies (On- 1.10 Treatment
covirinae, Lentivirinae, and Spumavirinae), but are now
divided into two: Orthoretrovirinae and SpumaretroviriAntiretroviral drugs are medications for the treatment
nae. The term oncovirus is now commonly used to deof infection by retroviruses, primarily HIV. Dierent
scribe a cancer-causing virus.
classes of antiretroviral drugs act on dierent stages of
Retroviruses were in 2 groups of the Virus classica- the HIV life cycle. Combination of several (typically
tion#Baltimore classication.
three or four) antiretroviral drugs is known as highly active anti-retroviral therapy (HAART).[10]
Group VI viruses
All members of Group VI use virally encoded reverse 1.11 Treatment of veterinary retrotranscriptase, an RNA-dependent DNA polymerase, to
viruses
produce DNA from the initial virion RNA genome. This
DNA is often integrated into the host genome, as in the
Feline leukemia virus and Feline immunodeciency virus
case of retroviruses and pseudoviruses, where it is repliinfections are treated with biologics, including the only
cated and transcribed by the host.
immunomodulator currently licensed for sale in the
Group VI includes:
United States, Lymphocyte T-Cell Immune Modulator
(LTCI).[11]
Family Metaviridae
Family Pseudoviridae
Family Retroviridae Retroviruses, e.g. HIV
Group VII viruses
Both families in Group VII have DNA genomes contained within the invading virus particles. The DNA
genome is transcribed into both mRNA, for use as a transcript in protein synthesis, and pre-genomic RNA, for use

1.12 References
[1] Kurth, Reinhard; Bannert, Norbert, eds.
(2010).
Retroviruses: Molecular Biology, Genomics and Pathogenesis. Horizon Scientic. ISBN 978-1-904455-55-4.
[2] Con, John M. (1992). Structure and Classication of
Retroviruses. In Levy, Jay A. The Retroviridae 1 (1st
ed.). New York: Plenum. p. 20. ISBN 0-306-44074-1.
[3] Con 1992, pp. 2634

1.13. EXTERNAL LINKS

[4] Kim FJ, Battini JL, Manel N, Sitbon M (January

2004).
Emergence of vertebrate retroviruses
and envelope capture. Virology 318 (1): 18391.
doi:10.1016/j.virol.2003.09.026. PMID 14972546.
[5] Robert Belshaw; Pereira V; Katzourakis A; Talbot G;
Paces J; Burt A; Tristem M. (April 2004). Long-term
reinfection of the human genome by endogenous retroviruses. Proc Natl Acad Sci USA 101 (14): 48949.
doi:10.1073/pnas.0307800101. PMC 387345. PMID
15044706.
[6] Medstrand P, van de Lagemaat L, Dunn C, Landry J,
Svenback D, Mager D (2005). Impact of transposable elements on the evolution of mammalian gene regulation. Cytogenet Genome Res 110 (1-4): 34252.
doi:10.1159/000084966. PMID 16093686.
[7] Svarovskaia ES; Cheslock SR; Zhang WH; Hu WS;
Pathak VK. (January 2003). Retroviral mutation rates
and reverse transcriptase delity.. Front Biosci. 8 (1-3):
d11734. doi:10.2741/957. PMID 12456349.
[8] Jolly C (March 2011).
Cell-to-cell transmission
of retroviruses: Innate immunity and interferoninduced restriction factors.. Virology 411 (2): 2519.
doi:10.1016/j.virol.2010.12.031. PMC 3053447. PMID
21247613.
[9] Desport, M, ed. (2010). Lentiviruses and Macrophages:
Molecular and Cellular Interactions. Caister Academic.
ISBN 978-1-904455-60-8.
[10] Haddad M, Inch C, Glazier RH, et al. (2000). Patient
support and education for promoting adherence to highly
active antiretroviral therapy for HIV/AIDS. Cochrane
Database of Systematic Reviews (Online) (3): CD001442.
doi:10.1002/14651858.CD001442. PMID 10908497.
[11] Gingerich DA (2008). Lymphocyte T-cell immunomodulator (LTCI): Review of the immunopharmacology of a
new biologic (PDF). Intern J Appl Res Vet Med 6 (2):
618.

1.13 External links

ViralZone A Swiss Institute of Bioinformatics resource for all viral families, providing general
molecular and epidemiological information (follow
links for Retro-transcribing viruses)
Retrovirus Animation (Flash Required)
Retrovirology Scientic journal
Retrovirus life cycle chapter From Kimballs Biology
(online biology textbook pages)
Con, John M; Hughes, Stephen H; Varmus,
Harold E, eds. (1997). Retroviruses. Cold
Spring Harbor Laboratory. ISBN 0-87969-571-4.
NBK19376.
Specter, Michael (3 December 2007). Annals of
Science: Darwins Surprise. The New Yorker.

Chapter 2

Lentivirus
Lentivirus (lente-, Latin for "slow") is a genus of viruses
of the Retroviridae family, characterized by a long
incubation period.[1] Lentiviruses can deliver a signicant
amount of viral RNA into the DNA of the host cell and
have the unique ability among retroviruses of being able
to infect non-dividing cells, so they are one of the most
ecient methods of a gene delivery vector.[2] HIV, SIV,
FIV, EIAV, and Visna are all examples of lentiviruses.[1]

ucts are involved in regulation of synthesis and processing

viral RNA and other replicative functions. The Long terminal repeat (LTR) is about 600 nt long, of which the
U3 region is 450, the R sequence 100 and the U5 region
some 70 nt long.
Viral proteins involved in early stages of replication include Reverse Transcriptase and Integrase. Reverse
Transcriptase is the virally encoded RNA-dependent
DNA polymerase. The enzyme uses the viral RNA
genome as a template for the synthesis of a complementary DNA copy. Reverse transcriptase also has RNaseH
activity for destruction of the RNA-template. Integrase
binds both the viral cDNA generated by reverse transcriptase and the host DNA. Integrase processes the LTR
before inserting the viral genome into the host DNA.
Tat acts as a trans-activator during transcription to enhance initiation and elongation. The Rev responsive element acts post-transcriptionally, regulating mRNA splicing and transport to the cytoplasm.[6]

2.1 Classication
Five serogroups of lentiviruses are recognized, reecting the vertebrate hosts with which they are associated
(primates, sheep and goats, horses, cats, and cattle).[3]
The primate lentiviruses are distinguished by the use of
CD4 protein as a receptor and the absence of dUTPase.[4]
Some groups have cross-reactive gag antigens (e.g., the
ovine, caprine and feline lentiviruses). Antibodies to
gag antigens in lions and other large felids indicate
the existence of other viruses related to FIV and the
ovine/caprine lentiviruses.

2.4 Proteome

The lentiviral proteome consists of ve major structural

proteins and 3-4 non-structural proteins (3 in the primate
lentiviruses). Structural proteins listed here by protein
The virions are enveloped, slightly pleomorphic, spheri- size:
cal and measure 80100 nm in diameter. Projections of
envelope make the surface appear rough, or tiny spikes
1. Gp120 glycosylated surface envelope protein SU,
(about 8 nm) may be dispersed evenly over the surface.
encoded by the viral gene env. Largest 120000 Da
The nucleocapsids (cores) are isometric. The nucleoids
(Daltons).
are concentric and rod-shaped, or shaped like a truncated
cone.[5]
2. Gp41 glycosylated transmembrane envelope protein

2.2 Morphology

2.3 Genome organization

replication

TM, also encoded by the viral gene env. 2nd largest

41000 Da.

and

3. P24 non-glycosylated capsid protein CA, encoded

by the viral gene gag. 3rd largest 24000 Da.

Features of the genome: infectious viruses have three

main genes coding for the viral proteins in the order: 5gag-pol-env-3. There are two regulatory genes, tat and
rev. There are additional accessory genes depending on
the virus (e.g., for HIV-1: vif, vpr, vpu, nef) whose prod-

4. P17 non-glycosylated matrix protein MA, also encoded by gag. 4th largest 17000 Da.
5. Non-glycosylated capsid protein NC, also encoded
by gag. 5th largest 7000-11000 Da.
6

2.8. PRACTICAL APPLICATIONS

The envelope proteins SU and TM are glycosylated

Infectivity not aected by UV irradiation
in at least some lentiviruses (HIV, SIV), if not all of
them. Glycosylation seems to play a structural role Classed as having class C morphology
in the concealment and variation of antigenic sites
necessary for the host to mount an immune system
Nucleic Acid
response.
Virions contain 2% nucleic acid
Non-structural proteins listed here:
1. Reverse transcriptase encoded by the pol gene. Protein size 66000 Da.
2. Integrase IN also encoded by the pol gene. Protein
size 32000 Da.
3. Protease PR encoded by the pro gene. dUPTase
DU, the role of which is still unknown. Protein size
14000 Da.

2.5 Antigenic properties

Serological Relationships: Antigen determinants are
type-specic and group-specic. Antigen determinants
that possess type-specic reactivity are found on the envelope. Antigen determinants that possess type-specic
reactivity and are involved in antibody mediated neutralization are found on the glycoproteins. Cross-reactivity
has been found among some species of the same serotype,
but not between members of dierent genera. Classication of members of this taxon is infrequently based on
their antigenic properties.

2.6 Biological

Genome consists of a dimer

Virions contain one molecule of (each) linear
positive-sense single stranded RNA.
Total genome length is of one monomer 9200
nt
Genome sequence has terminal repeated sequences; long terminal repeats (LTR) (of
about 600 nt
The 5' end of the genome has a cap
Cap sequence of type 1 m7G5ppp5'GmpNp
3' end of each monomer has a poly (A) tract;
3'-terminus has a tRNA-like structure (and accepts lysin)
Encapsidated nucleic acid are solely genomic
2 copies packed per particle (held together by
hydrogen bonds to form a dimer).
There are 11 proteins
Virions contain 60% protein
Five (major)structural virion proteins have
been found so far
Lipids: Virions contain 35% lipid.
Carbohydrates: Other compounds detected in the
particles 3% carbohydrates.

Symptoms and host range: The virus hosts

are found in the orders Primates, Perissodactyla, 2.8 Practical applications
Carnivora, and Artiodactyla (all within domain
Eukarya, kingdom Animalia, phylum Chordata, Lentivirus is primarily a research tool used to introsubphylum Vertebrata, class Mammalia, infraclass duce a gene product into in vitro systems or animal
Placentalia, and magnorder Boreoeutheria.)
models. Large-scale collaborative eorts are underway
to use lentiviruses to block the expression of a spe Transmission: Transmitted by means not involving cic gene using RNA interference technology in higha vector.
throughput formats.[7] The expression of short-hairpin
RNA (shRNA) reduces the expression of a specic gene,
Geographic distribution: Worldwide.
thus allowing researchers to examine the necessity and effects of a given gene in a model system. These studies can
be a precursor to the development of novel drugs which
2.7 Physicochemical and physical aim to block a gene-product to treat diseases.

properties

Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For exam General
ple, a model of mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated
Buoyant density 1.161.18 g cm3 in sucrose in human hemophilia.[8] Lentiviral infection has advan Virions sensitive to heat, detergents, and tages over other gene-therapy methods including highformaldehyde
eciency infection of dividing and non-dividing cells,

CHAPTER 2. LENTIVIRUS

[6] Gilbert, James R., and Flossie Wong-Staal. HIV-2 and

SIV Vector Systems. Lentiviral Vector Systems for Gene
Transfer. Ed. Gary L. Buchschacher. Georgetown, TX:
Eurekah.com, 2003. https://books.google.com/books?
id=59FuGsgsI5wC&printsec=frontcover&source=gbs_
ge_summary_r&cad=0#v=onepage&q&f=false
[7] shRNA short hairpin RNA
[8] Shi Q, Wilcox DA, Fahs SA, et al. (February 2007).
Lentivirus-mediated platelet-derived factor VIII gene
therapy in murine haemophilia A. J. Thromb. Haemost.
5 (2): 35261. doi:10.1111/j.1538-7836.2007.02346.x.
PMID 17269937.
[9] Lee JA, Conejero JA, Mason JM, et al. (August 2005).
Lentiviral transfection with the PDGF-B gene improves
diabetic wound healing. Plast. Reconstr. Surg. 116
(2): 5328. doi:10.1097/01.prs.0000172892.78964.49.
PMID 16079687.
CDS

Lentiviral Delivery of designed shRNAs and the mechanism of

RNA interference in mammalian cells.

long-term stable expression of a transgene, and low immunogenicity. Lentiviruses have also been successfully
used for transfection of diabetic mice with the gene encoding PDGF (platelet-derived growth factor),[9] a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show
promise but are yet to be established as safe and eective in controlled human studies. Gammaretroviral and
lentiviral vectors have so far been used in more than 300
clinical trials, addressing treatment options for various
diseases.[10]

[10] Kurth, R; Bannert, N, ed. (2010). Retroviruses: Molecular

Biology, Genomics and Pathogenesis. Caister Academic
Press. ISBN 978-1-904455-55-4.

2.10 References
Ryan KJ, Ray CG, ed. (2004). Sherris Medical Microbiology: An Introduction to Infectious Diseases
(4th ed.). New York: McGraw Hill. ISBN 0-83858529-9.
Desport, M, ed.
(2010).
Lentiviruses and
Macrophages: Molecular and Cellular Interactions.
Caister Academic Press. ISBN 978-1-904455-608.

2.11 Further reading

ICTV taxonomy of Lentivirus

2.9 Notes
[1] What is Lentivirus?". News-Medical.net. https://
plus.google.com/109000124032577298634/. Retrieved
2015-11-30.
[2] Cockrell, Adam S.; Kafri, Tal (2007-07-01). Gene delivery by lentivirus vectors. Molecular Biotechnology 36
(3): 184204. ISSN 1073-6085. PMID 17873406.
[3] Mahy, Brian W. J. (2009-02-26). The Dictionary of Virology. Academic Press. ISBN 9780080920368.
[4] Piguet, V.; Schwartz, O.; Le Gall, S.; Trono, D. (1999-0401). The downregulation of CD4 and MHC-I by primate
lentiviruses: a paradigm for the modulation of cell surface
receptors. Immunological Reviews 168: 5163. ISSN
0105-2896. PMID 10399064.
[5] ViralZone: Lentivirus. viralzone.expasy.org. Retrieved
2015-11-30.

Lentiviruses In Ungulates. I. General Features,

History And Prevalence (PDF). Bulgarian Journal
of Veterinary Medicine 9 (3): 175181. 2006.
Tim Ravenscroft (2008-06-15). Are Lentiviral
Vectors on Cusp of Breakout?". Genetic Engineering & Biotechnology News (Mary Ann Liebert,
Inc.). pp. 5455. Retrieved 2008-07-06. (subtitle)
Rapidly emerging technology has potential to treat
hemophilia, AIDS, and Cancer

2.12 External links

Viralzone: Lentivirus

Chapter 3

Simian immunodeciency virus

3.1 History
Immunodeciency resembling human AIDS was reported in captive monkeys in the United States beginning
in 1983.[6][7][8] SIV was isolated in 1985 from some of
these animals, captive rhesus macaques suering from
simian AIDS (SAIDS).[7] The discovery of SIV was made
shortly after HIV-1 had been isolated as the cause of
AIDS and led to the discovery of HIV-2 strains in West
Africa. HIV-2 was more similar to the then-known SIV
strains than to HIV-1, suggesting for the rst time the
simian origin of HIV. Further studies indicated that HIV2 is derived from the SIVsmm strain found in sooty
mangabeys, whereas HIV-1, the predominant virus found
in humans, is derived from SIV strains infecting chimpanzees (SIVcpz).

Diagrammatical representation of the molecular structure of

HIV-1 protease complexed with the inhibitor indinavir.

Simian immunodeciency viruses (SIVs) are

retroviruses able to infect at least 45 species of African
non-human primates.[1][2] Based on analysis of strains
found in four species of monkeys from Bioko Island,
which was isolated from the mainland by rising sea levels
about 11,000 years ago, it has been concluded that SIV
has been present in monkeys and apes for at least 32,000
years, and probably much longer.[3][4]

3.2 Tropism

Dierences in species specicity of SIV and related retroviruses may be partly explained by variants of the protein TRIM5 in humans and non-human primate species.
This intracellular protein recognizes the capsid of various
retroviruses and blocks their reproduction. Other proVirus strains from two of these primate species, SIVsmm teins such as APOBEC3G/3F may also be important in
in sooty mangabeys and SIVcpz in chimpanzees, are be- restricting cross-species transmission.
lieved to have crossed the species barrier into humans,
resulting in HIV-2 and HIV-1, respectively. The most
likely route of transmission of HIV-1 to humans involves
contact with the blood of chimps that are often hunted 3.3 Research
for bushmeat in Africa.[3]
Unlike HIV-1 and HIV-2 infections in humans, SIV in- SHIV, a virus combining parts of the HIV and SIV
fections in their natural hosts appear in many cases to be genomes, was created for various research purposes, inrespond
non-pathogenic. Extensive studies in sooty mangabeys cluding analyzing how dierent parts of the virus
[9]
to
dierent
antimicrobial
drugs
and
vaccines.
have established that SIVsmm infection does not cause
any disease in these animals, despite high levels of circulating virus. However, if this virus infects an Asian or
Indian rhesus macaque, the animal will develop simian
AIDS (SAIDS).[5] A recent study of SIVcpz in wild living
chimpanzees suggests that infected chimpanzees experience an AIDS-like illness similar to HIV-1 infected humans. The later stages of SIV infection turn into SAIDS,
much as HIV infection turns into AIDS.

Beatrice Hahn of the University of Pennsylvania recently

led a team of researchers to nd that chimpanzees do die
from simian AIDS in the wild and that the AIDS outbreak
in Africa has contributed to the decline of chimpanzee
populations. Testing wild chimpanzees, researchers detected organ and tissue damage similar to late-stage human AIDS. The infected chimpanzees had a 10 to 16
times greater risk of dying than uninfected ones; infected
9

10
females were less likely to give birth, could pass the virus
to their infants, and had a higher infant mortality rate than
uninfected females.[10][11]
The ICTVdB code of SIV is 61.0.6.5.003.[12]
In 2010, researchers reported that SIV had infected
monkeys in Bioko for at least 32,000 years. Based on
molecular clock analyses of sequences, it was previously
thought by many that SIV infection in monkeys had happened over the past few hundred years.[13] Scientists estimated that it would take a similar amount of time before
humans would adapt naturally to HIV infection in the way
monkeys in Africa have adapted to SIV and not suer any
harm from the infection.[14]
In 2012, researchers reported that initial infection
of Rhesus monkeys by neutralization-resistant SIV
strains[15] could be partially prevented through use of an
anti-SIVSME vaccine obligately including Env protein
antigens.[16]
In 2013, a study by a group of authors reported on
successful testing of a vaccine containing SIV proteinexpressing rhesus cytomegalovirus vector. Approximately 50% of vaccinated rhesus macaques manifested
durable, aviraemic control of infection with the highly
pathogenic strain SIVmac239.[17]
Bonobos appear to avoid simian immunodeciency virus
(SIV) and its eects, though it is not known why.[18]

3.4 See also

Origin of AIDS
OPV AIDS hypothesis
eu-FEDS
List of monkey viruses (and human transmissions)
SV40

3.5 References
[1] Peeters, M.; Courgnaud, V.; Abela, B. (2001). Genetic
Diversity of Lentiviruses in Non-Human Primates
(PDF). AIDS Reviews 3: 310. Retrieved 2010-09-19.
[2] Peeters, M.; Courgnaud, V. (2002). Overview of Primate Lentiviruses and their Evolution in Non-human Primates in Africa (PDF). In C. Kuiken, B. Foley, E. Freed,
B. Hahn, B. Korber, P. A. Marx, F. E. McCutchan, J. W.
Mellors, and S. Wolinsky. HIV sequence compendium.
Los Alamos, NM: Theoretical Biology and Biophysics
Group, Los Alamos National Laboratory. pp. 223. Retrieved 2010-09-19 Missing or empty |title= (help)
[3] Donald G. McNeil, Jr. (September 16, 2010). Precursor
to H.I.V. Was in Monkeys for Millennia. New York
Times. Retrieved 2010-09-17. In a discovery that sheds

CHAPTER 3. SIMIAN IMMUNODEFICIENCY VIRUS

new light on the history of AIDS, scientists have found evidence that the ancestor to the virus that causes the disease
has been in monkeys and apes for at least 32,000 years
not just a few hundred years, as had been previously
thought. ... That means humans have presumably been
exposed many times to S.I.V., the simian immunodeciency virus, because people have been hunting monkeys
for millenniums, risking infection every time they butcher
one for food.
[4] Worobey, Michael; Telfer, Paul; Souquire, Sandrine; Hunter, Meredith; Coleman, Clint A.;
Metzger, Michael J.; Reed, Patricia; Makuwa,
Maria; Hearn, Gail (2010).
Island Biogeography Reveals the Deep History of SIV.
Science
Bibcode:2010Sci...329.1487W.
329 (5998): 1487.
doi:10.1126/science.1193550. PMID 20847261..
[5] Kestler, H.; Kodama, T.; Ringler, D.; Marthas, M.; Pedersen, N.; Lackner, A.; Regier, D.; Sehgal, P.; Daniel,
M.; King, N.; Et, A. (1990). Induction of AIDS in
rhesus monkeys by molecularly cloned simian immunodeciency virus. Science 248 (4959): 11091112.
doi:10.1126/science.2160735. PMID 2160735.
[6] Letvin, N.; Eaton, K.; Aldrich, W.; Sehgal, P.;
Blake, B.; Schlossman, S.; King, N.; Hunt, R. (1983).
Acquired immunodeciency syndrome in a colony
of macaque monkeys. Proceedings of the National
Academy of Sciences of the United States of America
80 (9): 27182722. Bibcode:1983PNAS...80.2718L.
doi:10.1073/pnas.80.9.2718. PMC 393899. PMID
6221343.
[7] Daniel, M. D.; Letvin, N. L.; King, N. W.; Kannagi,
M.; Sehgal, P. K.; Hunt, R. D.; Kanki, P. J.; Essex, M.; Desrosiers, R. C. (1985). Isolation of T-cell
tropic HTLV-III-like retrovirus from macaques. Science
228 (4704): 12011204. Bibcode:1985Sci...228.1201D.
doi:10.1126/science.3159089. PMID 3159089.
[8] King, N. W.; Hunt, R. D.; Letvin, N. L. (1983).
Histopathologic changes in macaques with an acquired
immunodeciency syndrome (AIDS)". The American
journal of pathology 113 (3): 382388. PMC 1916356.
PMID 6316791.
[9] e., L.; Srinivasan, P.; m., J. (2012). Simian-Human
Immunodeciency Viruses and Their Impact on NonHuman Primate Models for AIDS. Immunodeciency.
doi:10.5772/53556. ISBN 978-953-51-0791-0.
[10] Chimpanzees Do Die From Simian AIDS, Study Finds by
Lawrence K. Altman Chimpanzees Do Die from Simian
AIDS, Study Finds
[11] Jonathan L. Heeney; Angus G. Dalgleish; Robin A.
Weiss (July 2006). Origins of HIV and the evolution of resistance to AIDS (PDF). Science 313
Bibcode:2006Sci...313..462H.
(5786):
462466.
doi:10.1126/science.1123016. PMID 16873637.
[12] ICTV database entry: 61.0.6.5.003
[13] McNeil Jr, Donald (17 September 2010). Precursor to
H.I.V. Was in Monkeys for Millenniums. The New York
Times. Retrieved 17 September 2010.

3.6. EXTERNAL LINKS

[14] HIV precursor in monkeys ancient: study. CBC News.

17 September 2010. Retrieved 17 September 2010.
[15] Neutralization-resistant refers to strains which are not
able to be neutralized by the native immune response due
to compensating mutation; see HIV-1 related information.
[16] Barouch, Dan H.; et al.
(25 additional authors)
(4 Jan 2012), Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys, Nature, advance online
publication,
Bibcode:2012Natur.482...89B,
doi:10.1038/nature10766, retrieved 6 Jan 2012.
Lay summary available from Bloomberg at "J&J AIDS
Vaccine Protects Monkeys in Study as Testing in Humans
Begins", published 4 Jan 2012.
[17] Hansen, Scott G.; et al. (2013). Immune clearance of
highly pathogenic SIV infection. Nature 502 (7469):
100104. doi:10.1038/nature12519.
[18] Paul M. Sharp; George M. Shaw; Beatrice H. Hahn (April
2005). Simian Immunodeciency Virus Infection of
Chimpanzees. Journal of Virology 79. p. 3891-3902.

3.6 External links

Description of SIV, including links to subspecies
and sequence data, from the International Committee on Taxonomy of Viruses
NIH Taxonomy Browser entry for SIV, access to sequence data and published articles
Peeters et al.: Risk to Human Health from a
Plethora of Simian Immunodeciency Viruses in
Primate Bushmeat, Emerging Infectious Diseases,
Vol 8, No 5, May 2002. Contains a picture of the
relationship among the various SIV/HIV strains.
HIV origin 'found in wild chimps" BBC News article

11

Chapter 4

HIV
This article is about the virus. For the disease caused Many species are infected by lentiviruses, which are charby the virus, see HIV/AIDS. For other uses, see HIV acteristically responsible for long-duration illnesses with
(disambiguation).
a long incubation period.[10] Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA
viruses. Upon entry into the target cell, the viral RNA
AIDS virus redirects here. For the computer virus, see
genome is converted (reverse transcribed) into doubleAIDS (computer virus).
stranded DNA by a virally encoded reverse transcriptase
that is transported along with the viral genome in the virus
The human immunodeciency virus (HIV) is a particle. The resulting viral DNA is then imported into
lentivirus (a subgroup of retrovirus) that causes HIV the cell nucleus and integrated into the cellular DNA by a
infection and acquired immunodeciency syndrome virally encoded integrase and host co-factors.[11] Once in(AIDS).[1][2] AIDS is a condition in humans in which tegrated, the virus may become latent, allowing the virus
progressive failure of the immune system allows life- and its host cell to avoid detection by the immune systhreatening opportunistic infections and cancers to thrive. tem. Alternatively, the virus may be transcribed, producWithout treatment, average survival time after infection ing new RNA genomes and viral proteins that are packwith HIV is estimated to be 9 to 11 years, depending aged and released from the cell as new virus particles that
on the HIV subtype.[3] Infection with HIV occurs by the begin the replication cycle anew.
transfer of blood, semen, vaginal uid, pre-ejaculate, or
breast milk. Within these bodily uids, HIV is present as Two types of HIV have been characterized: HIV-1 and
both free virus particles and virus within infected immune HIV-2. HIV-1 is the virus that was initially discovered
and termed both LAV and HTLV-III. It is more virulent,
cells.
more infective,[12] and is the cause of the majority of HIV
HIV infects vital cells in the human immune system infections globally. The lower infectivity of HIV-2 comsuch as helper T cells (specically CD4+ T cells), pared to HIV-1 implies that fewer of those exposed to
macrophages, and dendritic cells.[4] HIV infection leads HIV-2 will be infected per exposure. Because of its relto low levels of CD4+ T cells through a number of atively poor capacity for transmission, HIV-2 is largely
mechanisms, including pyroptosis of abortively infected conned to West Africa.[13]
T cells,[5] apoptosis of uninfected bystander cells,[6] direct viral killing of infected cells, and killing of infected
CD4+ T cells by CD8 cytotoxic lymphocytes that recog- 4.1.2 Structure and genome
nize infected cells.[7] When CD4+ T cell numbers decline
below a critical level, cell-mediated immunity is lost, and Main article: Structure and genome of HIV
the body becomes progressively more susceptible to op- HIV is dierent in structure from other retroviruses. It
is roughly spherical[14] with a diameter of about 120 nm,
portunistic infections.
around 60 times smaller than a red blood cell, yet large
for a virus.[15] It is composed of two copies of positive
single-stranded RNA that codes for the viruss nine genes
4.1 Virology
enclosed by a conical capsid composed of 2,000 copies
of the viral protein p24.[16] The single-stranded RNA is
4.1.1 Classication
tightly bound to nucleocapsid proteins, p7, and enzymes
needed for the development of the virion such as reverse
See also: Subtypes of HIV
transcriptase, proteases, ribonuclease and integrase. A
matrix composed of the viral protein p17 surrounds the
[16]
[8]
HIV is a member of the genus Lentivirus,
part capsid ensuring the integrity of the virion particle.
of the family Retroviridae.[9] Lentiviruses have many This is, in turn, surrounded by the viral envelope, that
morphologies and biological properties in common. is composed of the lipid bilayer taken from the mem12

4.1. VIROLOGY

13
The RNA genome consists of at least seven structural
landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS),
and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr,
vpu, and sometimes a tenth tev, which is a fusion of tat
env and rev), encoding 19 proteins. Three of these genes,
gag, pol, and env, contain information needed to make the
structural proteins for new virus particles.[16] For example, env codes for a protein called gp160 that is broken
down by a cellular protease to form gp120 and gp41. The
six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx
in the case of HIV-2), are regulatory genes for proteins
that control the ability of HIV to infect cells, produce new
copies of virus (replicate), or cause disease.[16]

Diagram of HIV virion

The two Tat proteins (p16 and p14) are transcriptional

transactivators for the LTR promoter acting by binding
the TAR RNA element. The TAR may also be processed into microRNAs that regulate the apoptosis genes
ERCC1 and IER3.[20][21] The Rev protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the RRE RNA element. The Vif
protein (p23) prevents the action of APOBEC3G (a cellular protein that deaminates Cytidine to Uridine in the
single stranded viral DNA and/or interferes with reverse
transcription[22] ). The Vpr protein (p14) arrests cell division at G2/M. The Nef protein (p27) down-regulates
CD4 (the major viral receptor), as well as the MHC class
I and class II molecules.[23][24][25]

Nef also interacts with SH3 domains. The Vpu protein

(p16) inuences the release of new virus particles from
infected cells.[16] The ends of each strand of HIV RNA
contain an RNA sequence called the long terminal repeat
(LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins
from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by Gag
HIV
and Rev proteins. The SLIP element (TTTTTT) is involved in the frameshift in the Gag-Pol reading frame re[16]
brane of a human cell when the newly formed virus par- quired to make functional Pol.
ticle buds from the cell. The viral envelope contains proteins from the host cell and relatively few copies of the
HIV Envelope protein,[16] which consists of a cap made 4.1.3 Tropism
of three molecules known as glycoprotein (gp) 120, and
a stem consisting of three gp41 molecules which anchor Main article: HIV tropism
the structure into the viral envelope.[17][18] The Envelope The term viral tropism refers to the cell types a virus inprotein, encoded by the HIV env gene, allows the virus to fects. HIV can infect a variety of immune cells such as
attach to target cells and fuse the viral envelope with the CD4+ T cells, macrophages, and microglial cells. HIVtarget cell membrane releasing the viral contents into the 1 entry to macrophages and CD4+ T cells is mediated
cell and initiating the infectious cycle.[17] As the sole viral through interaction of the virion envelope glycoproteins
protein on the surface of the virus, the Envelope protein (gp120) with the CD4 molecule on the target cells and
also with chemokine coreceptors.[17][26]
is a major target for HIV vaccine eorts.[19]

Structure of the RNA genome of HIV-1

Macrophage (M-tropic) strains of HIV-1, or nonsyncytia-inducing strains (NSI; now called R5 viruses[27]
) use the -chemokine receptor CCR5 for entry and
are, thus, able to replicate in macrophages and CD4+ T
cells.[28] This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.
Indeed, macrophages play a key role in several critical

14

CHAPTER 4. HIV
HIV from binding to this coreceptor, reducing its ability
to infect target cells.

Diagram of the immature and mature forms of HIV

aspects of HIV infection. They appear to be the rst

cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient.
Macrophages and microglial cells are the cells infected by
HIV in the central nervous system. In tonsils and adenoids
of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus.
T-tropic isolates, or syncytia-inducing (SI; now called X4
viruses[27] ) strains replicate in primary CD4+ T cells
as well as in macrophages and use the -chemokine receptor, CXCR4, for entry.[28][29][30] Dual-tropic HIV-1
strains are thought to be transitional strains of HIV-1
and thus are able to use both CCR5 and CXCR4 as coreceptors for viral entry.
The -chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this
by down-regulating the expression of CXCR4 on the surface of these cells. HIV that use only the CCR5 receptor
are termed R5; those that use only CXCR4 are termed
X4, and those that use both, X4R5. However, the use
of coreceptor alone does not explain viral tropism, as not
all R5 viruses are able to use CCR5 on macrophages for a
productive infection[28] and HIV can also infect a subtype
of myeloid dendritic cells,[31] which probably constitute a
reservoir that maintains infection when CD4+ T cell numbers have declined to extremely low levels.

Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal
uid, which is passed from a male to his sexual partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However,
a selection process leads to a predominant transmission of
the R5 virus through this pathway.[33][34][35] How this selective process works is still under investigation, but one
model is that spermatozoa may selectively carry R5 HIV
as they possess both CCR3 and CCR5 but not CXCR4
on their surface[36] and that genital epithelial cells preferentially sequester X4 virus.[37] In patients infected with
subtype B HIV-1, there is often a co-receptor switch in
late-stage disease and T-tropic variants appear that can
infect a variety of T cells through CXCR4.[38] These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system
collapse, and opportunistic infections that mark the advent of AIDS.[39] Thus, during the course of infection,
viral adaptation to the use of CXCR4 instead of CCR5
may be a key step in the progression to AIDS. A number
of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients
can harbour viruses of the SI and, it is presumed, the X4
phenotypes.[40][41]
HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution. The adoption
of accessory genes by HIV-2 and its more promiscuous pattern of coreceptor usage (including CD4independence) may assist the virus in its adaptation
to avoid innate restriction factors present in host cells.
Adaptation to use normal cellular machinery to enable
transmission and productive infection has also aided the
establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host
but ultimately become a commensal organism. Having
achieved a low pathogenicity, over time, variants more
successful at transmission will be selected.[42]

4.1.4 Replication cycle

Entry to the cell
The HIV virion enters macrophages and CD4+ T cells by
the adsorption of glycoproteins on its surface to receptors
on the target cell followed by fusion of the viral envelope
with the cell membrane and the release of the HIV capsid
into the cell.[43][44]

Entry to the cell begins through interaction of the trimeric

envelope complex (gp160 spike) and both CD4 and a
chemokine receptor (generally either CCR5 or CXCR4,
Some people are resistant to certain strains of HIV.[32] but others are known to interact) on the cell surface.[43][44]
For example, people with the CCR5-32 mutation are gp120 binds to integrin 4 7 activating LFA-1 the cenresistant to infection with R5 virus, as the mutation stops tral integrin involved in the establishment of virological

4.1. VIROLOGY

15
to play an important role by transmitting HIV to T-cells
when the virus is captured in the mucosa by DCs.[46] The
presence of FEZ-1, which occurs naturally in neurons, is
believed to prevent the infection of cells by HIV.[47]

The HIV replication cycle

1.

HIV

2.

3.
gp41

gp120

CD4

CD4
gp120

CCR5

HIV
gp41

CD4

Cellular membrane

CD4+ T-Cell

CD4+ T-Cell

HIV

4.

HIV

gp41

gp41

gp120
CCR 5

CD4+ T-Cell

CCR5

CD4+ T-Cell

Mechanism of viral entry

1. Initial interaction between gp120 and CD4. 2. Conformational change in gp120 allows for secondary interaction with
CCR5. 3. The distal tips of gp41 are inserted in to the cellular membrane. 4. gp41 undergoes signicant conformational
change; folding in half and forming coiled-coils. This process
pulls the viral and cellular membranes together, fusing them.

Clathrin-dependent endocytosis

HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at
the plasma membrane. More recently, however, productive infection by pH-independent, clathrin-dependent
endocytosis of HIV-1 has also been reported and was recently suggested to constitute the only route of productive
entry.[48][49][50][51][52]

synapses, which facilitate ecient cell-to-cell spreading

of HIV-1.[45] The gp160 spike contains binding domains
Replication and transcription
for both CD4 and chemokine receptors.[43][44]
The rst step in fusion involves the high-anity attachment of the CD4 binding domains of gp120 to CD4.
Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the
chemokine binding domains of gp120 and allowing them
to interact with the target chemokine receptor.[43][44]
This allows for a more stable two-pronged attachment,
which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.[43][44] Repeat sequences in gp41,
HR1, and HR2 then interact, causing the collapse of the
extracellular portion of gp41 into a hairpin. This loop
structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent
entry of the viral capsid.[43][44]

Shortly after the viral capsid enters the cell, an

enzyme called reverse transcriptase liberates the singlestranded (+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA)
molecule.[53] The process of reverse transcription is extremely error-prone, and the resulting mutations may
cause drug resistance or allow the virus to evade the
bodys immune system. The reverse transcriptase also has
ribonuclease activity that degrades the viral RNA during
the synthesis of cDNA, as well as DNA-dependent DNA
polymerase activity that creates a sense DNA from the
antisense cDNA.[54] Together, the cDNA and its complement form a double-stranded viral DNA that is then
transported into the cell nucleus. The integration of the
viral
DNA into the host cells genome is carried out by
After HIV has bound to the target cell, the HIV RNA
another
viral enzyme called integrase.[53]
and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the This integrated viral DNA may then lie dormant, in the
cell.[43] During the microtubule-based transport to the nu- latent stage of HIV infection.[53] To actively produce
cleus, the viral single-strand RNA genome is transcribed the virus, certain cellular transcription factors need to
into double-strand DNA, which is then integrated into a be present, the most important of which is NF-B (NF
kappa B), which is upregulated when T-cells become
host chromosome.
[55]
This means that those cells most likely to
HIV can infect dendritic cells (DCs) by this CD4-CCR5 activated.
be
killed
by
HIV
are those currently ghting infection.
route, but another route using mannose-specic C-type
lectin receptors such as DC-SIGN can also be used.[46] During viral replication, the integrated DNA provirus
DCs are one of the rst cells encountered by the virus is transcribed into mRNA, which is then spliced into
during sexual transmission. They are currently thought smaller pieces. These small pieces are exported from the

16

CHAPTER 4. HIV
arate progenitor parental viruses of diering genetic constitution. It is unknown how often such mixed packaging
occurs under natural conditions.[62]

Bonhoeer et al.[63] suggested that template switching

by the reverse transcriptase acts as a repair process to
deal with breaks in the ssRNA genome. In addition, Hu
and Temin[59] suggested that recombination is an adaptation for repair of damage in the RNA genomes. Strand
switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic
DNA from two damaged ssRNA genome copies. This
view of the adaptive benet of recombination in HIV
could explain why each HIV particle contains two complete genomes, rather than one. Furthermore, the view
that recombination is a repair process implies that the
benet of repair can occur at each replication cycle, and
Reverse transcription of the HIV genome into double strand DNA
that this benet can be realized whether or not the two
genomes dier genetically. On the view that that recomnucleus into the cytoplasm, where they are translated into bination in HIV is a repair process, the generation of rebut not
the regulatory proteins Tat (which encourages new virus combinational variation would be a consequence, [63]
the
cause
of,
the
evolution
of
template
switching.
production) and Rev. As the newly produced Rev protein
accumulates in the nucleus, it binds to viral mRNAs and HIV-1 infection causes chronic ongoing inammation
allows unspliced RNAs to leave the nucleus, where they and production of reactive oxygen species.[64] Thus, the
are otherwise retained until spliced.[56] At this stage, the HIV genome may be vulnerable to oxidative damages, instructural proteins Gag and Env are produced from the cluding breaks in the single-stranded RNA. For HIV, as
full-length mRNA. The full-length RNA is actually the well as for viruses generally, successful infection depends
virus genome; it binds to the Gag protein and is packaged on overcoming host defensive strategies that often include
into new virus particles.[57]
production of genome-damaging reactive oxygen. Thus,
[65]
HIV-1 and HIV-2 appear to package their RNA dier- Michod et al. suggested that recombination by viruses
ently. HIV-1 will bind to any appropriate RNA. HIV-2 is an adaptation for repair of genome damages, and that
will preferentially bind to the mRNA that was used to recombinational variation is a byproduct that may provide
a separate benet.
create the Gag protein itself.[58]

Recombination

Assembly and release

Two RNA genomes are encapsidated in each HIV-1 particle (see Structure and genome of HIV). Upon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur.[59][60]
Recombination occurs as the single-strand (+)RNA
genomes are reverse transcribed to form DNA. During
reverse transcription the nascent DNA can switch multiple times between the two copies of the viral RNA. This
form of recombination is known as copy-choice. Recombination events may occur throughout the genome. From
2 to 20 events per genome may occur at each replication cycle, and these events can rapidly shue the genetic
information that is transmitted from parental to progeny
genomes.[60]
Viral recombination produces genetic variation that likely
contributes to the evolution of resistance to anti-retroviral
therapy.[61] Recombination may also contribute, in principle, to overcoming the immune defenses of the host.
Yet, for the adaptive advantages of genetic variation to HIV assembling on the surface of an infected macrophage.
be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from sep- The nal step of the viral cycle, assembly of new HIV-

4.1. VIROLOGY

17

1 virions, begins at the plasma membrane of the host

cell. The Env polyprotein (gp160) goes through the
endoplasmic reticulum and is transported to the Golgi
complex where it is cleaved by furin resulting in the two
HIV envelope glycoproteins, gp41 and gp120.[66] These
are transported to the plasma membrane of the host cell
where gp41 anchors gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma
membrane along with the HIV genomic RNA as the
forming virion begins to bud from the host cell. The
budded virion is still immature as the gag polyproteins
still need to be cleaved into the actual matrix, capsid
and nucleocapsid proteins. This cleavage is mediated by
the also packaged viral protease and can be inhibited by
antiretroviral drugs of the protease inhibitor class. The
various structural components then assemble to produce
a mature HIV virion.[67] Only mature virions are then able The phylogenetic tree of the SIV and HIV
to infect another cell.
genetic variability. This diversity is a result of its fast
replication cycle, with the generation of about 1010 virions every day, coupled with a high mutation rate of
HIV is now known to spread between CD4+ T cells
approximately 3 x 105 per nucleotide base per cycle
by two parallel routes: cell-free spread and cell-to-cell
of replication and recombinogenic properties of reverse
spread, i.e. it employs hybrid spreading mechanisms.[68]
transcriptase.[74][75][76]
In the cell-free spread, virus particles bud from an infected T cell, enter the blood/extracellular uid and then This complex scenario leads to the generation of many
infect another T cell following a chance encounter.[68] variants of HIV in a single infected patient in the course
HIV can also disseminate by direct transmission from one of one day.[74] This variability is compounded when a sincell to another by a process of cell-to-cell spread. Two gle cell is simultaneously infected by two or more dierpathways of cell-to-cell transmission have been reported. ent strains of HIV. When simultaneous infection occurs,
Firstly, an infected T cell can transmit virus directly the genome of progeny virions may be composed of RNA
to a target T cell via a virological synapse.[45][69] Sec- strands from two dierent strains. This hybrid virion then
ondly, an antigen presenting cell (APC) can also trans- infects a new cell where it undergoes replication. As this
mit HIV to T cells by a process that either involves pro- happens, the reverse transcriptase, by jumping back and
ductive infection (in the case of macrophages) or capture forth between the two dierent RNA templates, will genand transfer of virions in trans (in the case of dendritic erate a newly synthesized retroviral DNA sequence that
cells).[70] Whichever pathway is used, infection by cell- is a recombinant between the two parental genomes.[74]
to-cell transfer is reported to be much more ecient than This recombination is most obvious when it occurs becell-free virus spread.[71] A number of factors contribute tween subtypes.[74]
to this increased eciency, including polarised virus bud- The closely related simian immunodeciency virus (SIV)
ding towards the site of cell-to-cell contact, close ap- has evolved into many strains, classied by the natural
position of cells which minimizes uid-phase diusion host species. SIV strains of the African green monkey
of virions, and clustering of HIV entry receptors on the (SIVagm) and sooty mangabey (SIVsmm) are thought to
target cell to the contact zone.[69] Cell-to-cell spread is have a long evolutionary history with their hosts. These
thought to be particularly important in lymphoid tissues hosts have adapted to the presence of the virus,[77] which
where CD4+ T lymphocytes are densely packed and likely is present at high levels in the hosts blood but evokes only
to frequently interact.[68] Intravital imaging studies have a mild immune response,[78] does not cause the developsupported the concept of the HIV virological synapse in ment of simian AIDS,[79] and does not undergo the extenvivo.[72] The hybrid spreading mechanisms of HIV con- sive mutation and recombination typical of HIV infection
tribute to the viruss ongoing replication against antiretro- in humans.[80]
viral therapies.[68][73]
In contrast, when these strains infect species that have
not adapted to SIV (heterologous hosts such as rhesus
or cynomologus macaques), the animals develop AIDS
4.1.6 Genetic variability
and the virus generates genetic diversity similar to what
Further information: Subtypes of HIV
is seen in human HIV infection.[81] Chimpanzee SIV
HIV diers from many viruses in that it has very high (SIVcpz), the closest genetic relative of HIV-1, is associ-

4.1.5

Spread within the body

CHAPTER 4. HIV
CD4+ Lymphocyte Count (cells/mm 3 )

18

Three groups of HIV-1 have been identied on the basis of dierences in the envelope (env) region: M, N,
and O.[84] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole
genome, which are geographically distinct.[85] The most
prevalent are subtypes B (found mainly in North America
and Europe), A and D (found mainly in Africa), and C
(found mainly in Africa and Asia); these subtypes form
branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms
(CRFs). In 2000, the last year in which an analysis of
global subtype prevalence was made, 47.2% of infections
worldwide were of subtype C, 26.7% were of subtype
A/CRF02_AG, 12.3% were of subtype B, 5.3% were of
subtype D, 3.2% were of CRF_AE, and the remaining
5.3% were composed of other subtypes and CRFs.[86]
Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[87] The existence of a
fourth group, P, has been hypothesised based on a virus
isolated in 2009.[88] The strain is apparently derived from
gorilla SIV (SIVgor), rst isolated from western lowland
gorillas in 2006.[88]

1200

Symptoms of
AIDS

Acute HIV syndrome

Wide dissemination of virus
Seeding of lymphoid organs

Primary
infection

10 7

Death

1100
1000

Opportunistic
diseases

Clinical latency

900

10 6

800

10 5

Constitutional
symptoms

700
600
500

10 4

400
300

10 3

200
100
0

12

10

11

10 2

HIV RNA Copies per mL plasma

ated with increased mortality and AIDS-like symptoms in

its natural host.[82] SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.[77]
This virus has also lost a function of the Nef gene that
is present in most SIVs. For non-pathogenic SIV variants, Nef suppresses T-cell activation through the CD3
marker. Nefs function in non-pathogenic forms of SIV
is to downregulate expression of inammatory cytokines,
MHC-1, and signals that aect T cell tracking. In HIVYears
Weeks
1 and SIVcpz, Nef does not inhibit T-cell activation and it
has lost this function. Without this function, T cell deple- A generalized graph of the relationship between HIV copies
tion is more likely, leading to immunodeciency.[82][83]
(viral load) and CD4 counts over the average course of untreated
HIV infection; any particular individuals disease course may
vary considerably.
CD4+ T cell count (cells per L)
HIV RNA copies per mL of plasma

HIV-1 testing is initially by an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV1. Specimens with a nonreactive result from the initial
ELISA are considered HIV-negative unless new exposure
to an infected partner or partner of unknown HIV status
has occurred. Specimens with a reactive ELISA result are
retested in duplicate.[92] If the result of either duplicate
test is reactive, the specimen is reported as repeatedly
reactive and undergoes conrmatory testing with a more
specic supplemental test (e.g., Western blot or, less commonly, an immunouorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered
HIV-positive and indicative of HIV infection. Specimens
that are repeatedly ELISA-reactive occasionally provide
an indeterminate Western blot result, which may be either an incomplete antibody response to HIV in an inor nonspecic reactions in an uninfected
HIV-2s closest relative is SIVsm, a strain of SIV found in fected person
[93]
person.
Sooty Mangabees. Since HIV-1 is derived from SIVcpz,
and HIV-2 from SIVsm, the genetic sequence of HIV-2
is only partially homologous to HIV-1 and more closely
resembles that of SIVsm.[89]

4.2 Diagnosis
Main article: HIV test
Many HIV-positive people are unaware that they are infected with the virus.[90] For example, in 2001 less than
1% of the sexually active urban population in Africa
had been tested, and this proportion is even lower in rural populations.[90] Furthermore, in 2001 only 0.5% of
pregnant women attending urban health facilities were
counselled, tested or receive their test results.[90] Again,
this proportion is even lower in rural health facilities.[90]
Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine
and medical research are routinely screened for HIV.[91]

HIV deaths in 2014.[94]

Nigeria (15.76%)
South Africa (12.51%)
India (11.50%)
Tanzania (4.169%)

4.4. HISTORY
Mozambique (4.061%)
Zimbabwe (3.49%)
Cameroon (3.09%)
Indonesia (3.04%)
Kenya (2.98%)
Uganda (2.97%)
Malawi (2.94%)
DR Congo (2.17%)
Ethiopia (2.11%)
Other (29.21%)

19
fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.
Many governments and research institutions participate
in HIV/AIDS research. This research includes behavioral health interventions, such as research into sex education, and drug development, such as research into
microbicides for sexually transmitted diseases, HIV vaccines, and antiretroviral drugs. Other medical research
areas include the topics of pre-exposure prophylaxis,
post-exposure prophylaxis, circumcision and HIV, and
accelerated aging eects.

Although IFA can be used to conrm infection in these

ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than 4.4 History
a month later and retested for persons with indeterminate Western blot results. Although much less commonly
Main article: History of HIV/AIDS
available, nucleic acid testing (e.g., viral RNA or proviral DNA amplication method) can also help diagnosis in
certain situations.[92] In addition, a few tested specimens
might provide inconclusive results because of a low quan- 4.4.1 Discovery
tity specimen. In these situations, a second specimen is
collected and tested for HIV infection.
AIDS was rst clinically observed in 1981 in the United
[98]
Modern HIV testing is extremely accurate. A single States. The initial cases were a cluster of injection drug
[95]
users and gay men with no known cause of impaired imscreening test is correct more than 99% of the time.
The chance of a false-positive result in standard two-step munity who showed symptoms of Pneumocystis carinii
testing protocol is estimated to be about 1 in 250,000 in pneumonia (PCP), a rare opportunistic infection that was
a low risk population.[95] Testing post exposure is recom- known to occur in people with very compromised im[99]
Soon thereafter, additional gay men
mended initially and at six weeks, three months, and six mune systems.
[96]
developed a previously rare skin cancer called Kaposis
months.
sarcoma (KS).[100][101] Many more cases of PCP and KS
The latest recommendations of the CDC show that HIV
emerged, alerting U.S. Centers for Disease Control and
testing must start with an immunoassay combination test
Prevention (CDC) and a CDC task force was formed to
for HIV-1 and HIV-2 antibodies and p24 antigen. A negmonitor the outbreak.[102]
ative result rules out HIV exposure, while a positive one
must be followed by an HIV-1/2 antibody dierentiation In the beginning, the CDC did not have an ocial
immunoassay to detect which is present. This gives rise name for the disease, often referring to it by way of
the diseases that were associated with it, for example,
to four possible scenarios:
lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[103][104] They also
1. HIV-1 (+) & HIV-2 (-): HIV-1 antibodies deused Kaposis Sarcoma and Opportunistic Infections, the
tected
name by which a task force had been set up in 1981.[105]
In the general press, the term GRID, which stood for
2. HIV-1 (-) & HIV-2 (+): HIV-2 antibodies degay-related immune deciency, had been coined.[106] The
tected
CDC, in search of a name, and looking at the infected
3. HIV-1 (+) & HIV-2 (+): HIV antibodies detected communities coined the 4H disease, as it seemed to
single out homosexuals, heroin users, hemophiliacs, and
[107][108]
However, after determining that AIDS
4. HIV-1 (-) or indeterminate & HIV-2 (-): Nucleic Haitians.
[105]
it was realacid test must be carried out to detect the acute in- was not isolated to the gay community,
ized that the term GRID was misleading and AIDS was
fection of HIV-1 or its absence.[97]
introduced at a meeting in July 1982.[109] By September
1982 the CDC started using the name AIDS.[110]

4.3 Research

In 1983, two separate research groups led by Robert

Gallo and Luc Montagnier independently declared that
a novel retrovirus may have been infecting AIDS paMain article: HIV/AIDS research
tients, and published their ndings in the same issue of
the journal Science.[111][112] Gallo claimed that a virus his
HIV/AIDS research includes all medical research that at- group had isolated from an AIDS patient was strikingly
tempts to prevent, treat, or cure HIV/AIDS, as well as similar in shape to other human T-lymphotropic viruses

20

CHAPTER 4. HIV

Left to right: the African green monkey source of SIV, the sooty
mangabey source of HIV-2, and the chimpanzee source of HIV-1

tively low person-to-person transmission rate, it can only

spread throughout the population in the presence of one
or more of high-risk transmission channels, which are
(HTLVs) his group had been the rst to isolate. Gallos thought to have been absent in Africa prior to the 20th
group called their newly isolated virus HTLV-III. At the century.
same time, Montagniers group isolated a virus from a Specic proposed high-risk transmission channels, allowpatient presenting with swelling of the lymph nodes of ing the virus to adapt to humans and spread throughthe neck and physical weakness, two classic symptoms of out the society, depend on the proposed timing of the
AIDS. Contradicting the report from Gallos group, Mon- animal-to-human crossing. Genetic studies of the virus
tagnier and his colleagues showed that core proteins of suggest that the most recent common ancestor of the
this virus were immunologically dierent from those of HIV-1 M group dates back to circa 1910.[122] PropoHTLV-I. Montagniers group named their isolated virus nents of this dating link the HIV epidemic with the emerlymphadenopathy-associated virus (LAV).[102] As these gence of colonialism and growth of large colonial African
two viruses turned out to be the same, in 1986, LAV and cities, leading to social changes, including a higher deHTLV-III were renamed HIV.[113]
gree of sexual promiscuity, the spread of prostitution, and
the concomitant high frequency of genital ulcer diseases
(such as syphilis) in nascent colonial cities.[123] While
4.4.2 Origins
transmission rates of HIV during vaginal intercourse are
typically low, they are increased many fold if one of the
Both HIV-1 and HIV-2 are believed to have originated partners suers from a sexually transmitted infection rein non-human primates in West-central Africa, and are sulting in genital ulcers. Early 1900s colonial cities were
believed to have transferred to humans (a process known notable due to their high prevalence of prostitution and
genital ulcers to the degree that as of 1928 as many as
as zoonosis) in the early 20th Century.[114][115]
45% of female residents of eastern Leopoldville were
HIV-1 appears to have originated in southern Cameroon
thought to have been prostitutes and as of 1933 around
through the evolution of SIV(cpz), a simian immunode15% of all residents of the same city were infected by
ciency virus (SIV) that infects wild chimpanzees (HIV-1
one of the forms of syphilis.[123]
descends from the SIV(cpz) endemic in the chimpanzee
subspecies Pan troglodytes troglodytes).[116][117] The clos- An alternative view holds that unsafe medical practices
est relative of HIV-2 is SIV (smm), a virus of the sooty in Africa during years following World War II, such as
mangabey (Cercocebus atys atys), an Old World monkey unsterile reuse of single use syringes during mass vacciliving in litoral West Africa (from southern Senegal to nation, antibiotic, and anti-malaria treatment campaigns,
western Cte d'Ivoire).[13] New World monkeys such as were the initial vector that allowed the virus to adapt to
the owl monkey are resistant to HIV-1 infection, possi- humans and spread.[121][124][125]
bly because of a genomic fusion of two viral resistance The earliest well documented case of HIV in a human
genes.[118] HIV-1 is thought to have jumped the species dates back to 1959 in the Belgian Congo.[126] The virus
barrier on at least three separate occasions, giving rise to may have been present in the United States as early as the
the three groups of the virus, M, N, and O.[119]
mid-to-late 1950s, as a sixteen-year-old male presented
Robert Gallo, co-discoverer of HIV

There is evidence that humans who participate in with symptoms in 1966 died in 1969.[127]
bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV.[120] However, SIV is a weak
virus, and it is typically suppressed by the human immune 4.5 See also
system within weeks of infection. It is thought that several transmissions of the virus from individual to individ World AIDS Day
ual in quick succession are necessary to allow it enough
HIV/AIDS denialism
time to mutate into HIV.[121] Furthermore, due to its rela-

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4.7 Further reading

Joint United Nations Programme on HIV/AIDS
(UNAIDS) (2011). Global HIV/AIDS Response,
Epidemic update and health sector progress towards
universal access (PDF). Joint United Nations Programme on HIV/AIDS.

4.8 External links

HIV/AIDS at DMOZ

Chapter 5

History of HIV/AIDS
5.1 Transmission
from
humans to humans

non-

The majority of HIV researchers agree that HIV evolved

at some point from the closely related Simian immunodeciency virus (SIV), and that SIV or HIV (post mutation)
was transferred from non-human primates to humans in
the recent past (as a type of zoonosis). Research in this
area is conducted using molecular phylogenetics, comparing viral genomic sequences to determine relatedness.
False-color scanning electron micrograph of HIV-1, in green,
budding from cultured lymphocyte

AIDS is caused by the human immunodeciency virus

(HIV), which originated in non-human primates in
Central and West Africa. While various sub-groups of
the virus acquired human infectivity at dierent times,
the global pandemic had its origins in the emergence of
one specic strain HIV-1 subgroup M in Lopoldville
in the Belgian Congo (now Kinshasa in the Democratic
Republic of the Congo) in the 1920s.[1]
Two types of HIV exist: HIV-1 and HIV-2. HIV-1
is more virulent, is more easily transmitted and is the
cause of the vast majority of HIV infections globally.[2]
The pandemic strain of HIV-1 is closely related to a
virus found in the chimpanzees of the subspecies Pan
troglodytes troglodytes, which live in the forests of the
Central African nations of Cameroon, Equatorial Guinea,
Gabon, Republic of Congo (or Congo-Brazzaville), and
Central African Republic. HIV-2 is less transmittable
and is largely conned to West Africa, along with its
closest relative, a virus of the sooty mangabey (Cercocebus atys atys), an Old World monkey inhabiting southern
Senegal, Guinea-Bissau, Guinea, Sierra Leone, Liberia,
and western Ivory Coast.[2][3]

5.1.1 HIV-1 from chimpanzees and gorillas to humans

Scientists generally accept that the known strains (or
groups) of HIV-1 are most closely related to the simian
immunodeciency viruses (SIVs) endemic in wild ape
populations of West Central African forests. Particularly, each of the known HIV-1 strains is either closely
related to the SIV that infects the chimpanzee subspecies
Pan troglodytes troglodytes (SIVcpz) or closely related
to the SIV that infects Western lowland gorillas (Gorilla gorilla gorilla), called SIVgor.[4][5][6][7][8][9] The pandemic HIV-1 strain (group M or Main) and a very rare
strain only found in a few Cameroonian people (group N)
are clearly derived from SIVcpz strains endemic in Pan
troglodytes troglodytes chimpanzee populations living in
Cameroon.[4] Another very rare HIV-1 strain (group P)
is clearly derived from SIVgor strains of Cameroon.[7] Finally, the primate ancestor of HIV-1 group O, a strain infecting 100,000 people mostly from Cameroon but also
from neighboring countries, has been recently conrmed
to be SIVgor.[6] However, phylogenetic and DNA research has found that the strain HIV-1 group O is more
closely related to SIVgor.[10] The pandemic HIV-1 group
M is most closely related to the SIVcpz collected from
the southeastern rain forests of Cameroon (modern East
Province) near the Sangha River.[4] Thus, this region is
presumably where the virus was rst transmitted from
chimpanzees to humans. However, reviews of the epidemiological evidence of early HIV-1 infection in stored
blood samples, and of old cases of AIDS in Central Africa
have led many scientists to believe that HIV-1 group M

27

28

CHAPTER 5. HISTORY OF HIV/AIDS

early human center was probably not in Cameroon, but

rather farther south in the Democratic Republic of the
Congo, more probably in its capital city, Kinshasa (formerly Lopoldville).[4][11][12][13]

sooty mangabeys living in the same country where the

human infection was found.[3][13][21]

There are six additional known HIV-2 groups, each having been found in just one person. They all seem to derive
from independent transmissions from sooty mangabeys to
humans. Groups C and D have been found in two people from Liberia, groups E and F have been discovered in
two people from Sierra Leone, and groups G and H have
been detected in two people from the Ivory Coast. These
HIV-2 strains are probably dead-end infections, and each
of them is most closely related to SIVsmm strains from

types of apes, shown to carry the SIV virus, are dierent in South America. The primary point of entry, according to researchers, is somewhere in the jungles of
Argentina or Brazil.[28] An SIV strain, closely related to
HIV, was interspersed within a certain clade of primates.
This suggests that the zoonotic transmission of the virus
may have happened in this area.[28] Continual emigration
between countries escalated the transmission of the virus.
Other scientists believe that the HIV-1C strain circulated

Molecular dating studies suggest that both the epidemic

groups (A and B) started to spread among humans beUsing HIV-1 sequences preserved in human biological tween 1905 and 1961 (with the central estimates varying
samples along with estimates of viral mutation rates, sci- between 1932 and 1945).[22] [23]
entists calculate that the jump from chimpanzee to huSee also this article about HIV types, groups, and subman probably happened during the late 19th or early 20th types.
century, a time of rapid urbanisation and colonisation in
equatorial Africa. Exactly when the zoonosis occurred
is not known. Some molecular dating studies suggest
that HIV-1 group M had its most recent common an- 5.1.3 Bushmeat practice
cestor (MRCA) (that is, started to spread in the human
population) in the early 20th century, probably between According to the natural transfer theory (also called
1915 and 1941.[14][15][16] A study published in 2008, an- 'Hunter Theory' or 'Bushmeat Theory'), the simplest
explanation for the cross-species
alyzing viral sequences recovered from a recently dis- and most plausible
[8]
transmission
of
SIV
or HIV (post mutation), the virus
covered biopsy made in Kinshasa, in 1960, along with
was
transmitted
from
an
ape or monkey to a human when
previously known sequences, suggested a common ana
hunter
or
bushmeat
vendor/handler
was bitten or cut
cestor between 1873 and 1933 (with central estimates
[17][18]
while
hunting
or
butchering
the
animal.
The resulting
varying between 1902 and 1921).
Genetic recomexposure
to
blood
or
other
bodily
uids
of
the animal
bination had earlier been thought to seriously confound
[24]
can
result
in
SIV
infection.
Prior
to
WWII,
some Subsuch phylogenetic analysis, but later work has suggested
Saharan
Africans
were
forced
out
of
the
rural
areas bethat recombination is not likely to systematically bias [recause
of
the
European
demand
for
resources.
Since
rural
sults]", although recombination is expected to increase
[17]
Africans
were
not
keen
to
pursue
agricultural
practices
variance.
The results of a 2008 phylogenetics study
support the later work and indicate that HIV evolves in the jungle, they turned to non-domesticated meat as
fairly reliably.[17][19] Further research was hindered due their primary source of protein. This over exposure to
to the primates being critically endangered. Sample anal- bushmeat and malpractice of butchery increased bloodyses resulted in little data due to the rarity of experimental to-blood contact,[25]which then increased the probability
A recent serological survey showed
material. The researchers, however, were able to hypoth- of transmission.
that
human
infections
by SIV are not rare in Central
esize a phylogeny from the gathered data. They were also
Africa:
the
percentage
of
people showing seroreactivity
able to use the molecular clock of a specic strain of HIV
to
antigens

evidence
of
current or past SIV infection
to determine the initial date of transmission, which is es[20]

was
2.3%
among
the
general
population of Cameroon,
timated to be around 1915-1931.
7.8% in villages where bushmeat is hunted or used, and
17.1% in the most exposed people of these villages.[26]
How the SIV virus would have transformed into HIV af5.1.2 HIV-2 from sooty mangabeys to hu- ter infection of the hunter or bushmeat handler from the
mans
ape/monkey is still a matter of debate, although natural
selection would favor any viruses capable of adjusting so
Similar research has been undertaken with SIV strains that they could infect and reproduce in the T cells of a
collected from several wild sooty mangabey (Cercocebus human host.
atys atys) (SIVsmm) populations of the West African na- A study published in 2009 also discussed that bushmeat
tions of Sierra Leone, Liberia, and Ivory Coast. The re- in other parts of the world, such as Argentina, may be
sulting phylogenetic analyses show that the viruses most a possible location for where the disease originated.[27]
closely related to the two strains of HIV-2 that spread HIV-1C, a subtype of HIV, was theorized to have its oriconsiderably in humans (HIV-2 groups A and B) are the gins circulating among South America.[28] The consumpSIVsmm found in the sooty mangabeys of the Tai forest, tion of bushmeat is also the most probable cause for the
in western Ivory Coast.[3]
emergence of HIV-1C in South America. However, the

5.2. EMERGENCE

29

in South America at around the same time that the HIV1C strain was introduced in Africa.[28] Very little research
has been done on this theory because it is fairly young.
However, promising evidence indicates that there may be
some validity to this hypothesis.

HIV/SIV phylogenetic relationships, and also accept that

bushmeat practice was the most likely cause of the initial transfer to humans. All of them propose that the simultaneous epidemic emergences of four HIV groups in
the late 19th-early 20th century, and the lack of previous known emergences, are explained by new factor(s)
that appeared in the relevant African regions in that timeframe. These new factor(s) would have acted either to
5.2 Emergence
increase human exposures to SIV, to help it to adapt
to the human organism by mutation (thus enhancing its
5.2.1 Unresolved questions about HIV ori- between-humans transmissibility), or to cause an initial
gins and emergence
burst of transmissions crossing an epidemiological threshold, and therefore increasing the probability of continued
The discovery of the main HIV / SIV phylogenetic rela- spread.
tionships permits explaining broadly HIV biogeography:
Genetic studies of the virus suggested in 2008 that the
the early centers of the HIV-1 groups were in Cenmost recent common ancestor of the HIV-1 M group
tral Africa, where the primate reservoirs of the related
dates back to the Belgian Congo city of Lopoldville
SIVcpz and SIVgor viruses (chimpanzees and gorillas)
(modern Kinshasa), circa 1910.[17] Proponents of this
exist; similarly, the HIV-2 groups had their centers in
dating link the HIV epidemic with the emergence of
West Africa, where sooty mangabeys, which harbor the
colonialism and growth of large colonial African cities,
related SIVsmm virus, exist. However these relationleading to social changes, including a higher degree of
ships do not explain more detailed patterns of biogeogsexual promiscuity, the spread of prostitution, and the
raphy, such as why epidemic HIV-2 groups (A and B)
concomitant high frequency of genital ulcer diseases
only evolved in the Ivory Coast, which is one of only six
(such as syphilis) in nascent colonial cities.[12]
countries harboring the sooty mangabey. It is also unclear
why the SIVcpz endemic in the chimpanzee subspecies In 2014, a study conducted by scientists from the UniPan troglodytes schweinfurthii (inhabiting the Democratic versity of Oxford and the University of Leuven, in BelRepublic of Congo, Central African Republic, Rwanda, gium, revealed that because approximately one million
Burundi, Uganda, and Tanzania) did not spawn an epi- people every year would ow through the prominent city
demic HIV-1 strain to humans, while the Democratic Re- of Kinshasa,[1] which served as the origin of the rst
public of Congo was the main center of HIV-1 group M, known HIV cases in the 1920s,[1] passengers riding on
a virus descended from SIVcpz strains of a subspecies the regions Belgian railway trains were able to spread the
(Pan troglodytes troglodytes) that does not exist in this virus to larger areas.[1] The study also attributed a roarcountry. It is clear that the several HIV-1 and HIV- ing sex trade, rapid population growth and unsterilised
2 strains descend from SIVcpz, SIVgor, and SIVsmm needles used in health clinics as other factors which conviruses,[3][6][7][8][11][21] and that bushmeat practice pro- tributed to the emergence of the Africa HIV epidemic.[1]
vides the most plausible venue for cross-species transfer
to humans.[8][11][26] However, some loose ends remain
unresolved.
Social changes and urbanization
It is not yet explained why only four HIV groups (HIV1 groups M and O, and HIV-2 groups A and B) spread
considerably in human populations, despite bushmeat
practices being very widespread in Central and West
Africa,[12] and the resulting human SIV infections being
common.[26]
It also remains unexplained why all epidemic HIV groups
emerged in humans nearly simultaneously, and only in the
20th century, despite very old human exposure to SIV
(a recent phylogenetic study demonstrated that SIV is at
least tens of thousands of years old).[29]

5.2.2

Origin and epidemic emergence

It was proposed by Beatrice Hahn, Paul Sharp, and colleagues that "[the epidemic emergence of HIV] most
likely reects changes in population structure and behaviour in Africa during the 20th century and perhaps
medical interventions that provided the opportunity for
rapid human-to-human spread of the virus.[8] After the
Scramble for Africa started in the 1880s, European colonial powers established cities, towns, and other colonial
stations. A largely masculine labor force was hastily recruited to work in uvial and sea ports, railways, other
infrastructures, and in plantations. This disrupted traditional tribal values, and favored sexual promiscuity. In
the nascent cities women felt relatively liberated from rural tribal rules[30] and many remained unmarried or divorced during long periods,[12][31] this being very rare in
African traditional societies.[32] This was accompanied
by unprecedented increase in peoples movements.

Several of the theories of HIV origin put forward (described below) attempt to explain the unresolved loose
ends described in the previous section. Most of them accept the (above described) established knowledge of the Michael Worobey and colleagues observed that the

30

CHAPTER 5. HISTORY OF HIV/AIDS

growth of cities probably played a role in the epidemic

emergence of HIV, since the phylogenetic dating of the
two older strains of HIV-1 (groups M and O), suggest that
these viruses started to spread soon after the main Central
African colonial cities were founded.[17]

Unsterile injections

against smallpox, and injections, of which many would

be made without sterilising the equipment between uses
(unsafe or unsterile injections). Chitnis et al. proposed
that both these parenteral risks and the prostitution associated with forced labor camps could have caused serial
transmission (or serial passage) of SIV between humans
(see discussion of this in the next section).[33] In addition,
they proposed that the conditions of extreme stress associated with forced labor could depress the immune system of workers, therefore prolonging the primary acute
infection period of someone newly infected by SIV, thus
increasing the odds of both adaptation of the virus to humans, and of further transmissions.[36]

Marx et al. reported experiments of cross-species transfer of SIV in captive monkeys (some of which made by
themselves), in which the use of serial passage helped to
adapt SIV to the new monkey species after passage by
three or four animals.[21]

In several articles published since 2001, Preston Marx,

Philip Alcabes, and Ernest Drucker proposed that HIV
emerged because of rapid serial human-to-human transmission of SIV (after a bushmeat hunter or handler became SIV-infected) through unsafe or unsterile
injections.[18][21][38][39] Although both Chitnis et al.[33]
and Sharp et al.[8] also suggested that this may have been
one of the major risk factors at play in HIV emergence
Colonialism in Africa
(see above), Marx et al. enunciated the underlying mechanisms in greater detail, and wrote the rst review of the
[21][38]
Amit Chitnis, Diana Rawls, and Jim Moore proposed injection campaigns made in colonial Africa.
that HIV may have emerged epidemically as a result of Central to Marx et al. argument is the concept of
the harsh conditions, forced labor, displacement, and un- adaptation by serial passage (or serial transmission): an
safe injection and vaccination practices associated with adventitious virus (or other pathogen) can increase its bicolonialism, particularly in French Equatorial Africa.[33] ological adaptation to a new host species if it is rapidly
The workers in plantations, construction projects, and transmitted between hosts, while each host is still in the
other colonial enterprises were supplied with bushmeat, acute infection period. This process favors the accumuwhich would have contributed to an increase in hunting lation of adaptive mutations more rapidly, therefore inand, it follows, a higher incidence of human exposure creasing the odds that a better adapted viral variant will
to SIV. Several historical sources support the view that appear in the host before the immune system suppresses
bushmeat hunting indeed increased, both because of the the virus.[21] Such better adapted variant could then surnecessity to supply workers and because rearms became vive in the human host for longer than the short acute inmore widely available.[33][34][35]
fection period, in high numbers (high viral load), which
The colonial authorities also gave many vaccinations would grant it more possibilities of epidemic spread.

The authors proposed that HIV-1 originated in the area of

French Equatorial Africa in the early 20th century (when
the colonial abuses and forced labor were at their peak).
Later researches proved these predictions mostly correct:
HIV-1 groups M and O started to spread in humans in late
19thearly 20th century.[14][15][16][17] And all groups of
HIV-1 descend from either SIVcpz or SIVgor from apes
living to the west of the Ubangi River, either in countries
that belonged to the French Equatorial Africa federation
of colonies, in Equatorial Guinea (then a Spanish colony),
or in Cameroon (which was a German colony between
1884 and 1916, and then fell to Allied forces in World
War I, and had most of its area administered by France,
in close association with French Equatorial Africa).

In agreement with this model is also the fact that, while

both HIV-1 and HIV-2 attain substantial viral loads in the
human organism, adventitious SIV infecting humans seldom does so: people with SIV antibodies often have very
low or even undetectable SIV viral load.[26] This suggests
that both HIV-1 and HIV-2 are adapted to humans, and
serial passage could have been the process responsible for
it.
Marx et al. proposed that unsterile injections (that is,
injections where the needle or syringe is reused without
sterilization or cleaning between uses), which were likely
very prevalent in Africa, during both the colonial period
and afterwards, provided the mechanism of serial passage that permitted HIV to adapt to humans, therefore
explaining why it emerged epidemically only in the 20th
century.[21][38]

Massive injections of the antibiotic era Marx et al.

emphasize the massive number of injections administered in Africa after antibiotics were introduced (around
1950) as being the most likely implicated in the origin
This theory was later dubbed 'Heart of Darkness by Jim of HIV because, by these times (roughly in the period
Moore,[37] alluding to the book of the same title written 1950 to 1970), injection intensity in Africa was maxiby Joseph Conrad, the main focus of which is colonial mal. They argued that a serial passage chain of 3 or 4
abuses in equatorial Africa.
transmissions between humans is an unlikely event (the

5.2. EMERGENCE
probability of transmission after a needle reuse is something between 0.3% and 2%, and only a few people have
an acute SIV infection at any time), and so HIV emergence may have required the very high frequency of injections of the antibiotic era.[21]

31

the same procedures could have exponentially amplied

HIV-1, from a single hunter/cook occupationally infected
with SIVcpz to several thousand patients treated with arsenicals or other drugs, a threshold beyond which sexual transmission could prosper.[41] They do not suggest
The molecular dating studies place the initial spread specically serial passage as the mechanism of adaptaof the epidemic HIV groups before that time (see tion.
above).[14][15][16][17][22][23] According to Marx et al., these According to Ppins 2011 book, The Origins of AIDS,[42]
studies could have overestimated the age of the HIV the virus can be traced to a central African bush hunter
groups, because they depend on a molecular clock as- in 1921, with colonial medical campaigns using imsumption, may not have accounted for the eects of properly sterilized syringe and needles playing a key
natural selection in the viruses, and the serial passage pro- role in enabling a future epidemic. Ppin concludes
cess alone would be associated with strong natural selec- that AIDS spread silently in Africa for decades, fueled
tion.[21]
by urbanization and prostitution since the initial crossspecies infection. Ppin also claims that the virus was
brought to the Americas by a Haitian teacher returning
The injection campaigns against sleeping sickness home from Zaire in the 1960s.[43] Sex tourism and conDavid Gisselquist proposed that the mass injection taminated blood transfusion centers ultimately propelled
campaigns to treat trypanosomiasis (sleeping sickness) AIDS to public consciousness in the 1980s and a worldin Central Africa were responsible for the emergence wide pandemic.[42]
of HIV-1.[40] Unlike Marx et al.,[21] Gisselquist argued
that the millions of unsafe injections administered during these campaigns were sucient to spread rare HIV Genital ulcer diseases and sexual promiscuity
infections into an epidemic, and that evolution of HIV
through serial passage was not essential to the emergence Joo Dinis de Sousa, Viktor Mller, Philippe Lemey, and
of the HIV epidemic in the 20th century.[40]
Anne-Mieke Vandamme proposed that HIV became epiThis theory focuses on injection campaigns that peaked demic through sexual serial transmission, in nascent coloof genital ulcers,
in the period 191040, that is, around the time the HIV- nial cities, helped by a high frequency [12]
caused
by
genital
ulcer
diseases
(GUD).
GUD are sim[14][15][16][17]
1 groups started to spread.
It also focuses
ply
sexually
transmitted
diseases
that
cause
genital ulon the fact that many of the injections in these camcers;
examples
are
syphilis,
chancroid,
lymphogranuloma
paigns were intravenous (which are more likely to transmit SIV/HIV than subcutaneous or intramuscular injec- venereum, and genital herpes. These diseases increase
tions), and many of the patients received many (often the probability of HIV transmission dramatically, from
more than 10) injections per year, therefore increasing around 0.010.1% to 443% per heterosexual act, because the genital ulcers provide a portal of viral entry,
the odds of SIV serial passage.[40]
and contain many activated T cells expressing the CCR5
co-receptor, the main cell targets of HIV.[12][44]
Other early injection campaigns Jacques Ppin and
Annie-Claude Labb reviewed the colonial health reports
of Cameroon and French Equatorial Africa for the pe- The probable time interval of cross-species transfer
riod 192159, calculating the incidences of the diseases Sousa et al. use molecular dating techniques to estimate
requiring intravenous injections. They concluded that the time when each HIV group split from its closest SIV
trypanosomiasis, leprosy, yaws, and syphilis were respon- lineage. Each HIV group necessarily crossed to humans
sible for most intravenous injections. Schistosomiasis, between this time and the time when it started to spread
tuberculosis, and vaccinations against smallpox repre- (the time of the MRCA), because after the MRCA cersented lower parenteral risks: schistosomiasis cases were tainly all lineages were already in humans, and before the
relatively few; tuberculosis patients only became numer- split with the closest simian strain, the lineage was in a
ous after mid century; and there were few smallpox vac- simian. HIV-1 groups M and O split from their closest
SIVs around 1931 and 1915, respectively. This informacinations in the lifetime of each person.[41]
tion, together with the datations of the HIV groups MRThe authors suggested that the very high prevalence of CAs, mean that all HIV groups likely crossed to humans
the Hepatitis C virus in southern Cameroon and forested in the early 20th century.[12]
areas of French Equatorial Africa (around 4050%) can
be better explained by the unsterile injections used to
treat yaws, because this disease was much more prevalent Strong GUD incidence in nascent colonial cities
than syphilis, trypanosomiasis, and leprosy in these arThe authors reviewed colonial medical articles and
eas. They suggested that all these parenteral risks caused, archived medical reports of the countries at or near the
not only the massive spread of Hepatitis C but also the ranges of chimpanzees, gorillas and sooty mangabeys,
spread of other pathogens, and the emergence of HIV-1: and found that genital ulcer diseases peaked in the colo-

32

CHAPTER 5. HISTORY OF HIV/AIDS

nial cities during their early growth period (up to 1935).

The colonial authorities recruited men to work in railways, uvial and sea ports, and other infrastructure
projects, and most of these men did not bring their
wives with them. Then, the highly male-biased sex ratio favoured prostitution, which in its turn caused an explosion of GUD (especially syphilis and chancroid). After the mid-1930s, peoples movements were more tightly
controlled, and mass surveys and treatments (of arsenicals
and other drugs) were organized, and so the GUD incidences started to decline. They declined even further after World War II, because of the heavy use of antibiotics,
so that, by the late 1950s, Lopoldville (which is the probable center of HIV-1 group M) had a very low GUD
incidence. Similar processes happened in the cities of
Cameroon and Ivory Coast, where HIV-1 group O and
HIV-2 respectively evolved.[12]

forming circumcision by that time gradually adopted it,

to imitate other ethnic groups and enhance the social acceptance of their boys (colonialism produced massive intermixing between African ethnic groups).[12][32] About
1530% of men in Lopoldville and Douala in the early
20th century should be uncircumcised, and these cities
were the probable centers of HIV-1 groups M and O,
respectively.[12]

Sousa et al. charts reveal that male circumcision frequencies were much lower in several cities of western and central Africa in the early 20th century than they are currently. The reason is that many ethnic groups not per-

groups emerging in the nascent, GUD-riddled, colonial

cities, and no epidemically successful HIV group emerging in mid-20th century, when GUD was more controlled,
and cities were much bigger.

The authors studied early circumcision frequencies in 12

cities of Central and West Africa, to test if this variable correlated with HIV emergence. This correlation
was strong for HIV-2: among 6 West African cities that
could have received immigrants infected with SIVsmm,
the two cities from the Ivory Coast studied (Abidjan and
Bouak) had much higher frequency of uncircumcised
men (6085%) than the others, and epidemic HIV-2
groups emerged initially in this country only. This corTherefore, the peak GUD incidences in cities[12] have relation was less clear for HIV-1 in Central Africa.[12]
a good temporal coincidence with the period when
all main HIV groups crossed to humans and started
to spread.[12][14][15][16][17][22][23] In addition, the authors
gathered evidence that syphilis and the other GUDs were, Computer simulations of HIV emergence Sousa et
like injections, absent from the densely forested areas al. then built computer simulations to test if an 'illof Central and West Africa before organized colonialism adapted SIV' (meaning a simian immunodeciency virus
socially disrupted these areas (starting in the 1880s).[12] already infecting a human but incapable of transmission
Thus, this theory also potentially explains why HIV beyond the short acute infection period) could spread in
colonial cities. The simulations used parameters of sexemerged only after the late 19th century.
ual transmission obtained from the current HIV literature. They modelled peoples 'sexual links, with dierFemale genital mutilation Uli Linke has argued that ent levels of sexual partner change among dierent catthe practice of female genital mutilation is responsible for egories of people (prostitutes, single women with several
the high incidence of AIDS in Africa, since intercourse partners a year, married women, and men), according to
with a circumcised female is conducive to exchange of data obtained from modern studies of sexual promiscuity in African cities. The simulations let the parameters
blood.[45]
(city size, proportion of people married, GUD frequency,
male circumcision frequency, and transmission parameMale circumcision distribution and HIV origins ters) vary, and explored several scenarios. Each scenario
Male circumcision may reduce the probability of HIV was run 1,000 times, to test the probability of SIV generacquisition by men (see article Circumcision and HIV). ating long chains of sexual transmission. The authors posLeaving aside blood transfusions, the highest HIV-1 tulated that such long chains of sexual transmission were
transmissibility ever measured was from GUD-suering necessary for the SIV strain to adapt better to humans, befemale prostitutes to uncircumcised menthe measured coming an HIV capable of further epidemic emergence.
risk was 43% in a single sexual act.[44] Sousa et al. rea- The main result was that genital ulcer frequency was by
soned that the adaptation and epidemic emergence of far the most decisive factor. For the GUD levels prevaileach HIV group may have required such extreme con- ing in Lopoldville in the early 20th century, long chains
ditions, and thus reviewed the existing ethnographic lit- of SIV transmission had a high probability. For the lower
erature for patterns of male circumcision and hunting of GUD levels existing in the same city in the late 1950s (see
apes and monkeys for bushmeat, focusing on the period above), they were much less likely. And without GUD (a
18801960, and on most of the 318 ethnic groups liv- situation typical of villages in forested equatorial Africa
ing in Central and West Africa.[12] They also collected before colonialism) SIV could not spread at all. City size
censuses and other literature showing the ethnic composi- was not an important factor. The authors propose that
tion of colonial cities in this period. Then, they estimated these ndings explain the temporal patterns of HIV emerthe circumcision frequencies of the Central African cities gence: no HIV emerging in tens of thousands of years of
over time.
human slaughtering of apes and monkeys, several HIV

5.4. HISTORY OF SPREAD

Male circumcision had little to moderate eect in
their simulations, but, given the geographical correlation
found, the authors propose that it could have had an indirect role, either by increasing genital ulcer disease itself
(it is known that syphilis, chancroid, and several other
GUDs have higher incidences in uncircumcised men), or
by permitting further spread of the HIV strain, after the
rst chains of sexual transmission permitted adaptation to
the human organism.

33
SIVcpz infection do experience an increased mortality,
and also suer from a Human AIDS-like illness.[48] SIV
pathogenicity in wild animals could exist in other chimpanzee subspecies and other primate species as well, and
stay unrecognized by lack of relevant long term studies.

5.4 History of spread

One of the main advantages of this theory is stressed by Main article: Timeline of early AIDS cases
the authors: It [the theory] also oers a conceptual simplicity because it proposes as causal factors for SIV adaptation to humans and initial spread the very same factors
that most promote the continued spread of HIV nowa- 5.4.1 1959: David Carr
days: promiscuous sex, particularly involving sex workers, GUD, and possibly lack of circumcision.[12]
David Carr was an apprentice printer (usually referred to,
mistakenly, as a sailor; Carr had served in the Navy between 1955 and 1957) from Manchester, England who
Iatrogenic and other theories
died August 31, 1959, and was for some time mistakenly
reported to have died from AIDS-dening opportunistic
Iatrogenic theories propose that medical interventions infections (ADOIs). Following the failure of his immune
were responsible for HIV origins. By proposing factors system, he succumbed to pneumonia. Doctors, baed by
that only appeared in Central and West Africa after the what he had died from, preserved 50 of his tissue samlate 19th century, they seek to explain why all HIV groups ples for inspection. In 1990, the tissues were found to be
also started after that.
HIV-positive. However, in 1992, a second test by AIDS
The theories centered on the role of parenteral risks, researcher David Ho found that the strain of HIV present
such as unsterile injections, transfusions,[21][33][40][41] or in the tissues was similar to those found in 1990 rather
smallpox vaccinations[33] are accepted as plausible by than an earlier strain (which would have mutated considmost scientists of the eld, and were already reviewed erably over the course of 30 years). He concluded that the
DNA samples provided actually came from a 1990 AIDS
above.
patient. Upon retesting David Carrs tissues, he found no
Discredited HIV/AIDS origins theories include several
sign of the virus.[49][50][51]
iatrogenic theories, such as Edward Hooper's 1999 claim
that early oral polio vaccines, contaminated with a chimpanzee virus, caused the Central African outbreak.[46]
5.4.2 1959: Congolese man

5.3 Pathogenicity of SIV in nonhuman primates

In most non-human primate species, natural [simian immunodeciency virus|SIV] infection does not cause a fatal disease (but see below). Comparison of the gene sequence of SIV with HIV should, therefore, give us information about the factors necessary to cause disease
in humans. The factors that determine the virulence of
HIV as compared to most SIVs are only now being elucidated. Non-human SIVs contain a nef gene that downregulates CD3, CD4, and MHC class I expression; most
non-human SIVs, therefore, do not induce immunodeciency; the HIV-1 nef gene, however, has lost its ability
to down-regulate CD3, which results in the immune activation and apoptosis that is characteristic of chronic HIV
infection.[47]

One of the earliest documented HIV-1 infections was discovered in a preserved blood sample taken in 1959 from
a man from Lopoldville in the Belgian Congo.[52] However, it is unknown whether this anonymous person ever
developed AIDS and died of its complications.[52]

5.4.3 1960: Congolese woman

A second early documented HIV-1 infection was discovered in a preserved lymph node biopsy sample taken
in 1960 from a woman from Lopoldville, Belgian
Congo.[17]

5.4.4 1969: Robert Rayford

Main article: Robert Rayford

In addition, a long-term survey of chimpanzees naturally In May 1969 16-year-old African-American Robert Rayinfected with SIVcpz in Gombe, Tanzania found that, ford died at the St. Louis City Hospital from Kaposis sarcontrary to the previous paradigm, chimpanzees with coma. In 1987 researchers at Tulane University School

34

CHAPTER 5. HISTORY OF HIV/AIDS

of Medicine detected a virus closely related or identical to[53] HIV-1 in his preserved blood and tissues. The
doctors who worked on his case at the time suspected he
was a prostitute or the victim of sexual abuse, though
the patient did not discuss his sexual history with them
in detail.[53][54][55][56][57]

5.4.5

1969: Arvid Noe

Main article: Arvid Noe

In 1975 and 1976, a Norwegian sailor, with the alias
name Arvid Noe, his wife, and his seven-year-old daughter died of AIDS. The sailor had rst presented symptoms
in 1969, eight years after he rst spent time in ports along
the West African coastline. A gonorrhea infection during
his rst African voyage shows he was sexually active at
this time. Tissue samples from the sailor and his wife
were tested in 1988 and found to contain HIV-1 (Group
O).[58][59]

Because of the long incubation period of HIV (up to a

decade or longer) before symptoms of AIDS appear, and,
because of the initially low incidence, HIV was not noticed at rst. By the time the rst reported cases of AIDS
were found in large United States cities, the prevalence of
HIV infection in some communities had passed 5%.[66]
Worldwide, HIV infection has spread from urban to rural areas, and has appeared in regions such as China and
India.

5.4.8 Canadian ight attendant theory

Main article: Gatan Dugas

From 1972 to 1973, researchers drew blood from 75 children in Uganda to serve as controls for a study of Burkitts
lymphoma. In 1985, retroactive testing of the frozen
blood serum indicated that antibodies to a virus related
to HIV were present in 50 of the children.[60]

A Canadian airline steward named Gatan Dugas was referred to as Patient 0 in an early AIDS study by Dr.
William Darrow of the Centers for Disease Control. Because of this, many people had considered Dugas to be
responsible for bringing HIV to North America. This is
not accurate, however, as HIV had spread long before
Dugas began his career. This rumor may have started
with Randy Shilts' 1987 book And the Band Played On
(and the 1993 movie based on it, in which Dugas is referred to as AIDS' Patient Zero), but neither the book
nor the movie states that he had been the rst to bring the
virus to North America. He was called Patient Zero because at least 40 of the 248 people known to be infected
by HIV in 1983 had had sex with him, or with someone
who had sexual intercourse with him.

5.4.7

5.4.9 1981: From GRID to AIDS

5.4.6

1973: Ugandan children

Spread to the western hemisphere

HIV-1 strains were once thought to have arrived in the

United States from Haiti in the late 1960s or early
1970s.[61][62] HIV-1 is believed to have arrived in Haiti
from central Africa, possibly from the Democratic Republic of the Congo.[63] The current consensus is that HIV
was introduced to Haiti by an unknown individual or individuals who contracted it while working in the Democratic Republic of the Congo circa 1966, or from another
person who worked there during that time.[62] A miniepidemic followed, and, circa 1969, yet another unknown
individual brought HIV from Haiti to the United States.
The vast majority of cases of AIDS outside sub-Saharan
Africa can be traced back to that single patient[61] (although numerous unrelated incidents of AIDS among
Haitian immigrants to the U.S. were recorded in the early
1980s, and, as evidenced by the case of Robert Rayford,
isolated incidents of this infection may have been occurring as early as 1966). The virus eventually entered male
gay communities in large United States cities, where a
combination of sexual promiscuity (with individuals reportedly averaging over 11 unprotected sexual partners
per year[64] ) and relatively high transmission rates associated with anal intercourse[65] allowed it to spread explosively enough to nally be noticed.[61]

The AIDS epidemic ocially began on June 5, 1981,

when the U.S. Centers for Disease Control and Prevention in its Morbidity and Mortality Weekly Report newsletter reported unusual clusters of Pneumocystis pneumonia
(PCP) caused by a form of Pneumocystis carinii (now recognized as a distinct species Pneumocystis jirovecii) in ve
homosexual men in Los Angeles.[67]
Over the next 18 months, more PCP clusters were discovered among otherwise healthy men in cities throughout the country, along with other opportunistic diseases
(such as Kaposis sarcoma[68] and persistent, generalized
lymphadenopathy[69] ), common in immunosuppressed
patients.
In June 1982, a report of a group of cases amongst
gay men in Southern California suggested that a sexually
transmitted infectious agent might be the etiological
agent,[70] and the syndrome was initially termed GRID,
or gay-related immune deciency.[71]
Health authorities soon realized that nearly half of the
people identied with the syndrome were not homosexual men. The same opportunistic infections were also
reported among hemophiliacs,[72] users of intravenous
drugs such as heroin, and Haitian immigrants leading

5.6. CLASSIFICATION

35

some researchers to call it the 4H disease.[73][74]

Gallo was left out.[83] Gallo said that it was a disappoint[84]

By August 1982, the disease was being referred to by its ment that he was not named a co-recipient. Montagnew CDC-coined name: Acquired Immune Deciency nier said he was surprised Gallo was not recognized by
the Nobel Committee: It was important to prove that
Syndrome (AIDS).[75]
HIV was the cause of AIDS, and Gallo had a very important role in that. I'm very sorry for Robert Gallo.[83]

5.5 Identication of the virus

5.5.1

May 1983: LAV

5.6 Classication

Since June 5, 1981, many denitions have been develIn May 1983, doctors from Dr. Luc Montagnier's team at oped for epidemiological surveillance such as the Bangui
the Pasteur Institute in France reported that they had iso- denition and the 1994 expanded World Health Organilated a new retrovirus from lymphoid ganglions that they zation AIDS case denition.
believed was the cause of AIDS.[76] The virus was later
named lymphadenopathy-associated virus (LAV) and a
sample was sent to the U.S. Centers for Disease Control,
which was later passed to the National Cancer Institute 5.7 Genetic studies
(NCI).[76][77]
According to a study published in the Proceedings of the
National Academy of Sciences in 2008, a team led by
5.5.2 May 1984: HTLV-III
Robert Shafer at Stanford University School of Medicine
has discovered that the Gray Mouse Lemur has an
In May 1984 a team led by Robert Gallo of the United endogenous lentivirus (the genus to which HIV belongs)
States conrmed the discovery of the virus, but they re- in its genetic makeup. This suggests that lentiviruses have
named it human T lymphotropic virus type III (HTLV- existed for at least 14 million years, much longer than
III).[78]
the currently known existence of HIV. In addition, the
time frame falls into place when Madagascar was still
yet connected to what is now the African continent; the
5.5.3 January 1985: both found to be the said lemurs later developed immunity to the virus strain
and survived an era when the lentivirus was widespread
same
among other mammalia. The study is being hailed as cruIn January 1985, a number of more-detailed reports cial, because it lls the blanks in the origin of the virus,
be important in the
were published concerning LAV and HTLV-III, and by as well as in its evolution, and may[85][86]
development
of
new
antiviral
drugs.
March it was clear that the viruses were the same, were
from the same source, and were the etiological agent of In 2010, researchers reported that SIV had infected monAIDS.[79][80]
keys in Bioko for at least 32,000 years. Previous to this
time, it was thought that SIV infection in monkeys had
happened over the past few hundred years.[87] Scientists
estimated that it would take a similar amount of time be5.5.4 May 1986: the name HIV
fore humans adapted naturally to HIV infection in the way
In May 1986, the International Committee on Taxonomy monkeys in Africa have adapted to SIV and not suer any
[88]
of Viruses ruled that both names should be dropped and harm from the infection.
a new name, HIV (Human Immunodeciency Virus), be
used.[81]

5.8 Discredited hypotheses

5.5.5

Nobel

Whether Gallo or Montagnier deserve more credit for the

discovery of the virus that causes AIDS has been a matter
of considerable controversy. Together with his colleague
Franoise Barr-Sinoussi, Montagnier was awarded one
half of the 2008 Nobel Prize in Physiology or Medicine
for his discovery of human immunodeciency virus.[82]
Harald zur Hausen also shared the prize for his discovery
that human papilloma virus leads to cervical cancer, but

Main article: Discredited AIDS origins theories

Other hypotheses for the origin of AIDS have been proposed. AIDS denialism argues that HIV or AIDS does
not exist or that AIDS is not caused by HIV; some of
its proponents believe that AIDS is caused by lifestyle,
including sexuality or drug use, and not by HIV. Some
conspiracy theories allege that HIV was created in a
bioweapons laboratory, perhaps as an agent of genocide

36
or an accident. These hypotheses have been rejected by
scientic consensus.

5.9 See also

Timeline of HIV/AIDS

5.10 Notes
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Simian Immunodeciency Virus Infection in FreeRanging Sooty Mangabeys (Cercocebus atys atys) from
the Tai Forest, Cote d'Ivoire: Implications for the
Origin of Epidemic Human Immunodeciency Virus
Type 2.
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[4] Keele BF, Van Heuverswyn F, Li Y, Bailes E, Takehisa J, Santiago ML, Bibollet-Ruche F, Chen Y, Wain
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Delaporte E, Brookeld JF, Sharp PM, Shaw GM,
Peeters M, Hahn BH (2006). Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1. Science 313 (5786): 5236. Bibcode:2006Sci...313..523K.
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[5] HIVs ancestry traced to wild chimps in Cameroon.
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[6] Van Heuverswyn F, Li Y, Neel C, Bailes E, Keele
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Y, Ngolle EM, Sharp PM, Shaw GM, Delaporte E,
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[8] Sharp PM, Bailes E, Chaudhuri RR, Rodenburg CM,
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11405934.

CHAPTER 5. HISTORY OF HIV/AIDS

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37

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Chapter 6

HIV/AIDS denialism
discourages HIV-positive people from using proven
treatments.[2][8][10][11][12][13] Public health researchers
have attributed 330,000 to 340,000 AIDS deaths, along
with 171,000 other HIV infections and 35,000 infant HIV
infections, to the South African governments former embrace of HIV/AIDS denialism.[14][15] The interrupted use
of antiviral treatments is also a major global concern as it
potentially increases the likelihood of the emergence of
antiviral resistance strains of the virus.[16]

6.1 History
In 1983, a group of scientists and doctors at the Pasteur
Institute in France, led by Luc Montagnier, discovered a new virus in a patient with signs and symptoms that often preceded AIDS.[17] They named the
virus lymphadenopathy-associated virus, or LAV, and
HIV/AIDS denialism is the belief, contradicted by con- sent samples to Robert Gallo's team in the United States.
clusive medical and scientic evidence,[1][2] that human Their ndings were peer reviewed and slated for publicaimmunodeciency virus (HIV) does not cause acquired tion in Science.
immune deciency syndrome (AIDS).[3] Some denialists At a 23 April 1984 press conference in Washington, D.C.,
reject the existence of HIV, while others accept that HIV Margaret Heckler, Secretary of Health and Human Serexists but say that it is a harmless passenger virus and vices, announced that Gallo and his co-workers had disnot the cause of AIDS. Insofar as denialists acknowledge covered a virus that is the probable cause of AIDS.
AIDS as a real disease, they attribute it to some combina- This virus was initially named HTLV-III.[18] That same
tion of sexual behavior, recreational drugs, malnutrition, year, Casper Schmidt responded to Gallos papers with
poor sanitation, haemophilia, or the eects of the drugs The Group-Fantasy Origins of AIDS, Journal of Psyused to treat HIV infection.[4][5]
chohistory.[19] Schmidt posited that AIDS was not an acThe scientic consensus is that the evidence showing tual disease, but rather an example of "epidemic hysteria"
HIV to be the cause of AIDS is conclusive[1][2] and in which groups of people are subconsciously acting out
that HIV/AIDS denialist claims are pseudoscience based social conicts. Schmidt compared AIDS to documented
on conspiracy theories,[6] faulty reasoning, cherry pick- cases of epidemic hysteria in the past which were mis(Schmidt himself would
ing, and misrepresentation of mainly outdated scientic takenly thought to be infectious.
[20][21]
later
die
of
AIDS
in
1994.)
[1][2][7]
data.
With the rejection of these arguments by
Electron micrograph of the human immunodeciency virus.
HIV/AIDS denialism disputes the existence of HIV or its role in
causing AIDS.

the scientic community, HIV/AIDS denialist material is In 1986, the viruses discovered by Montagnier and Gallo,
now targeted at less scientically sophisticated audiences found to be genetically indistinguishable, were renamed
HIV.[22]
and spread mainly through the Internet.[8][9]
Despite its lack of scientic acceptance, HIV/AIDS denialism has had a signicant political impact, especially in South Africa under the presidency of Thabo
Mbeki. Scientists and physicians have raised alarm
at the human cost of HIV/AIDS denialism, which

In 1987, Peter Duesberg questioned the link between HIV

and AIDS in the journal Cancer Research.[23] Duesbergs
publication coincided with the start of major public health
campaigns and the development of zidovudine (AZT) as
a treatment for HIV/AIDS.

40

6.1. HISTORY
In 1988, a panel of the Institute of Medicine of the U.S.
National Academy of Sciences found that the evidence
that HIV causes AIDS is scientically conclusive.[1]
That same year, Science published Blattner, Gallo, and
Temins HIV causes AIDS,[24] and Duesbergs HIV
is not the cause of AIDS.[25] Also that same year, the
Perth Group, a group of denialists based in Perth, Western Australia led by Eleni Papadopulos-Eleopulos, published in the non-peer-reviewed journal Medical Hypotheses their rst article questioning aspects of HIV/AIDS
research,[26] arguing that there was no compelling reason for preferring the viral hypothesis of AIDS to one
based on the activity of oxidising agents.
In 1989, Duesberg exercised his right, as a member of
the National Academy of Sciences, to bypass the peer review process and publish his arguments in Proceedings
of the National Academy of Sciences of the United States
of America (PNAS) unreviewed. The editor of PNAS initially resisted, but ultimately allowed Duesberg to publish,
saying, If you wish to make these unsupported, vague,
and prejudicial statements in print, so be it. But I cannot see how this would be convincing to any scientically
trained reader.[27]

41
claimed to have been drawn up by the Pasteur Institute
in 1973.[35] The challenge was later dismissed by various scientists, including Duesberg, asserting that HIV undoubtedly exists.[35] Stefan Lanka argued in the same year
that HIV does not exist.[36]
In 1996, the British Medical Journal published Response: arguments contradict the foreign proteinzidovudine hypothesis[37] as a response to a petition by
Duesberg: In 1991 Duesberg challenged researchers
We and Darby et al. have provided that evidence. The
paper argued that Duesberg was wrong regarding the
cause of AIDS in haemophiliacs. In 1997, The Perth
Group questioned the existence of HIV, and speculated
that the production of antibodies recognizing HIV proteins can be caused by allogenic stimuli and autoimmune
disorders.[38][39] They continued to repeat this speculation through at least 2006.[40]

In 2006, Celia Farber, a journalist and prominent

HIV/AIDS denialist, published an essay in the March issue of Harpers Magazine entitled Out of Control: AIDS
and the Corruption of Medical Science, in which she
summarized a number of arguments for HIV/AIDS denialism and alleged incompetence, conspiracy, and fraud
In 1990, Robert Root-Bernstein published his rst peer- on the part of the medical community.[41] Scientists and
reviewed article detailing his objections to the main- AIDS activists extensively criticized the article as inaccustream view of AIDS and HIV.[28] In it, he questioned rate, misleading, and poorly fact-checked.[42][43]
both the mainstream view and the dissident view as po- In 2007, members of the Perth Group testied at an
tentially inaccurate.
appeals hearing for Andre Chad Parenzee, asserting
In 1991, The Group for the Scientic Reappraisal of that HIV could not be transmitted by heterosexual sex.
the HIV-AIDS Hypothesis, comprising twelve scientists, The judge concluded, I reject the evidence of Ms
doctors, and activists, submitted a short letter to various Papadopulos-Eleopulos and Dr Turner. I conclude that
journals, but the letter was rejected.[29]
they are not qualied to give expert opinions.[44]
In 1993, Nature published an editorial arguing that Duesberg had forfeited his right of reply by engaging in
disingenuous rhetorical techniques and ignoring any evidence that conicted with his claims.[30] That same year,
Papadopulos-Eleopulos et al. of the Perth Group, alleged
in the journal Nature Biotechnology (then edited by fellow denialist Harvey Bialy) that the Western blot test for
HIV was not standardized, non-reproducible, and of unknown specicity due to a claimed lack of a "gold standard".[31][32]

6.1.1 U.S. courts

In 1998, HIV/AIDS denialism and parental rights clashed

with the medical establishment in court when Maine resident Valerie Emerson fought for the right to refuse to give
AZT to her four-year-old son, Nikolas Emerson, after she
witnessed the death of her daughter Tia, who died at the
age of three in 1996. Her right to stop treatment was upheld by the court in light of her unique experience.[45]
On 28 October 1994, Robert Willner, a physician whose Nikolas Emerson died eight years later. The family re[46]
medical license had been revoked for, among other fused to reveal whether the death was AIDS related.
things, treating an AIDS patient with ozone therapy, publicly jabbed his nger with blood he said was from an
HIV-infected patient.[10] Willner died in 1995 of a heart 6.1.2 South Africa
attack.[33]
In 2000, South Africas President Thabo Mbeki inIn 1995, a letter, similar to the one submitted by The vited several HIV/AIDS denialists to join his Presidential
Group for the Scientic Reappraisal of the HIV-AIDS AIDS Advisory Panel.[47] A response named the Durban
Hypothesis in 1991, was published in Science.[34] That Declaration was issued arming the scientic consensus
same year, Continuum, a denialist group, placed an ad- that HIV causes AIDS:
vertisement in the British gay and lesbian magazine The
Pink Paper oering a 1,000 reward to the rst perThe declaration has been signed by over 5,000
son nding one scientic paper establishing actual isopeople, including Nobel Prize winners, direclation of HIV, according to a set of seven steps they
tors of leading research institutions, scientic

42

CHAPTER 6. HIV/AIDS DENIALISM

academies and medical societies, notably the
US National Academy of Sciences, the US Institute of Medicine, Max Planck institutes, the
European Molecular Biology Organization, the
Pasteur Institute in Paris, the Royal Society of
London, the AIDS Society of India and the
National Institute of Virology in South Africa.
In addition, thousands of individual scientists
and doctors have signed, including many from
the countries bearing the greatest burden of
the epidemic. Signatories are of MD, PhD
level or equivalent, although scientists working
for commercial companies were asked not to
sign.[13]

In 2008, University of Cape Town researcher Nicoli Nattrass, and later that year a group of Harvard scientists led
by Zimbabwean physician Pride Chigwedere each independently estimated that Thabo Mbekis denialist policies led to the early deaths of more than 330,000 South
Africans.[14][15] Barbara Hogan, the health minister appointed by Mbekis successor, voiced shame over the
studies ndings and stated: The era of denialism is over
completely in South Africa.[48]

as long as they are not applied in a ridiculously stringent

way. The author then demonstrated how each postulate
has been met the suspected cause is strongly associated
with the disease, the suspected pathogen can be both isolated and spread outside the host, and when the suspected
pathogen is transmitted to a new and uninfected host, that
host develops the disease.[2][57] The latter was proven in
a number of tragic accidents, including an instance when
multiple scientic technicians with no other known risk
factors were exposed to concentrated HIV virus in a laboratory accident, and transmission by a dentist to patients,
the majority of whom had no other known risk factor or
source of exposure except the same dentist in common.[2]
Early denialist arguments held that the HIV/AIDS
paradigm was awed because it had not led to eective
treatments. However, the introduction of highly active
antiretroviral therapy in the mid-1990s and dramatic improvements in survival of HIV/AIDS patients reversed
this argument, as these treatments were based directly on
anti-viral activity and the HIV/AIDS paradigm.[58] The
development of eective anti-AIDS therapies based on
targeting of the HIV virus has been a major factor in convincing some denialist scientists to accept the causative
role of HIV in AIDS.[59]

In a 2010 article on conspiracy theories in science,

Ted Goertzel lists HIV/AIDS denialism as an example
6.2 HIV/AIDS denialists claims where scientic ndings are being disputed on irrational
grounds. He describes proponents as relying on rhetoric,
and scientic evidence
appeal to fairness, and the right to a dissenting opinion rather than on evidence. They frequently invoke the
See also: Duesberg hypothesis
meme of a courageous independent scientist resisting orthodoxy, invoking the name of persecuted physicist and
[60]
Regarding this compariAlthough members of the HIV/AIDS denialist commu- astronomer Galileo Galilei.
son,
Goertzel
states:
nity are united by their disagreement with the scientic
nding that HIV is the cause of AIDS, the specic positions taken by various groups dier. Denialists claim
...being a dissenter from orthodoxy is not
many incompatible things: HIV does not exist; HIV
dicult; the hard part is actually having a
has not been adequately isolated,[49] HIV does not fulbetter theory. Publishing dissenting theories is
ll Kochs postulates,[50] HIV testing is inaccurate,[31]
important when they are backed by plausible
and that antibodies to HIV neutralize the virus and renevidence, but this does not mean giving critics
der it harmless.[51] Suggested alternative causes of AIDS
'equal time' to dissent from every nding by a
include recreational drugs, malnutrition, and the very
mainstream scientist.
antiretroviral drugs used to treat the syndrome.[52]
Goertzel, 2010[60]
Such claims have been examined extensively in the peerreviewed medical and scientic literature; a scientic
consensus has arisen that denialist claims have been convincingly disproved, and that HIV does indeed cause
AIDS.[2][53] In the cases cited by Duesberg where HIV
cannot be isolated, PCR or other techniques demonstrate the presence of the virus,[54] and denialist claims
of HIV test inaccuracy result from an incorrect or outdated understanding of how HIV antibody testing is performed and interpreted.[55][56] Regarding Kochs postulates, New Scientist reported: It is debatable how appropriate it is to focus on a set of principles devised for bacterial infections in a century when viruses had not yet been
discovered. HIV does, however, meet Kochs postulates

6.3 The HIV/AIDS denialist community

Denialists often use their critique of the link between HIV
and AIDS to promote alternative medicine as a cure, and
attempt to convince HIV-infected individuals to avoid
ARV therapy in favour of vitamins, massage, yoga and
other unproven treatments.[61] Despite this promotion,
denialists will often downplay any association with alternative therapies, and attempt to portray themselves as

6.3. THE HIV/AIDS DENIALIST COMMUNITY

dissidents. An article in the Skeptical Inquirer stated:
AIDS denialists [prefer] to characterize
themselves as brave dissidents attempting to
engage a hostile medical/industrial establishment in genuine scientic debate. They complain that their attempts to raise questions and
pose alternative hypotheses have been unjustly
rejected or ignored at the cost of scientic
progress itself...Given their resistance to all
evidence to the contrary, todays AIDS dissidents are more aptly referred to as AIDS
denialists.[61]

43
the political aspects of the HIV/AIDS denialism movement, Sociology professor Steven Epstein wrote in Impure Science that "... the appeal of Duesbergs views to
conservativescertainly including those with little sympathy for the gay movementcannot be denied.[70] The
blog LewRockwell.com has also published articles supportive of HIV/AIDS denialism.[76]

In a follow-up article in Skeptical Inquirer,[77] Nattrass

overviewed the prominent members of the HIV/AIDS
denialist community and discussed the reasons of the intractable staying power of HIV/AIDS denialism in spite
of scientic and medical consensus supported by over two
decades of evidence. She observed that despite being a
disparate group of people with very dierent background
denialists self-organize to
Several scientists have been associated with HIV/AIDS and professions, the HIV/AIDS
[77]
ll
four
important
roles:
denialism, although they have not themselves studied
AIDS or HIV.[9] One of the most famous and inuen Hero scientists to provide scientic legitimacy:
tial is Duesberg, professor of molecular and cell biolMost notably Duesberg who plays the central role
ogy at the University of California, Berkeley, who since
of HIV/AIDS denialism from the beginning. Oth1987 has disputed that the scientic evidence shows that
ers include David Rasnick, tienne de Harven, and
[23]
HIV causes AIDS.
Other scientists associated with
Kary Mullis whose Nobel Prize makes him symbolHIV/AIDS denialism include biochemists David Rasically important.
nick and Harvey Bialy. Kary Mullis, who was awarded
a Nobel Prize for his role in the development of the
Cultropreneurs to oer fake cures in place of
polymerase chain reaction, has expressed sympathy for
antiretroviral therapy: Matthias Rath, Gary Null,
denialist theories.[62] Biologist Lynn Margulis argued that
Michael Ellner, and Roberto Giraldo all promote
theres no evidence that HIV is an infectious virus and
alternative medicine and remedies with a dose of
that AIDS symptoms overlap...completely with those of
conspiracy theories in the form of books, healing
syphilis.[63] Pathologist tienne de Harven also expressed
products, radio shows and counseling services.
sympathy for HIV/AIDS denial.[64][65]
HIV positive living icons to provide proof of conAdditional notable HIV/AIDS denialists include Auscept by appearing to live healthily without antiretrotralian academic ethicist Hiram Caton, the late mathviral therapy: Christine Maggiore was and still is
ematician Serge Lang,[66] former college administrator
the most important icon in the HIV/AIDS denialHenry Bauer, journalist Celia Farber, American talk raist movement despite the fact that she died of AIDS
dio host and author on alternative and complementary
related complications in 2008.
medicine and nutrition Gary Null, and the late activist
Praise singers: sympathetic journalists and lmChristine Maggiore, who encouraged HIV-positive mothmakers who publicize the movement with uncritiers to forgo anti-HIV treatment and whose 3-year-old
[67]
cal and favorable opinion. They include journalists
daughter died of complications of untreated AIDS.
Celia Farber, Liam Sche and Neville Hodgkinson;
Nate Mendel, bassist with the rock band Foo Fighters,
lmmakers Brent Leung and Robert Leppo.
expressed support for HIV/AIDS denialist ideas and organized a benet concert in January 2000 for Maggiores
organization Alive & Well AIDS Alternatives.[68] Organi- Some of them had overlapping roles as board members
zations of HIV/AIDS denialists include the Perth Group, of Rethinking AIDS and Alive and Well AIDS Alternacomposed of several Australian hospital workers, and the tives, were involved in the lm House of Numbers, The
Other Side of AIDS or on Thabo Mbeki's AIDS Advisory
Immunity Resource Foundation.[69]
Panel. Nattrass argued that HIV/AIDS denialism gains
HIV/AIDS denialism has received some support from social traction through powerful community-building efpolitical conservatives in the United States. Duesbergs fects where these four organized characters form a symwork has been published in Policy Review, a journal once biotic connection between AIDS denialism and alternapublished by the Heritage Foundation but now owned by tive healing modalities and they are facilitated by a
the Hoover Institution,[70][71][72] and by Regnery Press. shared conspiratorial stance toward HIV science.[77]
Regnery published Duesbergs Inventing the AIDS Virus
in 1996,[73] and journalist Tom Bethell's The Politically Incorrect Guide to Science, in which he endorses 6.3.1 Former denialists
HIV/AIDS denialism, in 2005.[74] Law professor Phillip
E. Johnson has accused the Centers for Disease Con- Several of the few prominent scientists who once voiced
trol of fraud in relation to HIV/AIDS.[75] Describing doubts about HIV/AIDS have since changed their views

44

CHAPTER 6. HIV/AIDS DENIALISM

and accepted the fact that HIV plays a role in causing

AIDS, in response to an accumulation of newer studies
and data.[78] Root-Bernstein, author of Rethinking AIDS:
The Tragic Cost of Premature Consensus and formerly a
critic of the causative role of HIV in AIDS, has since distanced himself from the HIV/AIDS denialist movement,
saying, Both the camp that says HIV is a pussycat and
the people who claim AIDS is all HIV are wrong...The
denialists make claims that are clearly inconsistent with
existing studies.[79]
Joseph Sonnabend, who until the late 1990s regarded
the issue of AIDS causation as unresolved, has reconsidered in light of the success of newer antiretroviral drugs,
stating, The evidence now strongly supports a role for
HIV Drugs that can save your life can also under different circumstances kill you. This is a distinction that
denialists do not seem to understand.[79] Sonnabend has
also criticized HIV/AIDS denialists for falsely implying
that he supports their position, saying:

Some individuals who believe that HIV

plays no role at all in AIDS have implied that
I support their misguided views on AIDS causation by including inappropriate references
to me in their literature and on their web sites.
Before HIV was discovered and its association
with AIDS established, I held the entirely
appropriate view that the cause of AIDS was
then unknown. I have successfully treated
hundreds of AIDS patients with antiretroviral
medications, and have no doubt that HIV plays
a necessary role in this disease.[80]

6.3.2 Death of HIV-positive denialists

In 2007, aidstruth.org, a website run by HIV researchers to counter denialist claims,[81] published a partial list of HIV/AIDS denialists who had died of AIDSrelated causes. For example, the editors of the magazine Continuum consistently denied the existence of
HIV/AIDS. The magazine shut down after both editors died of AIDS-related causes.[82] In each case, the
HIV/AIDS denialist community attributed the deaths to
unknown causes, secret drug use, or stress rather than
HIV/AIDS.[21][59] Similarly, several HIV-positive former
dissidents have reported being ostracized by the AIDSdenialist community after they developed AIDS and decided to pursue eective antiretroviral treatment.[83]
In 2008, activist Christine Maggiore died at the age of
52 while under a doctors care for pneumonia. Maggiore, mother of two children, had founded an organisation to help other HIV-positive mothers avoid taking antiretroviral drugs that reduce the risk of HIV transmission
from mother to child.[84] After her three-year-old daughter died of AIDS-related pneumonia in 2005, Maggiore
continued to believe that HIV is not the cause of AIDS,
and she and her husband Robin Scovill sued Los Angeles
County and others on behalf of their daughters estate,
for allegedly violating Eliza Scovill's civil rights by releasing an autopsy report that listed her cause of death as
AIDS-related pneumonia.[67] The litigants settled out of
court, with the county paying Scovill $15,000 in March
2009, with no admission of wrongdoing. The L.A. coroners ruling that Eliza Jane Scovill died of AIDS remains
standing as the ocial verdict.[85]

6.4 Impact beyond the scientic

community

Both Sonnabend and Root-Bernstein now favor a less

controversial hypothesis, suggesting that while HIV is
necessary for AIDS, cofactors may also contribute.
AIDS-denialist claims have failed to attract support in
A former denialist wrote in the Journal of Medical Ethics the scientic community, where the evidence for the
causative role of HIV in AIDS is considered conclusive.
in 2004:
However, the movement has had a signicant impact
in the political sphere, culminating with former South
African President Thabo Mbeki's embrace of AIDSThe group [of denialists] regularly points
denialist claims.[86] The resulting governmental refusal
to a substantial number of scientists supportive
to provide eective anti-HIV treatment in South Africa
of its agenda to re-evaluate the HIV/AIDS
has been blamed for hundreds of thousands of premature
hypothesis. Some of those members still
AIDS-related deaths in South Africa.[48]
listed are people who have been dead for a
number of years. While it is correct that these
people supported the objective of a scientic
6.4.1 Impact in North America and Eure-evaluation of the HIV/AIDS link when they
were alive, it is clearly dicult to ascertain
rope
what these people would have made of the
Skepticism about HIV being the cause of AIDS began
scientic developments and the accumulation
almost immediately after the discovery of HIV was anof evidence for HIV as the crucial causative
nounced. One of the earliest prominent skeptics was the
agent in AIDS, which has occurred in the
journalist John Lauritsen, who argued in his writings for
years after their deaths.[59]
the New York Native that AIDS was caused by amyl nitrite

6.4. IMPACT BEYOND THE SCIENTIFIC COMMUNITY

45

poppers, and that the government had conspired to hide protected anal sex and poppers on homosexual men, an
the truth.[87] Lauritsens The AIDS War was published in argument which does not account for AIDS in drug-free
1993.[88]
heterosexual women who deny participating in anal sex.
In this case, HIV/AIDS denialists claim the women are
having anal sex but refuse to disclose it. In haemophiliac
North American children who contracted AIDS from
In the scientic literature
blood transfusions, the haemophilia itself or its treatment
The publication of Duesbergs rst AIDS paper in 1987 is claimed to cause AIDS. In Africa, AIDS is blamed on
provided visibility for denialist claims. Shortly after- poor nutrition and sanitation due to poverty. For wealthy
wards, the journal Science reported that Duesbergs re- populations in South Africa with adequate nutrition and
marks had won him a large amount of media attention, sanitation, it is claimed that the antiretroviral drugs used
particularly in the gay press where he is something of a to treat AIDS cause the condition. In each case, the most
hero.[89] However, Duesbergs support in the gay com- parsimonious explanation and uniting factor HIV posimunity dried up as he made a series of statements per- tive status is ignored, as are the thousands of studies that
conclusion that AIDS is caused
ceived as homophobic; in an interview with the Village converge on the common
[5]
by
HIV
infection.
Voice in 1988, Duesberg stated his belief that the AIDS
epidemic was caused by a lifestyle that was criminal Haemophilia is considered the best test of the HIV-AIDS
twenty years ago.[90]
hypothesis by both denialists and AIDS researchers.
In the following few years, others became skeptical of the While Duesberg claims AIDS in haemophiliacs is caused
HIV theory as researchers initially failed to produce an by contaminated clotting factors and HIV is a harmless
eective treatment or vaccine for AIDS.[91] Journalists passenger virus, this result is contradicted by large studsuch as Neville Hodgkinson and Celia Farber regularly ies on haemophiliac patients who received contaminated
promoted denialist ideas in the American and British me- blood. A comparison of groups receiving high, medium
dia; several television documentaries were also produced and low levels of contaminated clotting factors found the
to increase awareness of the alternative viewpoint.[92] death rates diered signicantly depending on HIV staIn 19921993, The Sunday Times, where Hodgkinson tus. Of 396 HIV positive haemophiliacs followed beserved as scientic editor, ran a series of articles argu- tween 1985 and 1993, 153 died. The comparative ging that the AIDS epidemic in Africa was a myth. These ure for the HIV negative group was one out of 66, dearticles stressed Duesbergs claims and argued that antivi- spite comparable doses of contaminated clotting factors.
ral therapy was ineective, HIV testing unreliable, and A comparison of individuals receiving blood donations
that AIDS was not a threat to heterosexuals. The Sun- also supports the results; in 1994 there were 6888 indiday Times coverage was heavily criticized as slanted, mis- viduals with AIDS who had their HIV infection traced to
leading, and potentially dangerous; the scientic journal blood transfusions. Since the introduction of HIV testbe
Nature took the unusual step of printing a 1993 edito- ing, the number of individuals whose AIDS status can [4]
traced
to
blood
transfusions
was
only
29
(as
of
1994).
rial calling the papers coverage of HIV/AIDS seriously
mistaken, and probably disastrous.[93]
Finding diculty in publishing his arguments in the scientic literature, Duesberg exercised his right as a member of the National Academy of Sciences to publish in
Proceedings of the National Academy of Sciences of the
United States of America (PNAS) without going through
the peer review process. However, Duesbergs paper
raised a red ag at the journal and was submitted by
the editor for non-binding review. All of the reviewers found major aws in Duesbergs paper; the reviewer
specically chosen by Duesberg noted the presence of
misleading arguments, nonlogical statements, misrepresentations, and political overtones.[27] Ultimately,
the editor of PNAS acquiesced to publication,[94] writing
to Duesberg: If you wish to make these unsupported,
vague, and prejudicial statements in print, so be it. But I
cannot see how this would be convincing to any scientifically trained reader.[27]
HIV/AIDS denialists often resort to special pleading to
support their assertion, arguing for dierent causes of
AIDS in dierent locations and subpopulations. In North
America, AIDS is blamed on the health eects of un-

In lay press and on the Internet

With the introduction of highly active antiretroviral therapy (HAART) in 19961997, the survival and general
health of people with HIV improved signicantly.[58][95]
The positive response to treatment with anti-HIV medication cemented the scientic acceptance of the HIV/AIDS
paradigm, and led several prominent HIV/AIDS denialists to accept the causative role of HIV.[59][79] Finding
their arguments increasingly discredited by the scientic
community, denialists took their message to the popular
press. A former denialist wrote:
Scientists among the HIV dissidents used
their academic credentials and academic
aliations to generate interest, sympathy, and
allegiances in lay audiences. They were not
professionally troubled about recruiting lay
peoplewho were clearly unable to evaluate
the scientic validity or otherwise of their
viewsto their cause.[59]

46

CHAPTER 6. HIV/AIDS DENIALISM

171,000 infections resulted from the Mbeki administrations policies, an outcome she refers to in the words of
[15]
In addition to elements of the popular and alternative Peter Mandelson as genocide by sloth.
press, AIDS denialist ideas are propagated largely via the
Internet.[96]
Durban Declaration
A 2007 article in PLoS Medicine noted:
In 2000, when the International AIDS Conference was
held in Durban, Mbeki convened a Presidential Advisory
Because these denialist assertions are
Panel containing a number of HIV/AIDS denialists, inmade in books and on the Internet rather than
cluding Duesberg and David Rasnick.[99] The Advisory
in the scientic literature, many scientists are
Panel meetings were closed to the general press; an ineither unaware of the existence of organized
vited reporter from the Village Voice wrote that Rasnick
denial groups, or believe they can safely ignore
advocated that HIV testing be legally banned and denied
them as the discredited fringe. And indeed,
that he had seen any evidence of an AIDS catastrophe
most of the HIV deniers arguments were
in South Africa, while Duesberg gave a presentation so
answered long ago by scientists. However,
removed from African medical reality that it left several
many members of the general public do not
local doctors shaking their heads.[47]
have the scientic background to critique the
assertions put forth by these groups, and not
In his address to the International AIDS Conference,
only accept them but continue to propagate
Mbeki reiterated his view that HIV was not wholly rethem.[8]
sponsible for AIDS, leading hundreds of delegates to
AIDS activists have expressed concern that denialist arguments about HIVs harmlessness may be responsible
for an upsurge in HIV infections. Denialist claims continue to exert a signicant inuence in some communities; a survey conducted at minority gay pride events in
four American cities in 2005 found that 33% of attendees
doubted that HIV caused AIDS.[97] According to Stephen
Thomas, director of the University of Pittsburgh Center
for Minority Health, people are focusing on the wrong
thing. They're focusing on conspiracies rather than protecting themselves, rather than getting tested and seeking
out appropriate care and treatment.[98]

6.4.2

Impact in South Africa

Main article: HIV/AIDS denialism in South Africa

HIV/AIDS denialist claims have had a major political, social, and public health impact in South Africa. The government of then President Thabo Mbeki was sympathetic
to the views of HIV/AIDS denialists, with critics charging
that denialist inuence was responsible for the slow and
ineective governmental response to the countrys massive AIDS epidemic.
Independent studies have arrived at almost identical estimates of the human costs of HIV/AIDS denialism in
South Africa. According to a paper written by researchers from the Harvard School of Public Health, between 2000 and 2005, more than 330,000 deaths and
an estimated 35,000 infant HIV infections occurred because of a failure to accept the use of available [antiretroviral drugs] to prevent and treat HIV/AIDS in a timely
manner.[14] Nicoli Nattrass of the University of Cape
Town estimates that 343,000 excess AIDS deaths and

walk out on his speech.[100] Mbeki also sent a letter

to a number of world leaders likening the mainstream
AIDS research community to supporters of the apartheid
regime.[99] The tone and content of Mbekis letter led
diplomats in the U.S. to initially question whether it was
a hoax.[101][102]
AIDS scientists and activists were dismayed at the presidents behavior and responded with the Durban Declaration, a document arming that HIV causes AIDS, signed
by over 5,000 scientists and physicians.[13][100]
Criticism of governmental response
The former South African health minister Manto
Tshabalala-Msimang also attracted heavy criticism, as
she often promoted nutritional remedies such as garlic, lemons, beetroot and olive oil, to people suering
from AIDS,[103][104][105] while emphasizing possible toxicities of antiretroviral drugs, which she has referred to as
poison.[106] The South African Medical Association has
accused Tshabalala-Msimang of confusing a vulnerable
public.[107] In September 2006, a group of over 80 scientists and academics called for the immediate removal of
Dr. Tshabalala-Msimang as minister of health and for an
end to the disastrous, pseudoscientic policies that have
characterized the South African governments response to
HIV/AIDS.[108] In December 2006, deputy health minister Nozizwe Madlala-Routledge described denial at the
very highest levels over AIDS.[109] She was subsequently
red by Mbeki.[110]
Former South African president Thabo Mbeki's government was widely criticized for delaying the rollout
of programs to provide antiretroviral drugs to people
with advanced HIV disease and to HIV-positive pregnant women. The national treatment program began only
after the Treatment Action Campaign (TAC) brought a

6.5. SEE ALSO

legal case against Government ministers, claiming they
were responsible for the deaths of 600 HIV-positive people a day who could not access medication.[99][111] South
Africa was one of the last countries in the region to begin such a treatment program, and roll-out has been much
slower than planned.[106]
At the XVI International AIDS Conference, Stephen
Lewis, UN special envoy for AIDS in Africa, attacked
Mbekis government for its slow response to the AIDS
epidemic and reliance on denialist claims:
It [South Africa] is the only country in
Africa whose government is still obtuse,
dilatory and negligent about rolling out treatment It is the only country in Africa whose
government continues to promote theories
more worthy of a lunatic fringe than of a
concerned and compassionate state.[108]

In 2002, Mbeki requested that HIV/AIDS denialists no

longer use his name in denialist literature, and requested
that denialists stop signing documents with Member
of President Mbekis AIDS Advisory Panel.[99] This
coincided with the South African governments statement accompanying its 2002 AIDS campaign, that "...in
conducting this campaign, governments starting point
is based on the premise that HIV causes AIDS.[112]
Nonetheless, Mbeki himself continued to promote and
defend AIDS-denialist claims. His loyalists attacked former President Nelson Mandela in 2002 when Mandela
questioned the governments AIDS policy, and Mbeki
attacked Malegapuru William Makgoba, one of South
Africas leading scientists, as a racist defender of Western science for opposing HIV/AIDS denialism.[48]
In early 2005, former South African president Nelson
Mandela announced that his son had died of complications of AIDS. Mandelas public announcement was seen
as both an eort to combat the stigma associated with
AIDS, and as a political statement designed to force
the President [Mbeki] out of his denial.[113][114]

Post Mbeki government in South Africa

47

6.5 See also

Discredited HIV/AIDS origins theories
Misconceptions about HIV and AIDS
Retro - the October 28, 2008 episode of the TV
series Law & Order: Special Victims Unit, which
focuses on an AIDS denialist doctor and the HIVpositive patients he has inuenced.

6.6 Footnotes
[1] Confronting AIDS: Update 1988. Institute of Medicine
of the U.S. National Academy of Sciences. 1988. the
evidence that HIV causes AIDS is scientically conclusive.
[2] The Evidence that HIV Causes AIDS. National Institute of Allergy and Infectious Disease. 4 September 2009.
Retrieved 14 October 2009.
[3] Kalichman 2009, p. 205.
[4] Cohen, J. (1994).
Duesberg and critics agree:
hemophilia is the best test.
Science 266 (5191):
16451646.
Bibcode:1994Sci...266.1645C.
doi:10.1126/science.7992044. PMID 7992044.
[5] Kalichman 2009.
[6] Kalichman, Seth C. (1 January 2014). The Psychology
of AIDS Denialism. European Psychologist 19 (1): 13
22. doi:10.1027/1016-9040/a000175.
[7] Denying science. Nat. Med. 12 (4): 369. 2006.
doi:10.1038/nm0406-369. PMID 16598265. To support
their ideas, some AIDS denialists have also misappropriated a scientic review in Nature Medicine which opens
with this reasonable statement: Despite considerable advances in HIV science in the past 20 years, the reason why
HIV-1 infection is pathogenic is still debated.
[8] Smith, TC; Novella, SP (August 2007). HIV denial in the internet era. PLOS Medicine 4 (8): e256.
doi:10.1371/journal.pmed.0040256.
PMC 1949841.
PMID 17713982. Archived from the original on 6 May
2008.
[9] Steinberg, J (17 June 2009). AIDS denial: A lethal delusion. New Scientist 2713. Retrieved 14 October 2009.
[10] Cohen

(December

1994).

The

Duesberg

In 2008, Mbeki was ousted from power and replaced

(PDF).
Science
266
(5191):
phenomenon
as President of South Africa by Kgalema Motlanthe.
16424.
Bibcode:1994Sci...266.1642C.
On Motlanthes rst day in oce, he removed Manto
doi:10.1126/science.7992043.
PMID 7992043.
Tshabalala-Msimang, the controversial health minister
Retrieved 22 June 2009.
who had promoted AIDS-denialist claims and recommended garlic, beetroot, and lemon juice as treatments [11] Watson J. (2006). Scientists, activists sue South
Africas AIDS 'denialists". Nat Med. 12 (1): 6.
for AIDS. Barbara Hogan, newly appointed as health
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minister, voiced shame at the Mbeki governments embrace of HIV/AIDS denialism and vowed a new course, [12] Boseley, S (14 May 2005). Discredited doctors 'cure' for
stating: The era of denialism is over completely in South
Aids ignites life-and-death struggle in South Africa. The
Guardian (London). Retrieved 14 October 2009.
Africa.[48]

48

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49

[41] Farber, C (March 2006). Out of control: AIDS and

the corruption of medical science. Harpers Magazine.
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[56] Moore, John (16 May 2008). How Immunoassays Work:

The Curious Case of AIDS Denialist Roberto Giraldo and
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[42] Miller, L (13 March 2006). An article in Harpers ignites

a controversy over HIV. The New York Times. Retrieved
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[57] Steinberg, J (23 June 2009). Five myths about HIV and
AIDS. New Scientist. Retrieved 4 February 2011.

[43] Gallo, R; Geen, N; Gonsalves, G; Jeerys, R; Kuritzkes, DR; Mirken, B; Moore, JP; Safrit, JT (25 March
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17 December 2008.
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Turner and Robin Weiss. virusmyth.com.
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modern anti-HIV therapy include, but are not limited to:
Lima V, Hogg R, Harrigan P, Moore D, Yip
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Ivers L, Kendrick D, Doucette K (2005). Ecacy of antiretroviral therapy programs in resourcepoor settings: a meta-analysis of the published
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Mocroft A, Ledergerber B, Katlama C, Kirk O,
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Sterne J, Hernn M, Ledergerber B, Tilling K, Weber R, Sendi P, Rickenbach M, Robins J, Egger
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[64] Rohleder, P; Swartz, L; Kalichman, SC (2009).

HIV/AIDS in South Africa 25 years On: Psychosocial
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[78] Delaney, M (2005). HIV, AIDS, and the distortion of
science. Focus 15 (6). pp. 16. Archived from the original on 4 June 2011. Retrieved 9 June 2011.
[79] Lederer, B (1 April 2006). Dead Certain?". POZ.
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[83] Mirken, B (2 February 2000). Bad science: They once
thought HIV was harmless. Now, they say, AIDS has
forced them to reconsider. San Francisco Bay Guardian.
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[84] Ornstein, C; Costello, D (24 September 2005). A

mothers denial, a daughters death. Los Angeles Times.
Archived from the original on 22 December 2008. Retrieved 29 December 2008.
[85] Hennessy-Fiske, M (6 March 2009). Suit settled on autopsy of HIV skeptics child. The Los Angeles Times.
[86] Gray, Adrian. The Politics of AIDS Denialism: South
Africas Failure to Respond - By Pieter Fourie and Melissa
Meyer. Political Studies Review 10 (2): 309309.
doi:10.1111/j.1478-9302.2012.00269_2.x.
[87] Biography of John Lauritsen. virusmyth.com. Retrieved
7 September 2006.
[88] Lauritsen, John (1993). The AIDS War. New York: Pagan Press. p. 4. ISBN 0-943742-08-0.
[89] Booth, W (1988).
A rebel without a
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doi:10.1126/science.3281251. PMID 3281251.
[90] Epstein, S (1996). Impure Science: AIDS, Activism, and
the Politics of Knowledge. Berkeley: University of California Press. p. 118. ISBN 0520202333.
[91] Burkett, E (1996) The Gravest Show on Earth (Chapter
2) ISBN 0-312-14607-8
[92] Censorship. virusmyth.com. Retrieved 2 June 2006.
[93] Schmidt, WE (10 December 1993). British paper and
science journal clash on AIDS. The New York Times.
Retrieved 25 April 2008.
[94] Duesberg, PH (1989). Human immunodeciency virus
and acquired immunodeciency syndrome: Correlation but not causation. Proceedings of the National
Academy of Sciences of the United States of America 86 (3): 75564. Bibcode:1989PNAS...86..755D.
doi:10.1073/pnas.86.3.755.
PMC 286556.
PMID
2644642.
[95] May, M. T.; Sterne, J. A.; Costagliola, D.; Sabin, C.
A.; Phillips, A. N.; Justice, A. C.; Dabis, F.; Gill,
J.; Lundgren, J.; Hogg, R. S.; De Wolf, F.; Ftkenheuer, G.; Staszewski, S.; d'Arminio Monforte, A.; Egger, M.; Antiretroviral Therapy (ART) Cohort Collaboration (2006). HIV treatment response and prognosis in
Europe and North America in the rst decade of highly
active antiretroviral therapy: A collaborative analysis.
The Lancet 368 (9534): 451458. doi:10.1016/S01406736(06)69152-6. PMID 16890831.
[96] Deer, B (21 February 2012). Death by denial: The campaigners who continue to deny HIV causes Aids. The
Guardian.
[97] Hutchinson, AB; Begley, EB; et al. (2005). Mistrust and
conspiracy beliefs about HIV/AIDS among participants in
minority gay pride events. 2005 National HIV Prevention
Conference: Abstract TP-011.
[98] France, D (19 August 2000). The HIV Disbelievers.
Newsweek.

6.8. FURTHER READING

[99] The Politics of HIV/AIDS in South Africa. JournAIDS.

HIV & AIDS Media Project. Archived from the original
on 2 July 2007. Retrieved 26 February 2007.
[100] Controversy dogs AIDS forum. BBC News. 10 July
2000. Retrieved 26 February 2007.
[101] Schoof, M (511 July 2000). Proof positive: How
African science has demonstrated that HIV causes AIDS.
Village Voice. Retrieved 20 April 2007.
[102] Gellman, B (19 April 2000). South African president
escalates AIDS feud. Washington Post. Retrieved 26
February 2007. (subscription required (help)).
[103] Thom, A (21 August 2006). Beetroot battle at world
AIDS conference. Health-e. Retrieved 9 March 2007.
[104] "'Dr Beetroot' hits back at media over Aids exhibition.
Mail & Guardian. Retrieved 20 September 2006.

51

6.8 Further reading

Fourie, P (2006). The Political Management of HIV
and AIDS in South Africa: One Burden Too Many?.
Palgrave Macmillan. ISBN 0230006671.
Steinberg, J (23 June 2009). Five myths about HIV
and AIDS. New Scientist. Archived from the original on 2 January 2010. Retrieved 25 December
2009.
Nicoli Nattrass: The AIDS Conspiracy: Science
Fights Back: New York: Columbia University Press:
2012.

6.9 External links

[105] Manto again angers AIDS activists. AEGIS.com. Retrieved 20 September 2006.

National Institute of Allergy and Infectious Diseases

pages on the HIV-AIDS connection and evidence
that HIV causes AIDS

[106] Nattrass, N. AIDS, science and governance (PDF). aidstruth.org. Archived from the original (PDF) on 23 June
2006.

Series of articles in Science magazine examining denialist claims

[107] SAMA calls for end to misrepresentation on treatment of

AIDS (Press release). South African Medical Association. 29 August 2006. Retrieved 12 March 2007.
[108] Leonard, T (6 September 2006). Scientists rip S. African
AIDS policies. Washington Post. Retrieved 5 March
2007.
[109] Bevan, S (12 November 2006). African minister ends
decade of denial over AIDS. The Daily Telegraph (London). Archived from the original on 25 February 2007.
Retrieved 5 March 2007.
[110] Sacked S Africa minister hits out. BBC News. 10 August 2007. Retrieved 11 August 2007.
[111] Current Developments Preventing Mother-To-Child
HIV Transmission In South Africa: Background, Strategies And Outcomes Of The Treatment Action Campaign
Case Against The Minister Of Health.
[112] AIDS in South Africa: Treatment, transmission and the
government. avert.org.
[113] Robinson, S (9 January 2005). No place for denial.
Time. Retrieved 26 February 2007.
[114] Happold, T (6 January 2005). Mandelas eldest son dies
of AIDS. The Guardian. Retrieved 9 March 2007.

6.7 References
Kalichman, Seth (2009). Denying AIDS: Conspiracy Theories, Pseudoscience, and Human Tragedy.
New York: Copernicus Books (Springer Science+Business Media). ISBN 9780387794754.

Avert.org: Evidence that HIV causes AIDS

AidsTruth.org, an organization that advocates
against AIDS denialism

Chapter 7

Subtypes of HIV
One of the obstacles to treatment of the human immunodeciency virus is its high genetic variability.[1] HIV can
be divided into two major types, HIV type 1 (HIV-1) and
HIV type 2 (HIV-2). HIV-1 is related to viruses found in
chimpanzees and gorillas living in western Africa, while
HIV-2 viruses are related to viruses found in the endangered west African primate sooty mangabey.[2] HIV-1
viruses may be further divided into groups. The HIV-1
group M viruses predominate and are responsible for the
AIDS pandemic. Group M can be further subdivided into
subtypes based on genetic sequence data. Some of the
subtypes are known to be more virulent or are resistant
to dierent medications. Likewise, HIV-2 viruses are
thought to be less virulent and transmissible than HIV1 M group viruses, although HIV-2 is known to cause
AIDS.

Subtype B is the dominant form in Europe, the

Americas, Japan, Thailand, and Australia.[5]

7.1 Major types

Subtype H is limited to central Africa.[6]

7.1.1

(Subtype I) was originally used to describe a strain

that is now accounted for as CRF04_cpx, with the
cpx for a complex recombination of several subtypes.

HIV-1

HIV-1 is the most common and pathogenic strain of the

virus. Scientists divide HIV-1 into a major group (Group
M) and two or more minor groups. Each group is believed to represent an independent transmission of SIV
into humans (but subtypes within a group are not).[2] A total of 39 ORFs are found in all six possible reading frames
(RFs) of HIV-1 complete genome sequence,[3] but only a
few of them are functional.

Subtype C is the dominant form in Southern Africa,

Eastern Africa, India, Nepal, and parts of China.[5]
Subtype D is generally only seen in Eastern and central Africa.[5]
(Subtype E) has never been identied as a nonrecombinant, only recombined with subtype A as
CRF01_AE.[5]
Subtype F has been found in central Africa, South
America and Eastern Europe.[6]
Subtype G (and the CRF02_AG) have been found
in Africa and central Europe.[6]

Subtype J is primarily found in North, Central and

West Africa, and the Caribbean[7]
Subtype K is limited to the Democratic Republic of
Congo and Cameroon.[6]

These subtypes are sometimes further split into subsubtypes such as A1 and A2 or F1 and F2. In 2015, the
Group M
strain CRF19, a recombinant of subtype A, subtype D
and subtype G, with a subtype D protease, was found to
With 'M' for major, this is by far the most common type be strongly associated with rapid progression to AIDS in
of HIV, with more than 90% of HIV/AIDS cases deriv- Cuba.[8] This is not thought to be a complete or nal list,
ing from infection with HIV-1 group M. The M group is and further types are likely to be found.[9]
subdivided further into clades, called subtypes, that are
also given a letter. There are also circulating recombinant forms or CRFs derived from recombination be- Group N
tween viruses of dierent subtypes which are each given
a number. CRF12_BF, for example, is a recombination The 'N' stands for non-M, non-O. This group was disbetween subtypes B and F.
covered in 1998 and has only been seen in Cameroon.
As of 2006, only 10 Group N infections had been
Subtype A is common in West Africa.[4]
identied.[10]
52

7.1. MAJOR TYPES

53
which spread considerably in humans (HIV-2 groups A
and B) is the SIVsmm found in the sooty mangabeys of
the Tai forest, in western Ivory Coast.[18]

HIV-1 subtype prevalence in 2002

Group O
The O (Outlier) group is not usually seen outside of
West-central Africa. It is reportedly most common in
Cameroon, where a 1997 survey found that about 2% of
HIV-positive samples were from Group O.[11] The group
caused some concern because it could not be detected by
early versions of the HIV-1 test kits. More advanced HIV
tests have now been developed to detect both Group O
and Group N.[12]
Group P
In 2009, a newly analyzed HIV sequence was reported
to have greater similarity to a simian immunodeciency
virus recently discovered in wild gorillas (SIVgor) than
to SIVs from chimpanzees (SIVcpz). The virus had been
isolated from a Cameroonian woman residing in France
who was diagnosed with HIV-1 infection in 2004. The
scientists reporting this sequence placed it in a proposed
Group P pending the identication of further human
cases.[13][14][15]

7.1.2

HIV-2

HIV-2 has not been widely seen outside of Africa. The

rst case in the United States was in 1987.[16] Many test
kits for HIV-1 will also detect HIV-2.[17]
As of 2010, there are 8 known HIV-2 groups (A to H). Of
these, only groups A and B are epidemic. Group A spread
mainly in West Africa, but also to Angola, Mozambique,
Brazil, India, and very limitedly to Europe or the US.
Group B is mainly conned to West Africa.[18][19] Despite its relative connement, HIV-2 should be considered
in all patients exhibiting symptoms of HIV that not only
come from West Africa, but also anyone who has had any
body uid transfer with a person from West Africa (i.e.
needle sharing, sexual contact, etc.).[20]
HIV-2 is closely related to simian immunodeciency
virus endemic in sooty mangabeys (Cercocebus atys atys)
(SIVsmm), a monkey species inhabiting the forests of Littoral West Africa. Phylogenetic analyses show that the
virus most closely related to the two strains of HIV-2

There are six additional known HIV-2 groups, each having been found in just one person. They all seem to derive
from independent transmissions from sooty mangabeys to
humans. Groups C and D have been found in two people from Liberia, groups E and F have been discovered
in two people from Sierra Leone, and groups G and H
have been detected in two people from the Ivory Coast.
Each of these HIV-2 strains, for which humans are probably dead-end hosts, is most closely related to SIVsmm
strains from sooty mangabeys living in the same country
where the human infection was found.[18][19]
Diagnosis
HIV-2 diagnosis can be made when a patient has no
symptoms but positive blood work indicating the individual has HIV. The Multispot HIV-1/HIV-2 Rapid Test is
currently the only FDA approved method for such differentiation between the two viruses. Recommendations
for the screening and diagnosis of HIV has always been
to use enzyme immunoassays that detect HIV-1, HIV-1
group O, and HIV-2.[20] When screening the combination, if the test is positive followed by an indeterminate
HIV-1 western blot, a follow up test, such as amino acid
testing, must be performed to distinguish which infection
is present.[21] According to the NIH, a dierential diagnosis of HIV-2 should be considered when a person is of
West African descent or has had sexual contact or shared
needles with such a person. West Africa is at the highest
risk as it is the origin of the virus.
Treatments
HIV-2 has been found to be less pathogenic than HIV1. The mechanism of HIV-2 is not clearly dened, nor
the dierence from HIV-1, however the transmission
rate is much lower in HIV-2 than HIV-1. Both infections can lead to AIDS in aected individuals and both
can mutate to develop drug resistance.[20] Disease Monitoring in patients with HIV-2 includes clinical evaluation and CD4 cell counts, while treatment includes AntiRetroviral Therapy (ART), Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Protease Inhibitors (PI),
and Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs) with the addition of CCR5 co-receptor antagonists and fusion inhibitors.[22] Choice of initial and/or
second-line therapy for HIV-2 has not yet been dened.
HIV-2 appears to be resistant to NNRTIs intrinsically,
but may be sensitive to NRTIs, though the mechanism is
poorly understood. Protease inhibitors have shown variable eect, while integrase inhibitors are also being evaluated. Combination regimens of the above listed therapies are being looked into as well, also showing variable eect depending on the types of therapies com-

54

CHAPTER 7. SUBTYPES OF HIV

bined. While the mechanisms are not clearly understood

for HIV-1 and HIV-2, it is known that they use dierent pathways and patterns, making the algorithms used
to evaluate HIV-1 resistance-associated mutations irrelevant to HIV-2.[20] Each virus can be contracted individually, or they can be contracted together in what is
referred to as co-infection. HIV-2 seems to have lower
mortality rates than HIV-1 alone or the co-infection. In
co-infection, however, this is largely dependent on which
virus was contracted rst. HIV-1 tends to out compete
HIV-2 for disease progression. Co-infection seems to be
a growing problem globally as time progresses, with most
cases being identied in West African countries, as well
as some cases in the US.[22]

Pregnancy
If a pregnant mother is exposed, screening is performed
as normal. If HIV-2 is present, a number of perinatal
ART drugs may be given as a prophylactic to lower the
risk of mother-to-child transmission. After the child is
born, a standard 6-week regimen of these prophylactics
should be initiated. Breast milk may also contain particles of HIV-2; therefore, breastfeeding is strictly advised
against.[21]

7.2 Evolution
The AIDS virus is evolving to a milder form but is an
awfully long way from no longer being deadly.[23]

7.2.1

Drug resistance mutations

7.4 References
[1] Robertson DL, Hahn BH, Sharp PM; Hahn; Sharp (March
1995). Recombination in AIDS viruses. J. Mol. Evol.
40 (3): 24959. doi:10.1007/BF00163230. PMID
7723052.
[2] Sharp, P. M.; Hahn, B. H. (2011). Origins of
HIV and the AIDS Pandemic (PDF). Cold Spring
Harbor Perspectives in Medicine 1 (1): a006841
doi:10.1101/cshperspect.a006841.
PMC
a006835.
3234451. PMID 22229120.
[3] Dhar, D. V., Amit, P., & Kumar, M. S. In-Silico Identication of New Genes in HIV-1 by ORF Prediction
Method. I. Res. J. Biological Sci., 1(7), 52-54(2012)
[4] Bobkov AF, Kazennova EV, Selimova LM; et al. (October 2004). Temporal trends in the HIV-1 epidemic in
Russia: predominance of subtype A. J. Med. Virol. 74
(2): 1916. doi:10.1002/jmv.20177. PMID 15332265.
[5] Goudsmit, Jaap. Viral Sex; The Nature of AIDS. Oxford
University Press. New York, New York, 1997. Pg. 51-58.
Retrieved May 25, 2008.
[6] Introduction to HIV types, groups and subtypes. March
3, 2008. Retrieved May 25, 2008.
[7] Hemelaar J, Gouws E, Ghys PD, Osmanov S.; Gouws;
Ghys; Osmanov (March 2006).
Global and regional distribution of HIV-1 genetic subtypes and
recombinants in 2004.
AIDS 20 (16): W13
23. doi:10.1097/01.aids.0000247564.73009.bc. PMID
17053344.
[8] CRF19_cpx is an Evolutionary t HIV-1 Variant Strongly Associated With Rapid Progression to
AIDS in Cuba. EBioMedicine. 28 January 2015.
doi:10.1016/j.ebiom.2015.01.015. Retrieved 17 Feb
2015.

Isolates of HIV-1 and HIV-2 with resistance to antiretro- [9] HIV types, subtypes, groups & strains
viral drugs arise through genetic mutations, which have
been tracked and analyzed. The Stanford HIV Drug Re- [10] Julie Yamaguchi, Ruthie Coey, Ana Vallari, Charlotte
sistance Database and the International AIDS Society
Ngansop, Dora Mbanya, Nicaise Ndembi, Lazare Kaptu, Lutz G. Grtler, Pierre Bodelle, Gerald Schochetpublish lists of the most important of these; rst year listman, Sushil G. Devare, Catherine A. Brennan (January
ing 80 common mutations, and the latest year 93 common
2006). Identication of HIV Type 1 Group N Infections
mutations, and made available through the Stanford HIV
in a Husband and Wife in Cameroon: Viral Genome SeRT and Protease Sequence Database.

quences Provide Evidence for Horizontal Transmission.

AIDS Research and Human Retroviruses 22 (1): 8392.
doi:10.1089/aid.2006.22.83. PMID 16438650.

7.3 See also

HIV superinfection
HIV/AIDS research
Discovery and development of CCR5 receptor antagonists
The Origin of HIV and AIDS

[11] Peeters M, Gueye A, Mboup S, Bibollet-Ruche F, Ekaza

E, Mulanga C, Ouedrago R, Gandji R, Mpele P, Dibanga
G, Koumare B, Saidou M, Esu-Williams E, Lombart JP,
Badombena W, Luo N, Vanden Haesevelde M, Delaporte E (March 1997). Geographical distribution of
HIV-1 group O viruses in Africa. AIDS 11 (4): 493
8. doi:10.1097/00002030-199704000-00013. PMID
9084797.
[12] http://www.abbottmolecular.com/PDF/E0608633_
RealTimeHIV_rev.pdf

7.5. EXTERNAL LINKS

[13] Plantier JC, Leoz M, Dickerson JE, De Oliveira F, Cordonnier F, Leme V, Damond F, Robertson DL, Simon F
(August 2009). A new human immunodeciency virus
derived from gorillas. Nature Medicine 15 (8): 8712.
doi:10.1038/nm.2016. PMID 19648927.
[14] New HIV strain discovered. Associated Press (CBC
News). 2009-08-03. Retrieved 2009-08-03.
[15] Donald G. McNeil, Jr. (September 16, 2010). Precursor
to H.I.V. Was in Monkeys for Millennia. New York
Times. Retrieved 2010-09-17. But P appears to have
crossed over from a gorilla; it was discovered only last
year, and in only one woman, who was from Cameroon,
where lowland gorillas are hunted for meat.
[16] HIV-2
[17] CBER - Donor Screening Assays for Infectious Agents
and HIV Diagnostic Assays
[18] Santiago, Mario L.; Range, Friederike; Keele, Brandon
F.; Li, Yingying; Bailes, Elizabeth; Bibollet-Ruche, Frederic; Fruteau, Cecile; No, Ronald; Peeters, Martine;
Brookeld, John F. Y.; Shaw, George M.; Sharp, Paul M.;
Hahn, Beatrice H. (2005). Simian Immunodeciency
Virus Infection in Free-Ranging Sooty Mangabeys (Cercocebus atys atys) from the Ta Forest, Cte d'Ivoire: Implications for the Origin of Epidemic Human Immunodeciency Virus Type 2. Journal of Virology 79 (19):
1251527. doi:10.1128/JVI.79.19.12515-12527.2005.
PMC 1211554. PMID 16160179.
[19] Marx PA, Alcabes PG, Drucker E (2001). Serial human
passage of simian immunodeciency virus by unsterile injections and the emergence of epidemic human immunodeciency virus in Africa. Philos Trans R Soc Lond B Biol
Sci 356 (1410): 91120. doi:10.1098/rstb.2001.0867.
PMC 1088484. PMID 11405938.
[20] http://aidsinfo.nih.gov/guidelines
[21] Human Immunodeciency Virus Type 2 (HIV-2) by New
York State Department of Health AIDS Institute: http:
//www.hivguidelines.org
[22] R Kannangai, S David, G Sridharan. Human immunodeciency virus type 2-A milder, kinder virus: An update.
Indian Journal of Medical Micobiology, (2012) 30(1): 615.
[23] HIV evolving 'into milder form'

7.5 External links

HIV/AIDS at DMOZ
HIV Types at Avert.org
3D macromolecular structures of HIV-1 at the EM
Data Bank(EMDB)

55

Chapter 8

HIV/AIDS
This article is about the disease. For the virus, see HIV. large area and is actively spreading.[14] Genetic research
For other uses, see AIDS (disambiguation).
indicates that HIV originated in west-central Africa during the late 19th or early 20th century.[15] AIDS was
rst recognized by the United States Centers for Disease
Human immunodeciency virus infection and acquired immune deciency syndrome (HIV/AIDS) is Control and Prevention (CDC) in 1981 and its cause
HIV infectionwas identied in the early part of the
a spectrum of conditions caused by infection with the
[16]
human immunodeciency virus (HIV).[2][3][4] It may also decade.
be referred to as HIV disease or HIV infection.[5][6] Following initial infection, a person may experience a brief
period of inuenza-like illness. This is typically followed
by a prolonged period without symptoms. As the infection progresses, it interferes more and more with the
immune system, making the person much more susceptible to common infections, like tuberculosis, as well as
opportunistic infections and tumors that do not usually
aect people who have working immune systems. The
late symptoms of the infection are referred to as AIDS.
This stage is often complicated by an infection of the lung
known as pneumocystis pneumonia, severe weight loss,
skin lesions caused by Kaposis sarcoma, or other AIDSdening conditions.
HIV is transmitted primarily via unprotected sexual intercourse (including anal and oral sex), contaminated
blood transfusions, hypodermic needles, and from mother
to child during pregnancy, delivery, or breastfeeding.[7]
Some bodily uids, such as saliva and tears, do not
transmit HIV.[8] Common methods of HIV/AIDS prevention include encouraging and practicing safe sex,
needle-exchange programs, and treating those who are
infected.[9] There is no cure or vaccine; however,
antiretroviral treatment can slow the course of the disease
and may lead to a near-normal life expectancy. While antiretroviral treatment reduces the risk of death and complications from the disease, these medications are expensive and have side eects. Treatment is recommended
as soon as the diagnosis is made.[10] Without treatment,
the average survival time after infection with HIV is
estimated to be 9 to 11 years, depending on the HIV
subtype.[11]
Since its discovery, AIDS has caused an estimated 36
million deaths worldwide (as of 2012).[12] In 2014 it resulted in about 1.2 million deaths and about 36.9 million
people were living with HIV.[13] HIV/AIDS is considered
a pandemica disease outbreak which is present over a

HIV/AIDS has had a great impact on society, both as an

illness and as a source of discrimination. The disease
also has signicant economic impacts. There are many
misconceptions about HIV/AIDS such as the belief that it
can be transmitted by casual non-sexual contact. The disease has become subject to many controversies involving
religion. It has attracted international medical and political attention as well as large-scale funding since it was
identied in the 1980s.[17]

8.1 Signs and symptoms

Main article: Signs and symptoms of HIV/AIDS
There are three main stages of HIV infection: acute infection, clinical latency and AIDS.[18][5]

8.1.1 Acute infection

The initial period following the contraction of HIV
is called acute HIV, primary HIV or acute retroviral syndrome.[18][19] Many individuals develop an
inuenza-like illness or a mononucleosis-like illness 2
4 weeks post exposure while others have no signicant symptoms.[20][21] Symptoms occur in 4090% of
cases and most commonly include fever, large tender
lymph nodes, throat inammation, a rash, headache,
and/or sores of the mouth and genitals.[19][21] The rash,
which occurs in 2050% of cases, presents itself on the
trunk and is maculopapular, classically.[22] Some people also develop opportunistic infections at this stage.[19]
Gastrointestinal symptoms such as nausea, vomiting or
diarrhea may occur, as may neurological symptoms of
peripheral neuropathy or Guillain-Barre syndrome.[21]
The duration of the symptoms varies, but is usually one

56

8.1. SIGNS AND SYMPTOMS

57

Main symptoms of

8.1.3 Acquired
drome

Acute HIV infection

Systemic:
- Fever
- Weight loss
Pharyngitis
Mouth:
- Sores
- Thrush

Esophagus:
- Sores

Central:
- Malaise

syn-

Main symptoms of

AIDS

- Headache
- Neuropathy

Lymph nodes:
- Lymphadenopathy

Central
- Encephalitis
- Meningitis

Skin:
- Rash

Eyes
- Retinitis

Muscles:
- Myalgia

Gastric:
-Nausea
-Vomiting

Liver and
spleen:
- Enlargement

immunodeciency

Main symptoms of acute HIV infection

[21]

or two weeks.

Lungs
- Pneumocystis
pneumonia
- Tuberculosis
(multiple organs)
- Tumors
Skin
- Tumors

Gastrointestinal
Due to their nonspecic character, these symptoms are
- Esophagitis
not often recognized as signs of HIV infection. Even
- Chronic diarrhea
cases that do get seen by a family doctor or a hospi- Tumors
tal are often misdiagnosed as one of the many common
infectious diseases with overlapping symptoms. Thus, it
Main symptoms of AIDS.
is recommended that HIV be considered in people presenting an unexplained fever who may have risk factors
Acquired immunodeciency syndrome (AIDS) is dened
for the infection.[21]
in terms of either a CD4+ T cell count below 200 cells
per L or the occurrence of specic diseases in association with an HIV infection.[21] In the absence of specic treatment, around half of people infected with HIV
8.1.2 Clinical latency
develop AIDS within ten years.[21] The most common
The initial symptoms are followed by a stage called clini- initial conditions that alert to the presence of AIDS are
cal latency, asymptomatic HIV, or chronic HIV.[5] With- pneumocystis pneumonia (40%), cachexia in the form of
wasting syndrome (20%), and esophageal candidiaout treatment, this second stage of the natural history of HIV
sis.[21] Other common signs include recurring respiratory
[23]
HIV infection can last from about three years to over
[21]
20 years[24] (on average, about eight years).[25] While typ- tract infections.

ically there are few or no symptoms at rst, near the end

of this stage many people experience fever, weight loss,
gastrointestinal problems and muscle pains.[5] Between
50 and 70% of people also develop persistent generalized
lymphadenopathy, characterized by unexplained, nonpainful enlargement of more than one group of lymph
nodes (other than in the groin) for over three to six
months.[18]
Although most HIV-1 infected individuals have a detectable viral load and in the absence of treatment
will eventually progress to AIDS, a small proportion
(about 5%) retain high levels of CD4+ T cells (T helper
cells) without antiretroviral therapy for more than 5
years.[21][26] These individuals are classied as HIV controllers or long-term nonprogressors (LTNP).[26] Another group consists of those who maintain a low or
undetectable viral load without anti-retroviral treatment,
known as elite controllers or elite suppressors. They
represent approximately 1 in 300 infected persons.[27]

Opportunistic infections may be caused by bacteria,

viruses, fungi, and parasites that are normally controlled
by the immune system.[28] Which infections occur depends partly on what organisms are common in the persons environment.[21] These infections may aect nearly
every organ system.[29]
People with AIDS have an increased risk of developing various viral-induced cancers, including Kaposis sarcoma, Burkitts lymphoma, primary central nervous system lymphoma, and cervical cancer.[22] Kaposis sarcoma
is the most common cancer occurring in 10 to 20% of
people with HIV.[30] The second most common cancer
is lymphoma, which is the cause of death of nearly 16%
of people with AIDS and is the initial sign of AIDS in 3
to 4%.[30] Both these cancers are associated with human
herpesvirus 8.[30] Cervical cancer occurs more frequently
in those with AIDS because of its association with human
papillomavirus (HPV).[30] Conjunctival cancer (of the
layer that lines the inner part of eyelids and the white part

58

CHAPTER 8. HIV/AIDS

of the eye) is also more common in those with HIV.[31]

sexually transmitted infections[51] and genital ulcers.[45]

Genital ulcers appear to increase the risk approximately
vefold.[45] Other sexually transmitted infections, such as
gonorrhea, chlamydia, trichomoniasis, and bacterial vaginosis, are associated with somewhat smaller increases in
risk of transmission.[50]

Additionally, people with AIDS frequently have systemic

symptoms such as prolonged fevers, sweats (particularly
at night), swollen lymph nodes, chills, weakness, and
unintended weight loss.[32] Diarrhea is another common
symptom, present in about 90% of people with AIDS.[33]
They can also be aected by diverse psychiatric and neu- The viral load of an infected person is an imporrological symptoms independent of opportunistic infec- tant risk factor in both sexual and mother-to-child
tions and cancers.[34]
transmission.[52] During the rst 2.5 months of an HIV
infection a persons infectiousness is twelve times higher
due to this high viral load.[50] If the person is in the
late stages of infection, rates of transmission are approx8.2 Transmission
imately eightfold greater.[45]
HIV is transmitted by three main routes: sexual contact, exposure to infected body uids or tissues, and from
mother to child during pregnancy, delivery, or breastfeeding (known as vertical transmission).[7] There is no risk
of acquiring HIV if exposed to feces, nasal secretions,
saliva, sputum, sweat, tears, urine, or vomit unless these
are contaminated with blood.[42] It is possible to be coinfected by more than one strain of HIVa condition
known as HIV superinfection.[43]

8.2.1

Sexual

Commercial sex workers (including those in pornography) have an increased rate of HIV.[53][54] Rough sex
can be a factor associated with an increased risk of
transmission.[55] Sexual assault is also believed to carry
an increased risk of HIV transmission as condoms are
rarely worn, physical trauma to the vagina or rectum is
likely, and there may be a greater risk of concurrent sexually transmitted infections.[56]

8.2.2 Body uids

The most frequent mode of transmission of HIV is

through sexual contact with an infected person.[7] The
majority of all transmissions worldwide occur through
heterosexual contacts (i.e. sexual contacts between people of the opposite sex);[7] however, the pattern of transmission varies signicantly among countries. In the
United States, as of 2009, most sexual transmission occurred in men who had sex with men,[7] with this population accounting for 64% of all new cases.[44]
With regard to unprotected heterosexual contacts, estimates of the risk of HIV transmission per sexual act appear to be four to ten times higher in low-income countries than in high-income countries.[45] In low-income
countries, the risk of female-to-male transmission is estimated as 0.38% per act, and of male-to-female transmission as 0.30% per act; the equivalent estimates for
high-income countries are 0.04% per act for female-tomale transmission, and 0.08% per act for male-to-female
transmission.[45] The risk of transmission from anal intercourse is especially high, estimated as 1.41.7% per
act in both heterosexual and homosexual contacts.[45][46]
While the risk of transmission from oral sex is relatively
low, it is still present.[47] The risk from receiving oral
sex has been described as nearly nil";[48] however, a few
cases have been reported.[49] The per-act risk is estimated
at 00.04% for receptive oral intercourse.[50] In settings
involving prostitution in low income countries, risk of
female-to-male transmission has been estimated as 2.4%
per act and male-to-female transmission as 0.05% per
act.[45]

CDC poster from 1989 highlighting the threat of AIDS associated

with drug use

The second most frequent mode of HIV transmission is

via blood and blood products.[7] Blood-borne transmission can be through needle-sharing during intravenous
Risk of transmission increases in the presence of many drug use, needle stick injury, transfusion of contaminated

8.3. VIROLOGY
blood or blood product, or medical injections with unsterilised equipment. The risk from sharing a needle during
drug injection is between 0.63 and 2.4% per act, with
an average of 0.8%.[57] The risk of acquiring HIV from
a needle stick from an HIV-infected person is estimated
as 0.3% (about 1 in 333) per act and the risk following
mucous membrane exposure to infected blood as 0.09%
(about 1 in 1000) per act.[42] In the United States intravenous drug users made up 12% of all new cases of HIV
in 2009,[44] and in some areas more than 80% of people
who inject drugs are HIV positive.[7]

59
fant decrease the risk of transmission in those who do
breastfeed.[68] Many of these measures are however not
available in the developing world.[67] If blood contaminates food during pre-chewing it may pose a risk of
transmission.[63]

8.3 Virology
Main article: HIV
HIV is the cause of the spectrum of disease known

HIV is transmitted in about 93% of blood transfusions using infected blood.[57] In developed countries the risk of
acquiring HIV from a blood transfusion is extremely low
(less than one in half a million) where improved donor selection and HIV screening is performed;[7] for example,
in the UK the risk is reported at one in ve million[58] and
in the United States it was one in 1.5 million in 2008.[59]
In low income countries, only half of transfusions may
be appropriately screened (as of 2008),[60] and it is estimated that up to 15% of HIV infections in these areas come from transfusion of infected blood and blood
products, representing between 5% and 10% of global
infections.[7][61]
Unsafe medical injections play a signicant role in HIV
spread in sub-Saharan Africa. In 2007, between 12 and
17% of infections in this region were attributed to med- Diagram of a HIV virion structure
ical syringe use.[62] The World Health Organization estimates the risk of transmission as a result of a medical injection in Africa at 1.2%.[62] Signicant risks are also associated with invasive procedures, assisted delivery, and
dental care in this area of the world.[62]
People giving or receiving tattoos, piercings, and
scarication are theoretically at risk of infection but no
conrmed cases have been documented.[63] It is not possible for mosquitoes or other insects to transmit HIV.[64]

8.2.3

Mother-to-child

Main articles: HIV and pregnancy and HIV and breastfeeding

Scanning electron micrograph of HIV-1, colored green, budding
from a cultured lymphocyte.

HIV can be transmitted from mother to child during pregnancy, during delivery, or through breast milk.[65][66] This
is the third most common way in which HIV is transmitted globally.[7] In the absence of treatment, the risk
of transmission before or during birth is around 20%
and in those who also breastfeed 35%.[65] As of 2008,
vertical transmission accounted for about 90% of cases
of HIV in children.[65] With appropriate treatment the
risk of mother-to-child infection can be reduced to about
1%.[65] Preventive treatment involves the mother taking
antiretrovirals during pregnancy and delivery, an elective caesarean section, avoiding breastfeeding, and administering antiretroviral drugs to the newborn.[67] Antiretrovirals when taken by either the mother or the in-

as HIV/AIDS. HIV is a retrovirus that primarily infects

components of the human immune system such as CD4+
T cells, macrophages and dendritic cells. It directly and
indirectly destroys CD4+ T cells.[69]
HIV is a member of the genus Lentivirus,[70] part
of the family Retroviridae.[71] Lentiviruses share many
morphological and biological characteristics. Many
species of mammals are infected by lentiviruses, which
are characteristically responsible for long-duration illnesses with a long incubation period.[72] Lentiviruses are
transmitted as single-stranded, positive-sense, enveloped
RNA viruses. Upon entry into the target cell, the viral RNA genome is converted (reverse transcribed) into

60
double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome
in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host cofactors.[73] Once integrated, the virus may become latent,
allowing the virus and its host cell to avoid detection by
the immune system.[74] Alternatively, the virus may be
transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new
virus particles that begin the replication cycle anew.[75]
HIV is now known to spread between CD4+ T cells
by two parallel routes: cell-free spread and cell-to-cell
spread, i.e. it employs hybrid spreading mechanisms.[76]
In the cell-free spread, virus particles bud from an infected T cell, enter the blood/extracellular uid and then
infect another T cell following a chance encounter.[76]
HIV can also disseminate by direct transmission from one
cell to another by a process of cell-to-cell spread.[77][78]
The hybrid spreading mechanisms of HIV contribute
to the viruss ongoing replication against antiretroviral
therapies.[76][79]
Two types of HIV have been characterized: HIV-1 and
HIV-2. HIV-1 is the virus that was originally discovered
(and initially referred to also as LAV or HTLV-III). It is
more virulent, more infective,[80] and is the cause of the
majority of HIV infections globally. The lower infectivity of HIV-2 as compared with HIV-1 implies that fewer
people exposed to HIV-2 will be infected per exposure.
Because of its relatively poor capacity for transmission,
HIV-2 is largely conned to West Africa.[81]

8.4 Pathophysiology

CHAPTER 8. HIV/AIDS
ated with activation of CD8+ T cells, which kill HIVinfected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is
thought to be important in controlling virus levels, which
peak and then decline, as the CD4+ T cell counts recover.
A good CD8+ T cell response has been linked to slower
disease progression and a better prognosis, though it does
not eliminate the virus.[83]
Ultimately, HIV causes AIDS by depleting CD4+ T
cells. This weakens the immune system and allows
opportunistic infections. T cells are essential to the immune response and without them, the body cannot ght
infections or kill cancerous cells. The mechanism of
CD4+ T cell depletion diers in the acute and chronic
phases.[84] During the acute phase, HIV-induced cell lysis
and killing of infected cells by cytotoxic T cells accounts
for CD4+ T cell depletion, although apoptosis may also be
a factor. During the chronic phase, the consequences of
generalized immune activation coupled with the gradual
loss of the ability of the immune system to generate new
T cells appear to account for the slow decline in CD4+ T
cell numbers.[85]
Although the symptoms of immune deciency characteristic of AIDS do not appear for years after a person is infected, the bulk of CD4+ T cell loss occurs during the rst
weeks of infection, especially in the intestinal mucosa,
which harbors the majority of the lymphocytes found in
the body.[86] The reason for the preferential loss of mucosal CD4+ T cells is that the majority of mucosal CD4+
T cells express the CCR5 protein which HIV uses as a coreceptor to gain access to the cells, whereas only a small
fraction of CD4+ T cells in the bloodstream do so.[87] A
specic genetic change that alters the CCR5 protein when
present in both chromosomes very eectively prevents
HIV-1 infection.[88]

HIV seeks out and destroys CCR5 expressing CD4+ T

Main article: Pathophysiology of HIV/AIDS
[89]
A vigorous immune reAfter the virus enters the body there is a period of cells during acute infection.
sponse eventually controls the infection and initiates the
clinically latent phase. CD4+ T cells in mucosal tissues
remain particularly aected.[89] Continuous HIV replication causes a state of generalized immune activation persisting throughout the chronic phase.[90] Immune activation, which is reected by the increased activation state of
immune cells and release of pro-inammatory cytokines,
results from the activity of several HIV gene products and
the immune response to ongoing HIV replication. It is
also linked to the breakdown of the immune surveillance
system of the gastrointestinal mucosal barrier caused by
the depletion of mucosal CD4+ T cells during the acute
phase of disease.[91]
HIV/AIDS explained in a simple way
rapid viral replication, leading to an abundance of virus
in the peripheral blood. During primary infection, the
level of HIV may reach several million virus particles 8.5 Diagnosis
per milliliter of blood.[82] This response is accompanied
by a marked drop in the number of circulating CD4+ Main article: Diagnosis of HIV/AIDS
T cells. The acute viremia is almost invariably associ- HIV/AIDS is diagnosed via laboratory testing and then

8.5. DIAGNOSIS

61
the WHO disease staging system for HIV infection and
disease,[19] and the CDC classication system for HIV
infection.[95] The CDC's classication system is more
frequently adopted in developed countries. Since the
WHO's staging system does not require laboratory tests,
it is suited to the resource-restricted conditions encountered in developing countries, where it can also be used
to help guide clinical management. Despite their dierences, the two systems allow comparison for statistical
purposes.[18][19][95]

A generalized graph of the relationship between HIV copies

(viral load) and CD4+ T cell counts over the average course of
untreated HIV infection.
CD4+ T Lymphocyte count (cells/mm)
HIV RNA copies per mL of plasma

staged based on the presence of certain signs or symptoms.[19] HIV screening is recommended by the United
States Preventive Services Task Force for all people 15
years to 65 years of age including all pregnant women.[92]
Additionally, testing is recommended for those at high
risk, which includes anyone diagnosed with a sexually
transmitted illness.[22] In many areas of the world, a third
of HIV carriers only discover they are infected at an advanced stage of the disease, when AIDS or severe immunodeciency has become apparent.[22]

8.5.1

HIV testing

Most people infected with HIV develop specic

antibodies (i.e. seroconvert) within three to twelve weeks
of the initial infection.[21] Diagnosis of primary HIV
before seroconversion is done by measuring HIV-RNA
or p24 antigen.[21] Positive results obtained by antibody
or PCR testing are conrmed either by a dierent
antibody or by PCR.[19]
Antibody tests in children younger than 18 months are
typically inaccurate due to the continued presence of
maternal antibodies.[93] Thus HIV infection can only be
diagnosed by PCR testing for HIV RNA or DNA, or via
testing for the p24 antigen.[19] Much of the world lacks
access to reliable PCR testing and many places simply
wait until either symptoms develop or the child is old
enough for accurate antibody testing.[93] In sub-Saharan
Africa as of 20072009 between 30 and 70% of the population was aware of their HIV status.[94] In 2009, between 3.6 and 42% of men and women in Sub-Saharan
countries were tested[94] which represented a signicant
increase compared to previous years.[94]

8.5.2

Classications

Two main clinical staging systems are used to classify

HIV and HIV-related disease for surveillance purposes:

The World Health Organization rst proposed a denition for AIDS in 1986.[19] Since then, the WHO classication has been updated and expanded several times, with
the most recent version being published in 2007.[19] The
WHO system uses the following categories:
Primary HIV infection: May be either asymptomatic or associated with acute retroviral
syndrome.[19]
Stage I: HIV infection is asymptomatic with a
CD4+ T cell count (also known as CD4 count)
greater than 500 per microlitre (l or cubic mm)
of blood.[19] May include generalized lymph node
enlargement.[19]
Stage II: Mild symptoms which may include minor
mucocutaneous manifestations and recurrent upper
respiratory tract infections. A CD4 count of less
than 500/l.[19]
Stage III: Advanced symptoms which may include
unexplained chronic diarrhea for longer than a
month, severe bacterial infections including tuberculosis of the lung, and a CD4 count of less than
350/l.[19]
Stage IV or AIDS: severe symptoms which include toxoplasmosis of the brain, candidiasis of the
esophagus, trachea, bronchi or lungs and Kaposis
sarcoma. A CD4 count of less than 200/l.[19]
The United States Center for Disease Control and Prevention also created a classication system for HIV, and
updated it in 2008 and 2014.[95][96] This system classies
HIV infections based on CD4 count and clinical symptoms, and describes the infection in ve groups.[96] In
those greater than six years of age it is:[96]
Stage 0: the time between a negative or indeterminate HIV test followed less than 180 days by a positive test
Stage 1: CD4 count 500 cells/l and no AIDS
dening conditions
Stage 2: CD4 count 200 to 500 cells/l and no AIDS
dening conditions

62

CHAPTER 8. HIV/AIDS

Stage 3: CD4 count 200 cells/l or AIDS dening Circumcision in Sub-Saharan Africa reduces the acconditions
quisition of HIV by heterosexual men by between 38%
and 66% over 24 months.[102] Based on these stud Unknown: if insucient information is available to ies, the World Health Organization and UNAIDS both
make any of the above classications
recommended male circumcision as a method of preventing female-to-male HIV transmission in 2007.[103]
For surveillance purposes, the AIDS diagnosis still stands Whether it protects against male-to-female transmiseven if, after treatment, the CD4+ T cell count rises to sion is disputed[104][105] and whether it is of benet in
above 200 per L of blood or other AIDS-dening ill- developed countries and among men who have sex with
nesses are cured.[18]
men is undetermined.[106][107][108] The International Antiviral Society, however, does recommend for all sexually
active heterosexual males and that it be discussed as an
option with men who have sex with men.[109] Some ex8.6 Prevention
perts fear that a lower perception of vulnerability among
circumcised men may cause more sexual risk-taking beMain article: Prevention of HIV/AIDS
havior, thus negating its preventive eects.[110]
Programs encouraging sexual abstinence do not appear to
aect subsequent HIV risk.[111] Evidence of any benet
from peer education is equally poor.[112] Comprehensive
sexual education provided at school may decrease high
risk behavior.[113] A substantial minority of young people
continues to engage in high-risk practices despite knowing about HIV/AIDS, underestimating their own risk of
becoming infected with HIV.[114] Voluntary counseling
and testing people for HIV does not aect risky behavior in those who test negative but does increase condom
use in those who test positive.[115] It is not known whether
treating other sexually transmitted infections is eective
in preventing HIV.[51]

8.6.2 Pre-exposure
Antiretroviral treatment among people with HIV whose
CD4 count 550 cells/L is a very eective way to prevent HIV infection of their partner (a strategy known
as treatment as prevention, or TASP).[116] TASP is associated with a 10 to 20 fold reduction in transmission risk.[117][116] Pre-exposure prophylaxis (PrEP) with
a daily dose of the medications tenofovir, with or withAIDS Clinic, McLeod Ganj, Himachal Pradesh, India, 2010
out emtricitabine, is eective in a number of groups including men who have sex with men, couples where one
is HIV positive, and young heterosexuals in Africa.[100]
It may also be eective in intravenous drug users with
8.6.1 Sexual contact
a study nding a decrease in risk of 0.7 to 0.4 per 100
[118]
Consistent condom use reduces the risk of HIV trans- person years.
mission by approximately 80% over the long term.[97] Universal precautions within the health care environment
When condoms are used consistently by a couple in which are believed to be eective in decreasing the risk of
one person is infected, the rate of HIV infection is less HIV.[119] Intravenous drug use is an important risk factor
than 1% per year.[98] There is some evidence to sug- and harm reduction strategies such as needle-exchange
gest that female condoms may provide an equivalent level programmes and opioid substitution therapy appear efof protection.[99] Application of a vaginal gel containing fective in decreasing this risk.[120][121]
tenofovir (a reverse transcriptase inhibitor) immediately
before sex seems to reduce infection rates by approximately 40% among African women.[100] By contrast, use 8.6.3 Post-exposure
of the spermicide nonoxynol-9 may increase the risk of
transmission due to its tendency to cause vaginal and rec- A course of antiretrovirals administered within 48 to
72 hours after exposure to HIV-positive blood or genital irritation.[101]

8.7. TREATMENT
tal secretions is referred to as post-exposure prophylaxis
(PEP).[122] The use of the single agent zidovudine reduces the risk of a HIV infection ve-fold following a
needle-stick injury.[122] As of 2013, the prevention regimen recommended in the United States consists of three
medicationstenofovir, emtricitabine and raltegravir
as this may reduce the risk further.[123]
PEP treatment is recommended after a sexual assault
when the perpetrator is known to be HIV positive, but
is controversial when their HIV status is unknown.[124]
The duration of treatment is usually four weeks[125] and
is frequently associated with adverse eectswhere zidovudine is used, about 70% of cases result in adverse
eects such as nausea (24%), fatigue (22%), emotional
distress (13%) and headaches (9%).[42]

8.6.4

63
(HAART) which slows progression of the disease.[134] As
of 2010 more than 6.6 million people were taking them
in low and middle income countries.[135] Treatment also
includes preventive and active treatment of opportunistic
infections.

8.7.1 Antiviral therapy

Mother-to-child

Main article: HIV and pregnancy

Programs to prevent the vertical transmission of HIV
(from mothers to children) can reduce rates of transmission by 9299%.[65][120] This primarily involves the use
of a combination of antiviral medications during pregnancy and after birth in the infant and potentially includes bottle feeding rather than breastfeeding.[65][126] If
replacement feeding is acceptable, feasible, aordable,
sustainable, and safe, mothers should avoid breastfeeding their infants; however exclusive breastfeeding is recommended during the rst months of life if this is not
the case.[127] If exclusive breastfeeding is carried out, the
provision of extended antiretroviral prophylaxis to the infant decreases the risk of transmission.[128] In 2015, Cuba
became the rst country in the world to eradicate motherto-child transmission of HIV.[129]

8.6.5

Vaccination

Main article: HIV vaccine

Currently, there is no licensed vaccine for HIV or
AIDS.[130] The most eective vaccine trial to date, RV
144, was published in 2009 and found a partial reduction
in the risk of transmission of roughly 30%, stimulating
some hope in the research community of developing a
truly eective vaccine.[131] Further trials of the RV 144
vaccine are ongoing.[132][133]

8.7 Treatment
Main article: Management of HIV/AIDS

Stribild - a common once-daily ART regime consisting of

elvitegravir, emtricitabine, tenofovir and the booster cobicistat

Current HAART options are combinations (or cocktails) consisting of at least three medications belonging
to at least two types, or classes, of antiretroviral
agents.[136] Initially treatment is typically a nonnucleoside reverse transcriptase inhibitor (NNRTI) plus
two nucleoside analogue reverse transcriptase inhibitors
(NRTIs).[137] Typical NRTIs include: zidovudine
(AZT) or tenofovir (TDF) and lamivudine (3TC) or
emtricitabine (FTC).[137] Combinations of agents which
include protease inhibitors (PI) are used if the above
regimen loses eectiveness.[136]
The World Health Organization and United States recommends antiretrovirals in people of all ages including
pregnant women as soon as the diagnosis is made regardless of CD4 count.[10][109][138] Once treatment is begun
it is recommended that it is continued without breaks
or holidays.[22] Many people are diagnosed only after
treatment ideally should have begun.[22] The desired outcome of treatment is a long term plasma HIV-RNA count
below 50 copies/mL.[22] Levels to determine if treatment
is eective are initially recommended after four weeks
and once levels fall below 50 copies/mL checks every
three to six months are typically adequate.[22] Inadequate
control is deemed to be greater than 400 copies/mL.[22]
Based on these criteria treatment is eective in more than
95% of people during the rst year.[22]

There is currently no cure or eective HIV vaccine. Benets of treatment include a decreased risk of proTreatment consists of highly active antiretroviral therapy gression to AIDS and a decreased risk of death.[139] In

64

CHAPTER 8. HIV/AIDS

the developing world treatment also improves physical

and mental health.[140] With treatment there is a 70%
reduced risk of acquiring tuberculosis.[136] Additional
benets include a decreased risk of transmission of the
disease to sexual partners and a decrease in mother-tochild transmission.[136] The eectiveness of treatment depends to a large part on compliance.[22] Reasons for nonadherence include poor access to medical care,[141] inadequate social supports, mental illness and drug abuse.[142]
The complexity of treatment regimens (due to pill numbers and dosing frequency) and adverse eects may reduce adherence.[143] Even though cost is an important issue with some medications,[144] 47% of those who needed
them were taking them in low and middle income countries as of 2010[135] and the rate of adherence is similar
in low-income and high-income countries.[145]
Specic adverse events are related to the antiretroviral
agent taken.[146] Some relatively common adverse events
include: lipodystrophy syndrome, dyslipidemia, and
diabetes mellitus, especially with protease inhibitors.[18]
Other common symptoms include diarrhea,[146][147] and
an increased risk of cardiovascular disease.[148] Newer
recommended treatments are associated with fewer adverse eects.[22] Certain medications may be associated
with birth defects and therefore may be unsuitable for
women hoping to have children.[22]
Treatment recommendations for children are somewhat
dierent from those for adults. The World Health Organisation recommends treating all children less than 5 years
of age; children above 5 are treated like adults.[149] The
United States guidelines recommend treating all children
less than 12 months of age and all those with HIV RNA
counts greater than 100,000 copies/mL between one year
and ve years of age.[150]

8.7.2

Opportunistic infections

Measures to prevent opportunistic infections are eective in many people with HIV/AIDS. In addition to improving current disease, treatment with antiretrovirals
reduces the risk of developing additional opportunistic
infections.[146] Adults and adolescents who are living with
HIV (even on anti-retroviral therapy) with no evidence
of active tuberculosis in settings with high tuberculosis burden should receive isoniazid preventive therapy
(IPT), the tuberculin skin test can be used to help decide if IPT is needed.[151] Vaccination against hepatitis
A and B is advised for all people at risk of HIV before they become infected; however it may also be given
after infection.[152] Trimethoprim/sulfamethoxazole prophylaxis between four and six weeks of age and ceasing breastfeeding in infants born to HIV positive mothers is recommended in resource limited settings.[153] It is
also recommended to prevent PCP when a persons CD4
count is below 200 cells/uL and in those who have or
have previously had PCP.[154] People with substantial immunosuppression are also advised to receive prophylac-

tic therapy for toxoplasmosis and Cryptococcus meningitis.[155] Appropriate preventive measures have reduced
the rate of these infections by 50% between 1992 and
1997.[156]

8.7.3 Diet
Main article: Nutrition and HIV/AIDS
The World Health Organization (WHO) has issued
recommendations regarding nutrient requirements in
HIV/AIDS.[157] A generally healthy diet is promoted.
Some evidence has shown a benet from micronutrient
supplements.[158] Evidence for supplementation with
selenium is mixed with some tentative evidence of
benet.[159] There is some evidence that vitamin A
supplementation in children reduces mortality and improves growth.[158] In Africa in nutritionally compromised pregnant and lactating women a multivitamin supplementation has improved outcomes for both mothers and children.[158] Dietary intake of micronutrients
at RDA levels by HIV-infected adults is recommended
by the WHO; higher intake of vitamin A, zinc, and
iron can produce adverse eects in HIV positive adults,
and is not recommended unless there is documented
deciency.[157][160][161][162]

8.7.4 Alternative medicine

In the US, approximately 60% of people with HIV
use various forms of complementary or alternative
medicine,[163] even though the eectiveness of most
of these therapies has not been established.[164] There
is not enough evidence to support the use of herbal
medicines.[165] There is insucient evidence to recommend or support the use of medical cannabis to try to
increase appetite or weight gain.[166]

8.8 Prognosis

Disability-adjusted life year for HIV and AIDS per 100,000

inhabitants as of 2004.

HIV/AIDS has become a chronic rather than an acutely

fatal disease in many areas of the world.[167] Progno-

8.9. EPIDEMIOLOGY

65

sis varies between people, and both the CD4 count and
viral load are useful for predicted outcomes.[21] Without treatment, average survival time after infection with
HIV is estimated to be 9 to 11 years, depending on
the HIV subtype.[11] After the diagnosis of AIDS, if
treatment is not available, survival ranges between 6
and 19 months.[168][169] HAART and appropriate prevention of opportunistic infections reduces the death rate
by 80%, and raises the life expectancy for a newly diagnosed young adult to 2050 years.[167][170][171] This
% of HIV among young adults (1549)
is between two thirds[170] and nearly that of the gen- Estimated prevalence in[187]
[22][172]
per
country
as
of
2011.
eral population.
If treatment is started late in the
infection, prognosis is not as good:[22] for example, if
treatment is begun following the diagnosis of AIDS,
life expectancy is ~1040 years.[22][167] Half of infants
born with HIV die before two years of age without
treatment.[153]
The primary causes of death from HIV/AIDS are
opportunistic infections and cancer, both of which are
frequently the result of the progressive failure of the immune system.[156][173] Risk of cancer appears to increase
once the CD4 count is below 500/L.[22] The rate of
clinical disease progression varies widely between individuals and has been shown to be aected by a number
of factors such as a persons susceptibility and immune
function;[174] their access to health care, the presence of
co-infections;[168][175] and the particular strain (or strains)
of the virus involved.[176][177]

from a peak of 2.2 million in 2005.[135][189]

Sub-Saharan Africa is the region most aected. In
2010, an estimated 68% (22.9 million) of all HIV cases
and 66% of all deaths (1.2 million) occurred in this
region.[191] This means that about 5% of the adult population is infected[192] and it is believed to be the cause
of 10% of all deaths in children.[193] Here in contrast to
other regions women compose nearly 60% of cases.[191]
South Africa has the largest population of people with
HIV of any country in the world at 5.9 million.[191] Life
expectancy has fallen in the worst-aected countries due
to HIV/AIDS; for example, in 2006 it was estimated
that it had dropped from 65 to 35 years in Botswana.[14]
Mother-to-child transmission, as of 2013, in Botswana
and South Africa has decreased to less than 5% with improvement in many other African nations due to improved
access to antiretroviral therapy.[194]

Tuberculosis co-infection is one of the leading causes of

sickness and death in those with HIV/AIDS being present
in a third of all HIV infected people and causing 25%
of HIV related deaths.[178] HIV is also one of the most
important risk factors for tuberculosis.[179] Hepatitis C
is another very common co-infection where each disease increases the progression of the other.[180] The two
most common cancers associated with HIV/AIDS are
Kaposis sarcoma and AIDS-related non-Hodgkins lym- South & South East Asia is the second most aected; in
phoma.[173]
2010 this region contained an estimated 4 million cases
Even with anti-retroviral treatment, over the long term or 12% of all people living with HIV resulting in approxi[192]
Approximately 2.4 million of
HIV-infected people may experience neurocognitive mately 250,000 deaths.
[181]
[182]
[183]
these cases are in India.[191]
disorders,
osteoporosis,
neuropathy,
cancers,[184][185] nephropathy,[186] and cardiovascular In 2008 in the United States approximately 1.2 million
disease.[147] Some conditions like lipodystrophy may be people were living with HIV, resulting in about 17,500
caused both by HIV and its treatment.[147]
deaths. The US Centers for Disease Control and Preven-

8.9 Epidemiology
Main article: Epidemiology of HIV/AIDS
HIV/AIDS is a global pandemic.[188] As of 2012, approximately 35.3 million people have HIV worldwide
with the number of new infections that year being about
2.3 million.[189] This is down from 3.1 million new infections in 2001.[189] Of these approximately 16.8 million
are women and 3.4 million are less than 15 years old.[135]
It resulted in about 1.34 million deaths in 2013,[190] down

tion estimated that in 2008 20% of infected Americans

were unaware of their infection.[195] In the United Kingdom as of 2009 there were approximately 86,500 cases
which resulted in 516 deaths.[196] In Canada as of 2008
there were about 65,000 cases causing 53 deaths.[197] Between the rst recognition of AIDS in 1981 and 2009
it has led to nearly 30 million deaths.[198] Prevalence
is lowest in Middle East and North Africa at 0.1% or
less, East Asia at 0.1% and Western and Central Europe
at 0.2%.[192] The worst aected European countries, in
2009 and 2012 estimates, are Russia, Ukraine, Latvia,
Moldova, Portugal and Belarus, in decreasing order of
prevalence.[199]

66

CHAPTER 8. HIV/AIDS

8.10 History
Main article: History of HIV/AIDS

8.10.1

Discovery

At one point, the CDC coined the phrase the 4H disease, since the syndrome seemed to aect homosexuals, heroin users, hemophiliacs, and Haitians.[207][208] In
the general press, the term GRID, which stood for gayrelated immune deciency, had been coined.[209] However, after determining that AIDS was not isolated to the
gay community,[206] it was realized that the term GRID
was misleading and the term AIDS was introduced at a
meeting in July 1982.[210] By September 1982 the CDC
started referring to the disease as AIDS.[211]
In 1983, two separate research groups led by Robert
Gallo and Luc Montagnier declared that a novel retrovirus may have been infecting people with AIDS, and
published their ndings in the same issue of the journal
Science.[212][213] Gallo claimed that a virus his group had
isolated from a person with AIDS was strikingly similar in
shape to other human T-lymphotropic viruses (HTLVs)
his group had been the rst to isolate. Gallos group
called their newly isolated virus HTLV-III. At the same
time, Montagniers group isolated a virus from a person
presenting with swelling of the lymph nodes of the neck
and physical weakness, two characteristic symptoms of
AIDS. Contradicting the report from Gallos group, Montagnier and his colleagues showed that core proteins of
this virus were immunologically dierent from those of
HTLV-I. Montagniers group named their isolated virus
lymphadenopathy-associated virus (LAV).[203] As these
two viruses turned out to be the same, in 1986, LAV and
HTLV-III were renamed HIV.[214]

8.10.2 Origins

The Morbidity and Mortality Weekly Report reported in 1981

on what was later to be called AIDS.

AIDS was rst clinically observed in 1981 in the United

States.[30] The initial cases were a cluster of injecting drug users and homosexual men with no known
cause of impaired immunity who showed symptoms of
Pneumocystis carinii pneumonia (PCP), a rare opportunistic infection that was known to occur in people with
very compromised immune systems.[200] Soon thereafter,
an unexpected number of homosexual men developed
a previously rare skin cancer called Kaposis sarcoma
(KS).[201][202] Many more cases of PCP and KS emerged,
alerting U.S. Centers for Disease Control and Prevention
(CDC) and a CDC task force was formed to monitor the
outbreak.[203]
In the early days, the CDC did not have an ocial
name for the disease, often referring to it by way of
the diseases that were associated with it, for example,
lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[204][205] They also
used Kaposis sarcoma and opportunistic infections, the
name by which a task force had been set up in 1981.[206]

Left to right: the African green monkey source of SIV, the sooty
mangabey source of HIV-2 and the chimpanzee source of HIV-1

Both HIV-1 and HIV-2 are believed to have originated

in non-human primates in West-central Africa and were
transferred to humans in the early 20th century.[15] HIV-1
appears to have originated in southern Cameroon through
the evolution of SIV(cpz), a simian immunodeciency
virus (SIV) that infects wild chimpanzees (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies Pan troglodytes troglodytes).[215][216] The closest
relative of HIV-2 is SIV(smm), a virus of the sooty
mangabey (Cercocebus atys atys), an Old World monkey
living in coastal West Africa (from southern Senegal to
western Cte d'Ivoire).[81] New World monkeys such as
the owl monkey are resistant to HIV-1 infection, possi-

8.11. SOCIETY AND CULTURE

67

bly because of a genomic fusion of two viral resistance of New York and San Francisco was estimated at 5%,
genes.[217] HIV-1 is thought to have jumped the species suggesting that several thousand individuals in the counbarrier on at least three separate occasions, giving rise to try had been infected.[227]
the three groups of the virus, M, N, and O.[218]
There is evidence that humans who participate in
bushmeat activities, either as hunters or as bushmeat ven- 8.11
dors, commonly acquire SIV.[219] However, SIV is a weak
virus which is typically suppressed by the human immune 8.11.1
system within weeks of infection. It is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough
time to mutate into HIV.[220] Furthermore, due to its relatively low person-to-person transmission rate, SIV can
only spread throughout the population in the presence of
one or more high-risk transmission channels, which are
thought to have been absent in Africa before the 20th century.
Specic proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout
the society, depend on the proposed timing of the animalto-human crossing. Genetic studies of the virus suggest that the most recent common ancestor of the HIV1 M group dates back to circa 1910.[221] Proponents of
this dating link the HIV epidemic with the emergence of
colonialism and growth of large colonial African cities,
leading to social changes, including a higher degree of
sexual promiscuity, the spread of prostitution, and the
accompanying high frequency of genital ulcer diseases
(such as syphilis) in nascent colonial cities.[222] While
transmission rates of HIV during vaginal intercourse are
low under regular circumstances, they are increased many
fold if one of the partners suers from a sexually transmitted infection causing genital ulcers. Early 1900s colonial cities were notable due to their high prevalence of
prostitution and genital ulcers, to the degree that, as of
1928, as many as 45% of female residents of eastern
Kinshasa were thought to have been prostitutes, and, as
of 1933, around 15% of all residents of the same city had
syphilis.[222]
An alternative view holds that unsafe medical practices
in Africa after World War II, such as unsterile reuse
of single use syringes during mass vaccination, antibiotic and anti-malaria treatment campaigns, were the initial vector that allowed the virus to adapt to humans and
spread.[220][223][224]

Society and culture

Stigma

Ryan White became a poster child for HIV after being expelled
from school because he was infected.[228]

Main article:
HIV/AIDS

Discrimination against people with

AIDS stigma exists around the world in a variety of ways,

including ostracism, rejection, discrimination and avoidance of HIV infected people; compulsory HIV testing
without prior consent or protection of condentiality; violence against HIV infected individuals or people who
are perceived to be infected with HIV; and the quarantine
of HIV infected individuals.[229] Stigma-related violence
or the fear of violence prevents many people from seeking HIV testing, returning for their results, or securing
treatment, possibly turning what could be a manageable
chronic illness into a death sentence and perpetuating the
spread of HIV.[230]

The earliest well documented case of HIV in a human

dates back to 1959 in the Congo.[225] The virus may have
been present in the United States as early as 1966,[226]
but the vast majority of infections occurring outside subSaharan Africa (including the U.S.) can be traced back
to a single unknown individual who became infected with
HIV in Haiti and then brought the infection to the United
States some time around 1969.[227] The epidemic then AIDS stigma has been further divided into the following
rapidly spread among high-risk groups (initially, sexually three categories:
promiscuous men who have sex with men). By 1978, the
Instrumental AIDS stigmaa reection of the fear
prevalence of HIV-1 among homosexual male residents
and apprehension that are likely to be associated

68

CHAPTER 8. HIV/AIDS
with any deadly and transmissible illness.[231]

Symbolic AIDS stigmathe use of HIV/AIDS to express attitudes toward the social groups or lifestyles
perceived to be associated with the disease.[231]
Courtesy AIDS stigmastigmatization of people
connected to the issue of HIV/AIDS or HIVpositive people.[232]

Returning to work after beginning treatment for

HIV/AIDS is dicult, and aected people often work
less than the average worker. Unemployment in people
with HIV/AIDS also is associated with suicidal ideation,
memory problems, and social isolation; employment
increases self-esteem, sense of dignity, condence,
and quality of life. A 2015 Cochrane review found
low-quality evidence that antiretroviral treatment helps
people with HIV/AIDS work more, and increases
the chance that a person with HIV/AIDS will be
employed.[239]

Often, AIDS stigma is expressed in conjunction with

one or more other stigmas, particularly those associated By aecting mainly young adults, AIDS reduces the taxwith homosexuality, bisexuality, promiscuity, prostitu- able population, in turn reducing the resources available
tion, and intravenous drug use.[233]
for public expenditures such as education and health serIn many developed countries, there is an association be- vices not related to AIDS resulting in increasing pressure
tween AIDS and homosexuality or bisexuality, and this for the states nances and slower growth of the economy.
association is correlated with higher levels of sexual prej- This causes a slower growth of the tax base, an eect that
udice, such as anti-homosexual/bisexual attitudes.[234] is reinforced if there are growing expenditures on treating
There is also a perceived association between AIDS the sick, training (to replace sick workers), sick pay and
and all male-male sexual behavior, including sex be- caring for AIDS orphans. This is especially true if the
tween uninfected men.[231] However, the dominant mode sharp increase in adult mortality shifts the responsibility
of spread worldwide for HIV remains heterosexual and blame from the family to the government in caring
for these orphans.[238]
transmission.[235]
In 2003, as part of an overall reform of marriage and pop- At the household level, AIDS causes both loss of income
ulation legislation, it became legal for people with AIDS and increased spending on healthcare. A study in Cte
d'Ivoire showed that households having a person with
to marry in China.[236]
HIV/AIDS spent twice as much on medical expenses as
other households. This additional expenditure also leaves
less income to spend on education and other personal or
8.11.2 Economic impact
family investment.[240]
Main articles: Economic impact of HIV/AIDS and Cost
of HIV treatment
HIV/AIDS aects the economics of both individuals 8.11.3 Religion and AIDS
Main article: Religion and HIV/AIDS
The topic of religion and AIDS has become highly controversial in the past twenty years, primarily because
some religious authorities have publicly declared their opposition to the use of condoms.[241][242] The religious approach to prevent the spread of AIDS according to a report by American health expert Matthew Hanley titled
The Catholic Church and the Global AIDS Crisis argues
that cultural changes are needed including a re-emphasis
on delity within marriage and sexual abstinence outside
of it.[242]
Changes in life expectancy in some African countries, 1960-2012

and countries.[193] The gross domestic product of the

most aected countries has decreased due to the lack of
human capital.[193][237] Without proper nutrition, health
care and medicine, large numbers of people die from
AIDS-related complications. They will not only be unable to work, but will also require signicant medical
care. It is estimated that as of 2007 there were 12 million AIDS orphans.[193] Many are cared for by elderly
grandparents.[238]

Some religious organisations have claimed that prayer can

cure HIV/AIDS. In 2011, the BBC reported that some
churches in London were claiming that prayer would
cure AIDS, and the Hackney-based Centre for the Study
of Sexual Health and HIV reported that several people stopped taking their medication, sometimes on the
direct advice of their pastor, leading to a number of
deaths.[243] The Synagogue Church Of All Nations advertise an anointing water to promote Gods healing,
although the group deny advising people to stop taking
medication.[243]

8.12. RESEARCH

8.11.4

Media portrayal

Main article: Media portrayal of HIV/AIDS

One of the rst high-prole cases of AIDS was the American Rock Hudson, a gay actor who had been married and
divorced earlier in life, who died on October 2, 1985 having announced that he was suering from the virus on July
25 that year. He had been diagnosed during 1984.[244] A
notable British casualty of AIDS that year was Nicholas
Eden, a gay politician and son of the late prime minister Anthony Eden.[245] On November 24, 1991, the
virus claimed the life of British rock star Freddie Mercury, lead singer of the band Queen, who died from an
AIDS-related illness having only revealed the diagnosis
on the previous day.[246] However, he had been diagnosed as HIV positive in 1987.[247] One of the rst highprole heterosexual cases of the virus was Arthur Ashe,
the American tennis player. He was diagnosed as HIV
positive on August 31, 1988, having contracted the virus
from blood transfusions during heart surgery earlier in the
1980s. Further tests within 24 hours of the initial diagnosis revealed that Ashe had AIDS, but he did not tell the
public about his diagnosis until April 1992.[248] He died
as a result on February 6, 1993 at age 49.[249]
Therese Frares photograph of gay activist David Kirby,
as he lay dying from AIDS while surrounded by family, was taken in April 1990. LIFE magazine said the
photo became the one image most powerfully identied with the HIV/AIDS epidemic. The photo was displayed in LIFE magazine, was the winner of the World
Press Photo, and acquired worldwide notoriety after being used in a United Colors of Benetton advertising campaign in 1992.[250] In 1996, Johnson Aziga, a Ugandanborn Canadian was diagnosed with HIV, but subsequently
had unprotected sex with 11 women without disclosing
his diagnosis. By 2003 seven had contracted HIV, and
two died from complications related to AIDS.[251][252]
Aziga was convicted of rst-degree murder and is liable
to a life sentence.[253]

69

8.11.6 Misconceptions
Main articles: Misconceptions about HIV/AIDS, AIDS
denialism and Discredited HIV/AIDS origins theories
There are many misconceptions about HIV and AIDS.
Three of the most common are that AIDS can spread
through casual contact, that sexual intercourse with a
virgin will cure AIDS,[255][256][257] and that HIV can
infect only gay men and drug users. In 2014, some
among the British public wrongly thought you could get
HIV from kissing (16%), sharing a glass (5%), spitting
(16%), a public toilet seat (4%), and coughing or sneezing (5%).[258] Other misconceptions are that any act of
anal intercourse between two uninfected gay men can
lead to HIV infection, and that open discussion of HIV
and homosexuality in schools will lead to increased rates
of AIDS.[259][260]
A small group of individuals continue to dispute the
connection between HIV and AIDS,[261] the existence
of HIV itself, or the validity of HIV testing and treatment methods.[262][263] These claims, known as AIDS denialism, have been examined and rejected by the scientic community.[264] However, they have had a signicant political impact, particularly in South Africa, where
the governments ocial embrace of AIDS denialism
(19992005) was responsible for its ineective response
to that countrys AIDS epidemic, and has been blamed
for hundreds of thousands of avoidable deaths and HIV
infections.[265][266][267]
Several discredited conspiracy theories have held that
HIV was created by scientists, either inadvertently or deliberately. Operation INFEKTION was a worldwide Soviet active measures operation to spread the claim that the
United States had created HIV/AIDS. Surveys show that
a signicant number of people believed and continue
to believe in such claims.[268]

8.12 Research
Main article: HIV/AIDS research

Main article: Criminal transmission of HIV

HIV/AIDS research includes all medical research which

attempts to prevent, treat, or cure HIV/AIDS along with
fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.

Criminal transmission of HIV is the intentional or

reckless infection of a person with the human immunodeciency virus (HIV). Some countries or jurisdictions,
including some areas of the United States, have laws
that criminalize HIV transmission or exposure.[254] Others may charge the accused under laws enacted before the
HIV pandemic.

Many governments and research institutions participate

in HIV/AIDS research. This research includes behavioral health interventions such as sex education, and drug
development, such as research into microbicides for sexually transmitted diseases, HIV vaccines, and antiretroviral
drugs. Other medical research areas include the topics
of pre-exposure prophylaxis, post-exposure prophylaxis,
and circumcision and HIV.

8.11.5

Criminal transmission

70

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8.14 Further reading

Mandell, Gerald L.; Bennett, John E.; Dolin,
Raphael, eds. (2010). Mandell, Douglas, and
Bennetts Principles and Practice of Infectious Diseases (7th ed.). Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 978-0-443-06839-3.

8.15. EXTERNAL LINKS

Joint United Nations Programme on HIV/AIDS
(UNAIDS) (2011). Global HIV/AIDS Response,
Epidemic update and health sector progress towards
universal access (PDF). Joint United Nations Programme on HIV/AIDS.

8.15 External links

HIV/AIDS at DMOZ
Joint United Nations Program on HIV/AIDS
AIDSinfo HIV/AIDS Treatment Information,
U.S. Department of Health and Human Services

81

Chapter 9

Pathophysiology of HIV/AIDS
The HIV virus is commonly transmitted via unprotected
sexual activity, blood transfusions, hypodermic needles,
and from mother to child. Upon acquisition of the virus,
the virus replicates inside and kills T helper cells, which
are required for almost all adaptive immune responses.
There is an initial period of inuenza-like illness, and then
a latent, asymptomatic phase. When the CD4 lymphocyte count falls below 200 cells/ml of blood, the HIV host
has progressed to AIDS, a condition characterized by deciency in cell-mediated immunity and the resulting increased susceptibility to opportunistic infections and certain forms of cancer.

9.1 Immunology
After the virus enters the body there is a period of rapid
viral replication, leading to an abundance of virus in the
peripheral blood. During primary infection, the level
of HIV may reach several million virus particles per
milliliter of blood.[1]
This response is accompanied by a marked drop in the
numbers of circulating CD4+ T cells. This acute viremia
is associated in virtually all people with the activation of
CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion.
The CD8+ T cell response is thought to be important in
controlling virus levels, which peak and then decline, as
the CD4+ T cell counts rebound. A good CD8+ T cell
response has been linked to slower disease progression
and a better prognosis, though it does not eliminate the
virus.[2]
During the acute phase, HIV-induced cell lysis and killing
of infected cells by cytotoxic T cells accounts for CD4+
T cell depletion, although apoptosis may also be a factor.
During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of
the ability of the immune system to generate new T cells
appear to account for the slow decline in CD4+ T cell
numbers.
However, the symptoms of immune deciency characteristic of AIDS do not appear for years after a person is infected, the bulk of CD4+ T cell loss occurs during the rst

weeks of infection, especially in the intestinal mucosa,

which harbors the majority of the lymphocytes found in
the body.[3] The reason for the preferential loss of mucosal CD4+ T cells is that a majority of mucosal CD4+ T
cells express the CCR5 coreceptor, whereas a small fraction of CD4+ T cells in the bloodstream do so.[4]
HIV seeks out and destroys CCR5 expressing CD4+ cells
during acute infection. A vigorous immune response
eventually controls the infection and initiates the clinically latent phase. However, CD4+ T cells in mucosal tissues remain depleted throughout the infection, although
enough remain to initially ward o life-threatening infections.
Continuous HIV replication results in a state of generalized immune activation persisting throughout the chronic
phase.[5] Immune activation, which is reected by the increased activation state of immune cells and release of
proinammatory cytokines, results from the activity of
several HIV gene products and the immune response to
ongoing HIV replication. Another cause is the breakdown of the immune surveillance system of the mucosal
barrier caused by the depletion of mucosal CD4+ T cells
during the acute phase of disease.[6]
This results in the systemic exposure of the immune system to microbial components of the guts normal ora,
which in a healthy person is kept in check by the mucosal immune system. The activation and proliferation
of T cells that results from immune activation provides
fresh targets for HIV infection. However, direct killing
by HIV alone cannot account for the observed depletion
of CD4+ T cells since only 0.010.10% of CD4+ T cells
in the blood are infected.
A major cause of CD4+ T cell loss appears to result from
their heightened susceptibility to apoptosis when the immune system remains activated. Although new T cells are
continuously produced by the thymus to replace the ones
lost, the regenerative capacity of the thymus is slowly
destroyed by direct infection of its thymocytes by HIV.
Eventually, the minimal number of CD4+ T cells necessary to maintain a sucient immune response is lost,
leading to AIDS.

82

9.5. REFERENCES

9.2 Cells aected

The virus, entering through which ever route, acts primarily on the following cells:[7]
Lymphoreticular system:
CD4 + T-Helper cells
Macrophages
Monocytes
B-lymphocytes
Certain endothelial cells
Central nervous system:
Microglia of the nervous system
Astrocytes
Oligodendrocytes
Neurones indirectly by the action of
cytokines and the gp-120

9.3 The eect

The virus has cytopathic eects but how it does it is still
not quite clear. It can remain inactive in these cells for
long periods, though. This eect is hypothesized to be
due to the CD4 -gp120 interaction.[7]
The most prominent eect of HIV is its T-helper cell
suppression and lysis. The cell is simply killed o
or deranged to the point of being function-leapses
leading to the familiar AIDS complications, like infections and neoplasms (vide supra).
Infection of the cells of the CNS cause acute
aseptic meningitis, subacute encephalitis, vacuolar
myelopathy and peripheral neuropathy. Later it
leads to even AIDS dementia complex.
The CD4 -gp120 interaction (see above) is also
permissive to other viruses like Cytomegalovirus,
Hepatitis virus, Herpes simplex virus, etc. These
viruses lead to further cell damage i. e. cytopathy.

9.4 Molecular basis

For details, see:
Structure and genome of HIV
HIV replication cycle
HIV tropism

83

9.5 References
[1] Piatak, M., Jr, Saag, M. S., Yang, L. C., Clark,
S. J., Kappes, J. C., Luk, K. C., Hahn, B. H.,
Shaw, G. M. and Lifson, J.D. (1993). High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259
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[2] Pantaleo G, Demarest JF, Schacker T, Vaccarezza M,
Cohen OJ, Daucher M, Graziosi C, Schnittman SS,
Quinn TC, Shaw GM, Perrin L, Tambussi G, Lazzarin A, Sekaly RP, Soudeyns H, Corey L, Fauci
AS. (1997). The qualitative nature of the primary
immune response to HIV infection is a prognosticator of disease progression independent of the initial
level of plasma viremia. Proc Natl Acad Sci U S
A. 94 (1): 254258. Bibcode:1997PNAS...94..254P.
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[3] Mehandru S, Poles MA, Tenner-Racz K, Horowitz A,
Hurley A, Hogan C, Boden D, Racz P, Markowitz M
(September 2004). Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from eector sites in the gastrointestinal tract. J.
Exp. Med. 200 (6): 76170. doi:10.1084/jem.20041196.
PMC 2211967. PMID 15365095.
[4] Brenchley JM, Schacker TW, Ru LE, Price DA, Taylor
JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase
AT, Douek DC (September 2004). CD4+ T cell depletion during all stages of HIV disease occurs predominantly
in the gastrointestinal tract. J. Exp. Med. 200 (6): 749
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[5] Appay V, Sauce D (January 2008). Immune activation and inammation in HIV-1 infection: causes
and consequences. J. Pathol. 214 (2): 23141.
doi:10.1002/path.2276. PMID 18161758.
[6] Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L,
Landay A, Martin JN, Hecht FM, Picker LJ, Lederman
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[7] Textbook of Pathology by Harsh Mohan, ISBN 81-8061368-2

Chapter 10

Diagnosis of HIV/AIDS
sensitivity: The percentage of the results that will be
positive when HIV is present
specicity: The percentage of the results that will be
negative when HIV is not present.
All diagnostic tests have limitations, and sometimes their
use may produce erroneous or questionable results.
False positive: The test incorrectly indicates that
HIV is present in a non-infected person.
False negative: The test incorrectly indicates that
HIV is absent in an infected person.
Nonspecic reactions, hypergammaglobulinemia, or the
presence of antibodies directed to other infectious agents
that may be antigenically similar to HIV can produce false
positive results. Autoimmune diseases, such as systemic
lupus erythematosus, have also rarely caused false posHIV tests are used to detect the presence of the human itive results. Most false negative results are due to the
immunodeciency virus (HIV), the virus that causes window period.
acquired immunodeciency syndrome (AIDS), in serum,
saliva, or urine. Such tests may detect antibodies,
antigens, or RNA.
10.3 Principles
Randall L. Tobias, former U.S. Global AIDS Coordinator, being
publicly tested for HIV in Ethiopia in an eort to reduce the stigma
of being tested.[1]

10.3.1 Screening donor blood and cellular

products

10.1 AIDS diagnosis

Main article: AIDS-dening clinical condition

Tests selected to screen donor blood and tissue must provide a high degree of condence that HIV will be detected
if present (that is, a high sensitivity is required). A combination of antibody, antigen and nucleic acid tests are
used by blood banks in Western countries. The World
Health Organization estimated that, as of 2000, inadequate blood screening had resulted in 1 million new HIV
infections worldwide.

AIDS is diagnosed separately from HIV.

10.2 Terminology
The window period is the time from infection until a test
can detect any change. The average window period with
HIV-1 antibody tests is 25 days for subtype B. Antigen
testing cuts the window period to approximately 16 days
and NAT (Nucleic Acid Testing) further reduces this period to 12 days.[2]

In the US, the Food and Drug Administration requires

that all donated blood be screened for several infectious
diseases, including HIV-1 and HIV-2, using a combination of antibody testing (EIA) and more expeditious nucleic acid testing (NAT).[3][4] These diagnostic tests are
combined with careful donor selection. As of 2001, the
Performance of medical tests is often described in terms risk of transfusion-acquired HIV in the US was approxiof:
mately one in 2.5 million for each transfusion.[5]
84

10.4. ANTIBODY TESTS

10.3.2

Diagnosis of HIV infection

10.3.4

Condentiality

85

positive will not have the HIV infected individuals name

attached to the specimen. Sites that oer this service adTests used for the diagnosis of HIV infection in a par- vertise this testing option.
ticular person require a high degree of both sensitivity
and specicity. In the United States, this is achieved using an algorithm combining two tests for HIV antibodies. 10.3.6 Routine testing recommendation
If antibodies are detected by an initial test based on the
ELISA method, then a second test using the Western blot In the United States, one emerging standard of care is to
procedure determines the size of the antigens in the test screen all patients for HIV in all health care settings.[9]
kit binding to the antibodies. The combination of these In 2006, the Centers for Disease Control announced an
initiative for voluntary, routine testing of all Americans
two methods is highly accurate (see below).
aged 1364 during health care encounters. An estimated
25% of infected individuals were unaware of their sta10.3.3 Human rights
tus; If successful the eort was expected to reduce new
infections by 30% per year.[10] The CDC recommends
The UNAIDS/WHO policy statement on HIV Testing elimination of requirements for written consent or extenstates that conditions under which people undergo HIV sive pre-test counseling as barriers to widespread routine
testing must be anchored in a human rights approach that testing.[10] In 2006, the National Association of Commupays due respect to ethical principles.[6] According to nity Health Centers implemented a model for oering
these principles, the conduct of HIV testing of individ- free, rapid HIV testing to all patients between the ages of
uals must be
13 and 64 during routine primary medical and dental care
visits. The program increased testing rates, with 66% of
the 17,237 patients involved in the study agreeing to test Condential;
ing (56% were tested for the rst time).[11] In September
Accompanied by counseling (for those who test pos- 2010, New York became the rst state to require that hositive);
pitals and primary care providers oer an HIV test to all
patients between the ages of 13 and 64 years. A manda Conducted with the informed consent of the person
tory evaluation of the laws impact found that it increased
being tested.
testing signicantly throughout the state.[12]

Considerable controversy exists over the ethical obligations of health care providers to inform the sexual partners of individuals infected with HIV that they are at
risk of contracting the virus.[7] Some legal jurisdictions
permit such disclosure, while others do not. More state
funded testing sites are now using condential forms of
testing. This allows for monitoring of infected individuals
easily, compared to anonymous testing that has a number
attached to the positive test results. Controversy exists
over privacy issues.
In developing countries, home-based HIV testing and
counseling (HBHTC) is an emerging approach for addressing condentiality issues. HBHTC allows individuals, couples, and families to learn their HIV status in
the convenience and privacy of their home environment.
Rapid HIV tests are most often used, so results are available for the client between 15 and 30 minutes. Furthermore, when an HIV positive result is communicated, the
HTC provider can oer appropriate linkages for prevention, care, and treatment.[8]

10.3.5

Anonymous testing

Testing that has only a number attached to the specimen

that will be delivered for testing. Items that are conrmed

10.4 Antibody tests

HIV antibody tests are specically designed for routine
diagnostic testing of adults; these tests are inexpensive
and extremely accurate.

10.4.1 Window period

Antibody tests may give false negative (no antibodies
were detected despite the presence of HIV) results during the window period, an interval of three weeks to six
months between the time of HIV infection and the production of measurable antibodies to HIV seroconversion.
Most people develop detectable antibodies approximately
30 days after infection, although some seroconvert later.
The vast majority of people (97%) have detectable antibodies by three months after HIV infection; a sixmonth window is extremely rare with modern antibody
testing.[13] During the window period, an infected person can transmit HIV to others although their HIV infection may not be detectable with an antibody test.
Antiretroviral therapy during the window period can delay the formation of antibodies and extend the window
period beyond 12 months.[14] This was not the case with
patients that underwent treatment with post-exposure
prophylaxis (PEP). Those patients must take ELISA tests

86

CHAPTER 10. DIAGNOSIS OF HIV/AIDS

at various intervals after the usual 28 day course of

treatment, sometimes extending outside of the conservative window period of 6 months. Antibody tests may
also yield false negative results in patients with X-linked
agammaglobulinemia; other diagnostic tests should be
used in such patients.
Three instances of delayed HIV seroconversion occurring
in health-care workers have been reported;[15] in these
instances, the health-care workers[16] tested negative for
HIV antibodies greater than 6 months postexposure but
were seropositive within 12 months after the exposure.[17]
DNA sequencing conrmed the source of infection in one
instance. Two of the delayed seroconversions were associated with simultaneous exposure to hepatitis C virus
(HCV). In one case, co-infection was associated with
a rapidly fatal HCV disease course; however, it is not
known whether HCV directly inuences the risk for or
course of HIV infection or is a marker for other exposurerelated factors.

10.4.2

ELISA

The enzyme-linked immunosorbent assay (ELISA), or enzyme immunoassay (EIA), was the rst screening test
commonly employed for HIV. It has a high sensitivity.
In an ELISA test, a persons serum is diluted 400-fold
and applied to a plate to which HIV antigens have been
attached. If antibodies to HIV are present in the serum,
they may bind to these HIV antigens. The plate is then
washed to remove all other components of the serum. A
specially prepared "secondary antibody" an antibody
that binds to human antibodies is then applied to the
plate, followed by another wash. This secondary antibody
is chemically linked in advance to an enzyme. Thus the
plate will contain enzyme in proportion to the amount of
secondary antibody bound to the plate. A substrate for
the enzyme is applied, and catalysis by the enzyme leads
to a change in color or uorescence. ELISA results are reported as a number; the most controversial aspect of this
test is determining the cut-o point between a positive
and negative result.

10.4.3

ELISA dongle

Researchers from a university have produced ELISA dongle and have tested in Africa which can test HIV, and
syphilis. The dongle can be used in any smartphones
without additional battery, need only 15 minutes to see
the result of a tiny drop of blood. The manufacturing
cost of the dongle is only $34 each.[18]

10.4.4

Western blot

Like the ELISA procedure, the western blot is an antibody detection test. However, unlike the ELISA method,

Western blot test results. The rst two strips are a negative and a
positive control, respectively. The others are actual tests.

the viral proteins are separated rst and immobilized. In

subsequent steps, the binding of serum antibodies to specic HIV proteins is visualized.
Specically, cells that may be HIV-infected are opened
and the proteins within are placed into a slab of gel, to
which an electric current is applied. Dierent proteins
will move with dierent speeds in this eld, depending on
their size, while their electrical charge is leveled by a surfactant called sodium lauryl sulfate. Some commercially
prepared Western blot test kits contain the HIV proteins
already on a cellulose acetate strip. Once the proteins are
well-separated, they are transferred to a membrane and
the procedure continues similar to an ELISA: the persons diluted serum is applied to the membrane and antibodies in the serum may attach to some of the HIV proteins. Antibodies that do not attach are washed away, and
enzyme-linked antibodies with the capability to attach to
the persons antibodies determine to which HIV proteins
the person has antibodies.
There are no universal criteria for interpreting the western blot test: The number of viral bands that must be
present may vary. If no viral bands are detected, the result is negative. If at least one viral band for each of the
GAG, POL, and ENV gene-product groups are present,
the result is positive. The three-gene-product approach
to western blot interpretation has not been adopted for
public health or clinical practice. Tests in which less than
the required number of viral bands are detected are reported as indeterminate: a person who has an indeterminate result should be retested, as later tests may be more
conclusive. Almost all HIV-infected persons with indeterminate western blot results will develop a positive result when tested in one month; persistently indeterminate
results over a period of six months suggests the results are
not due to HIV infection. In a generally healthy low-risk
population, indeterminate results on western blot occur
on the order of 1 in 5,000 patients.[19] However, for those
individuals that have had high-risk exposures to individuals where HIV-2 is most prevalent, Western Africa, an
inconclusive western blot test may prove infection with

10.4. ANTIBODY TESTS

87

HIV-2.[20]
The HIV proteins used in western blotting can be produced by recombinant DNA in a technique called recombinant immunoblot assay (RIBA).[21]

10.4.5

Rapid or point-of-care tests

Blood being taken for HIV rapid test

10.4.6 Interpreting antibody tests

ELISA testing alone cannot be used to diagnose HIV,
even if the test suggests a high probability that antibody
to HIV-1 is present. In the United States, such ELISA
results are not reported as positive unless conrmed by
a Western Blot.
A woman demonstrates the use of the OraQuick rapid HIV test

Rapid antibody tests are qualitative immunoassays intended for use in point-of-care testing to aid in the diagnosis of HIV infection. These tests should be used in conjunction with the clinical status, history, and risk factors
of the person being tested. The positive predictive value
of Rapid Antibody Tests in low-risk populations has not
been evaluated. These tests should be used in appropriate
multi-test algorithms designed for statistical validation of
rapid HIV test results.
If no antibodies to HIV are detected, this does not mean
the person has not been infected with HIV. It may take
several months after HIV infection for the antibody response to reach detectable levels, during which time rapid
testing for antibodies to HIV will not be indicative of true
infection status. For most people, HIV antibodies reach
a detectable level after two to six weeks.
Although these tests have high specicity, false positives
do occur. Any positive test result should be conrmed by
a lab using the western blot.

The ELISA antibody tests were developed to provide a

high level of condence that donated blood was NOT infected with HIV. It is therefore not possible to conclude
that blood rejected for transfusion because of a positive
ELISA antibody test is in fact infected with HIV. Sometimes, retesting the donor in several months will produce
a negative ELISA antibody test. This is why a conrmatory Western Blot is always used before reporting a positive HIV test result.
Rare false positive results due to factors unrelated to HIV
exposure are found more often with the ELISA test than
with the Western Blot. False positives may be associated
with medical conditions such as recent acute illnesses and
allergies. A rash of false positive tests in the fall of 1991
was initially blamed on the inuenza vaccines used during
that u season, but further investigation traced the crossreactivity to several relatively non-specic test kits.[22] A
false positive result does not indicate a condition of signicant risk to health. When the ELISA test is combined
with Western Blot, the rate of false positives is extremely
low, and diagnostic accuracy is very high (see below).
HIV antibody tests are highly sensitive, mean-

88

CHAPTER 10. DIAGNOSIS OF HIV/AIDS

ing they react preferentially with HIV antibodies, but not all positive or inconclusive
HIV ELISA tests mean the person is infected
by HIV. Risk history, and clinical judgement
should be included in the assessment, and a
conrmation test (Western blot) should be administered. An individual with an inconclusive
test should be re-tested at a later date.

negative predictive value of all tests, including HIV tests,

take into account the prior probability of having a disease
along with the accuracy of the testing method to determine a new degree of belief that an individual has or does
not have a disease (also known as the posterior probability). The chance that a positive test accurately indicates
an HIV infection increases as the prevalence or rate of
HIV infection increases in the population. Conversely,
the negative predictive value will decrease as the HIV
prevalence rises. Thus a positive test in a high-risk pop10.4.7 Accuracy of HIV testing
ulation, such as people who frequently engage in unprotected anal intercourse with unknown partners, is more
Modern HIV testing is highly accurate. The evidence re- likely to correctly represent HIV infection than a positive
garding the risks and benets of HIV screening was re- test in a very low-risk population, such as unpaid blood
viewed in July 2005 by the U.S. Preventive Services Task donors.
Force.[23] The authors concluded that:
Many studies have conrmed the accuracy of current methods of HIV testing in the United States,
...the use of repeatedly reactive enzyme
reporting false-positive rates of 0.0004 to 0.0007
immunoassay followed by conrmatory Westand false-negative rates of 0.003 in the general
ern blot or immunouorescent assay remains
population.[24][25][26][27][28][29][30][31]
the standard method for diagnosing HIV-1
infection. A large study of HIV testing in
752 U.S. laboratories reported a sensitivity of
10.5 Antigen tests
99.7% and specicity of 98.5% for enzyme
immunoassay, and studies in U.S. blood
donors reported specicities of 99.8% and
The p24 antigen test detects the presence of the p24 progreater than 99.99%. With conrmatory
tein of HIV (also known as CA), the capsid protein of the
Western blot, the chance of a false-positive
virus. Monoclonal antibodies specic to the p24 protein
identication in a low-prevalence setting is
are mixed with the persons blood. Any p24 protein in
about 1 in 250 000 (95% CI, 1 in 173 000 to
the persons blood will stick to the monoclonal antibody
1 in 379 000).
and an enzyme-linked antibody to the monoclonal antibodies to p24 causes a color change if p24 was present in
the sample.
The specicity rate given here for the inexpensive enzyme This test is no longer used routinely in the US [32] or the
immunoassay screening tests indicates that, in 1,000 HIV EU [33] to screen blood donations since the objective was
test results of healthy individuals, about 15 of these re- to reduce the risk of false negatives in the window period.
sults will be a false positive. Conrming the test result Nucleic acid testing (NAT) is more eective for this pur(i.e., by repeating the test, if this option is available) could pose, and p24 antigen testing is no longer indicated if a
reduce the ultimate likelihood of a false positive to about NAT test is performed. The p24 antigen test is not useful
1 result in 250,000 tests given. The sensitivity rating, like- for general diagnostics, as it has very low sensitivity and
wise, indicates that, in 1,000 test results of HIV infected only works during a certain time period after infection
people, 3 will actually be a false negative result. However, before the body produces antibodies to the p24 protein.
based upon the HIV prevalence rates at most testing centers within the United States, the negative predictive value
of these tests is extremely high, meaning that a negative
acid-based
tests
test result will be correct more than 9,997 times in 10,000 10.6 Nucleic
(99.97% of the time). The very high negative predictive
(NAT)
value of these tests is why the CDC recommends that a
negative test result be considered conclusive evidence that Nucleic-acid-based tests amplify and detect one or more
an individual does not have HIV.
of several target sequences located in specic HIV genes,
Of course, the actual numbers vary depending on the testing population. This is because interpreting of the results of any medical test (assuming no test is 100% accurate) depends upon the initial degree of belief, or the
prior probability that an individual has, or does not have
a disease. Generally the prior probability is estimated using the prevalence of a disease within a population or at a
given testing location. The positive predictive value and

such as HIV-I GAG, HIV-II GAG, HIV-env, or the HIVpol.[34][35] Since these tests are relatively expensive, the
blood is screened by rst pooling some 8-24 samples and
testing these together; if the pool tests positive, each sample is retested individually. Although this results in a dramatic decrease in cost, the dilution of the virus in the
pooled samples decreases the eective sensitivity of the
test, lengthening the window period by 4 days (assum-

10.8. OTHER TESTS USED IN HIV TREATMENT

ing a 20-fold dilution, ~20hr virus doubling time, detection limit 50 copies/ml, making limit of detection 1,000
copies/ml). Since 2001, donated blood in the United
States has been screened with nucleic-acid-based tests,
shortening the window period between infection and detectability of disease to a median of 17 days (95% CI,
13-28 Days, assumes pooling of samples).[36] A dierent version of this test is intended for use in conjunction
with clinical presentation and other laboratory markers of
disease progress for the management of HIV-1-infected
patients.

89

10.8 Other tests used in HIV treatment

The CD4 T-cell count is not an HIV test, but rather a
procedure where the number of CD4 T-cells in the blood
is determined.
A CD4 count does not check for the presence of HIV.
It is used to monitor immune system function in HIVpositive people. Declining CD4 T-cell counts are considered to be a marker of progression of HIV infection. A
normal CD4 count can range from 500 cells/mm3 to 1000
cells/mm3. In HIV-positive people, AIDS is ocially
diagnosed when the count drops below 200 cells/L or
when certain opportunistic infections occur. This use of a
CD4 count as an AIDS criterion was introduced in 1992;
the value of 200 was chosen because it corresponded with
a greatly increased likelihood of opportunistic infection.
Lower CD4 counts in people with AIDS are indicators
that prophylaxis against certain types of opportunistic infections should be instituted.

In the RT-PCR test, viral RNA is extracted from the

patients plasma and is treated with reverse transcriptase (RT) to convert the viral RNA into cDNA. The
polymerase chain reaction (PCR) process is then applied,
using two primers unique to the viruss genome. After
PCR amplication is complete, the resulting DNA products are hybridized to specic oligonucleotides bound to
the vessel wall, and are then made visible with a probe
bound to an enzyme. The amount of virus in the sample
can be quantied with sucient accuracy to detect threefold changes.
Low CD4 T-cell counts are associated with a variety of
In the Quantiplex bDNA or branched DNA test, plasma conditions, including many viral infections, bacterial inis centrifugated to concentrate the virus, which is then fections, parasitic infections, sepsis, tuberculosis, cocopened to release its RNA. Special oligonucleotides that cidioidomycosis, burns, trauma, intravenous injections
bind to viral RNA and to certain oligonucleotides bound of foreign proteins, malnutrition, over-exercising, pregto the wall of the vessel are added. In this way, viral RNA nancy, normal daily variation, psychological stress, and
is fastened to the wall. Then new oligonucleotides that social isolation.
bind at several locations to this RNA are added, and other This test is also used occasionally to estimate immune sysoligonucelotides that bind at several locations to those tem function for people whose CD4 T cells are impaired
oligonucleotides. This is done to amplify the signal. Fi- for reasons other than HIV infection, which include sevnally, oligonucleotides that bind to the last set of oligonu- eral blood diseases, several genetic disorders, and the side
cleotides and that are bound to an enzyme are added; the eects of many chemotherapy drugs.
enzyme action causes a color reaction, which allows quantication of the viral RNA in the original sample. Moni- In general, the lower the number of T cells the lower the
toring the eects of antiretroviral therapy by serial mea- immune systems function will be. Normal CD4 counts
surements of plasma HIV-1 RNA with this test has been are between 500 and 1500 CD4+ T cells/microliter, and
validated for patients with viral loads greater than 25,000 the counts may uctuate in healthy people, depending on
recent infection status, nutrition, exercise, and other faccopies per milliliter.[37]
tors. Women tend to have somewhat lower counts than
Further information: Viral load testing
men.

10.7 Screening

10.9 Criticisms
10.9.1 Oral tests

The South African government announced a plan to

start screening for HIV in secondary schools by March
2011.[38] This plan was cancelled due to concerns it would
invade pupils privacy, schools typically don't have the facilities to securely store such information, and schools
generally do not have the capacity to provide counseling for HIV positive pupils. In South Africa, anyone
over the age of 12 may request an HIV test without
parental knowledge or consent. Some 80,000 pupils in
three provinces were tested under this programme before
it ended.[39]

As a result of an increase in false positive rates with rapid

oral HIV testing in 2005, New York Citys Department
of Health and Mental Hygiene added the option of testing
nger-stick whole blood after any reactive result, before
using a Western Blot test to conrm the positive result.
Following a further increase of false positives in NYC
DOHMH STD Clinics during the end of 2007 and beginning of 2008, their clinics opted to forgo further oral
screenings, and instead reinsituted testing using ngerstick whole blood.[40] Despite the increase in false posi-

90

CHAPTER 10. DIAGNOSIS OF HIV/AIDS

tives in NYC DOHMH, the CDC still continues to support the use of noninvasive oral uid specimens due to
their popularity in health clinics and convenience of use.
The director of the HIV control program for public health
at Seattle King county, reported OraQuick failed to spot
at least 8 percent of 133 people found to be infected with
a comparable diagnostic test.[41] Strategies implemented
to determine quality control and false positive rates were
implemented. It is to be understood that any reactive
OraQuick test result is a preliminary positive result and
will always require a conrmatory test, regardless of the
mean of testing (venipuncture whole blood, ngerstick
whole blood or oral mucosal transudate uid).[42] Several
other testing sites who did not experience a spike in false
positive rates continue to use OraSures OraQuick HIV
Anti-body Testing.[43][44]

10.9.2

AIDS denialism

[2] FDA Approves First Nucleic Acid Test (NAT) Systems to

Screen Plasma for Human Immunodeciency Virus (HIV)
and Hepatitis C Virus (HCV) , (archived copy) Archived
5 March 2005 at the Wayback Machine
[3] Keeping Blood Transfusions Safe: FDAs Multi-layered
Protections for Donated Blood. US Food and Drug Administration. Retrieved 12 October 2013.
[4] Blood Testing. American Red Cross. Retrieved 12 October 2013.
[5] Adverse reactions associated with blood transfusion.
From the Puget Sound Blood Center. Accessed 5 October
2006.
[6] UNAIDS/WHO policy statement on HIV Testing (PDF),
accessed 5 October 2006.
[7] JM Appel (June 2006). Must My Doctor Tell My
Partner? Rethinking Condentiality in the HIV Era.
Medicine and Health Rhode Island 89 (6): 2234. PMID
16875013.

HIV tests have been criticized by AIDS denialists (a [8] Getting in the Door: Home-Based HIV Testing and
fringe group whose members believe that HIV either does
Counseling in Kenya. Aidstar-One. Retrieved 2 Novemnot exist or is harmless). The accuracy of serologic testber 2013.
ing has been veried by isolation and culture of HIV and
[9] Armstrong WS, Taege AJ (April 2007). HIV screening
by detection of HIV RNA by PCR, which are widely
for all: the new standard of care. Cleve Clin J Med 74 (4):
[26][27]
While
accepted "gold standards" in microbiology.
297301. doi:10.3949/ccjm.74.4.297. PMID 17438679.
AIDS denialists focus on individual components of HIV
testing, the combination of ELISA and Western blot used [10] CDC fact sheet. Archived from the original on 16
September 2008.
for the diagnosis of HIV is remarkably accurate, with very
low false-positive and -negative rates as described above. [11] Community Health Centers Integrate Rapid HIV ScreenThe views of AIDS denialists are based on highly selecing Into Routine Primary Care, Leading to Signicant
tive analysis of mostly outdated scientic papers; there
Increases in Testing Rates. Agency for Healthcare Reis broad scientic consensus that HIV is the cause of
search and Quality. 5 April 2013. Retrieved 10 May
AIDS.[45][46][47]
2013.

10.10 Fraudulent testing

[12] New York State Legislation Leads to More HIV Testing

and Linking of HIV-Positive Patients to Followup Care.
Agency for Healthcare Research and Quality. 10 April
2013. Retrieved 10 May 2013.

There have been a number of cases of fraudulent tests [13] Skip CDC - HIV Testing Basics for Consumers, from the
being sold via mail order or the Internet to the general
Seattle and King County Public Health Department. Acpublic. In 1997, a California man was indicted on mail
cessed 21 February 2007.
fraud and wire charges for selling supposed home test kits.
[14] C B Hare, B L Pappalardo, M P Busch, B Phelps,
In 2004, the US Federal Trade Commission asked FedS S Alexander, C Ramstead, J A Levy, F M Hecht
eral Express and US Customs to conscate shipments of
(2004). Negative HIV antibody test results among indithe Discreet home HIV test kits, produced by Gregory
viduals treated with antiretroviral therapy (ART) during
Stephen Wong of Vancouver, BC.[48] In February 2005,
acute/early infection. The XV International AIDS Conthe US FDA issued a warning against using the rapid HIV
ference. pp. Abstract no. MoPeB3107.
test kits and other home use kits marketed by Globus Me[15] Ridzon R, Gallagher K, Ciesielski C, et al. (1997).
dia of Montreal, Canada.

10.11 References
[1] Blacklist of English teachers suspected of having AIDS
pursued. This image of Randall L. Tobias is used in a Korean news article suggesting that foreign English teachers
residing in Korea are at risk for AIDS. Accessed 16 Feb.,
2010.

Simultaneous transmission of human immunodeciency virus and hepatitis C virus from a needlestick injury. N Engl J Med 336 (13): 91922.
doi:10.1056/NEJM199703273361304. PMID 9070472.

[16] HIV Seroconversion in HEALTH-CARE WORKERS

[17] J.L. Gerberding, San Francisco General Hospital, unpublished data, May 1997, http://web.archive.org/web/
20150912145731/http://www.cdc.gov/mmwR/preview/
mmwrhtml/00052722.htm

10.11. REFERENCES

[18] Mariella Moon. Test for HIV in just 15 minutes with this
$34 smartphone dongle. Retrieved February 6, 2015.
[19] Bartlett, JG. Serologic tests for the diagnosis of HIV infection, in UpToDate. Accessed 5 October 2006.
[20] Scand J Infect Dis. 1992;24(4):419-21. Accessed 23
September 2008.
[21] Mas, A.; Soriano, V.; Gutirrez, M.; Fumanal, F.; Alonso,
A.; Gonzlez-Lahoz, J. (1997). Reliability of a new recombinant immunoblot assay (RIBA HIV-1/HIV-2 SIA)
as a supplemental (conrmatory) test for HIV-1 and HIV2 infections. Transfusion science 18 (1): 6369. PMID
10174294.
[22] Simonsen L, Bungton J, (June 1995). Multiple false
reactions in viral antibody screening assays after inuenza
vaccination. Am J Epidemiol 141 (11): 108996. PMID
7539579.
[23] Chou R, Human LH, Fu R, Smits AK, Korthuis PT (July
2005). Screening for HIV: a review of the evidence for
the U.S. Preventive Services Task Force. Ann. Intern.
Med. 143 (1): 5573. doi:10.7326/0003-4819-143-1200507050-00010. PMID 15998755.
[24] Kleinman S, Busch M, Hall L, Thomson R, Glynn S,
Gallahan D, Ownby H, Williams A (1998). Falsepositive HIV-1 test results in a low-risk screening setting of voluntary blood donation. Retrovirus Epidemiology Donor Study. JAMA 280 (12): 10805.
doi:10.1001/jama.280.12.1080. PMID 9757856.
[25] Burke D, Brundage J, Redeld R, Damato J, Schable C,
Putman P, Visintine R, Kim H (1988). Measurement
of the false positive rate in a screening program for human immunodeciency virus infections. N Engl J Med
319 (15): 9614. doi:10.1056/NEJM198810133191501.
PMID 3419477.
[26] MacDonald K, Jackson J, Bowman R, Polesky H, Rhame
F, Balfour H, Osterholm M (1989). Performance characteristics of serologic tests for human immunodeciency
virus type 1 (HIV-1) antibody among Minnesota blood
donors. Public health and clinical implications. Ann Intern Med 110 (8): 61721. doi:10.7326/0003-4819-1108-617. PMID 2648922.
[27] Busch M, Eble B, Khayam-Bashi H, Heilbron D, Murphy
E, Kwok S, Sninsky J, Perkins H, Vyas G (1991). Evaluation of screened blood donations for human immunodeciency virus type 1 infection by culture and DNA amplication of pooled cells. N Engl J Med 325 (1): 15.
doi:10.1056/NEJM199107043250101. PMID 2046708.
[28] Van de Perre P, Simonon A, Msellati P, Hitimana D,
Vaira D, Bazubagira A, Van Goethem C, Stevens A,
Karita E, Sondag-Thull D (1991). Postnatal transmission of human immunodeciency virus type 1 from
mother to infant. A prospective cohort study in Kigali, Rwanda.
N Engl J Med 325 (9): 5938.
doi:10.1056/NEJM199108293250901. PMID 1812850.
[29] Update: serologic testing for HIV-1 antibody United
States, 1988 and 1989. MMWR Morb Mortal Wkly Rep
1990; 39:380.

91

[30] Urnovitz H, Sturge J, Gottfried T (1997). Increased sensitivity of HIV-1 antibody detection. Nat Med 3 (11):
1258. doi:10.1038/nm1197-1258. PMID 9359701.
[31] Farzadegan H, Vlahov D, Solomon L, Muoz A, Astemborski J, Taylor E, Burnley A, Nelson K (1993). Detection of human immunodeciency virus type 1 infection
by polymerase chain reaction in a cohort of seronegative
intravenous drug users. J Infect Dis 168 (2): 32731.
doi:10.1093/infdis/168.2.327. PMID 8335969.
[32] https://web.archive.org/20090511203530/http:
//www.fda.gov/cber/gdlns/hivhcvnatbld.htm. Archived
from the original on 11 May 2009. Retrieved 2 November
2013. Missing or empty |title= (help)
[33] View Article. Eurosurveillance. 1 February 2005. Retrieved 2 November 2013.
[34] Defoort, J. P.; Martin, M.; Casano, B.; Prato, S.;
Camilla, C.; Fert, V. (2000). Simultaneous detection of
multiplex-amplied human immunodeciency virus type
1 RNA, hepatitis C virus RNA, and hepatitis B virus DNA
using a ow cytometer microsphere-based hybridization
assay. Journal of clinical microbiology 38 (3): 1066
1071. PMC 86341. PMID 10698998.
[35] Instruction Manual - MPCR Kit for Human Immunodeciency Virus (HIV) Type I/II, MaximBio (PDF). Retrieved 4 December 2013.
[36] Fiebig, E. W.; Wright, D. J.; Rawal, B. D.; Garrett,
P. E.; Schumacher, R. T.; Peddada, L.; Heldebrant,
C.; Smith, R.; Conrad, A.; Kleinman, S. H.; Busch,
M. P. (2003). Dynamics of HIV viremia and antibody seroconversion in plasma donors: Implications
for diagnosis and staging of primary HIV infection. AIDS (London, England) 17 (13): 18711879.
doi:10.1097/01.aids.0000076308.76477.b8.
PMID
12960819.
[37] FDA summary of branched DNA test, accessed 5 October
2006.
[38] South Africa teaching unions criticise HIV testing
in schools http://www.guardian.co.uk/world/2011/feb/
02/south-africa-hiv-testing-schools
[39] Die Burger. Die Burger. M.news24.com. Retrieved 2
November 2013.
[40] False-Positive Oral Fluid Rapid HIV Tests - New York
City, 2005-2008. Cdc.gov. Retrieved 2 November 2013.
[41] http://www.aboutmyhealth.us/oraquick.htm. Retrieved 2
November 2013. Missing or empty |title= (help)
[42] https://web.archive.org/20121214141410/http:
//www.cdc.gov/hiv/topics/testing/rapid/oral-fluid.htm.
Archived from the original on 14 December 2012.
Retrieved 2 November 2013. Missing or empty |title=
(help)
[43] Testing for HIV - Why and How | Free Testing Site
HAF. Freehivtesting.hafnyc.org. Retrieved 2 November
2013.

92

CHAPTER 10. DIAGNOSIS OF HIV/AIDS

[44] https://web.archive.org/20121019035954/http:
//www.harlemunited.org/pep/testing.html.
Archived
from the original on 19 October 2012. Retrieved 2
November 2013. Missing or empty |title= (help)
[45] The scientic evidence for HIV/AIDS. AIDSTruth.org.
Retrieved 13 March 2012.
[46] The Evidence That HIV Causes AIDS. Retrieved 13
March 2012.
[47] The Controversy over HIV and AIDS. Retrieved 13
March 2012.
[48] Defective HIV Test Kit Marketer Settles FTC Charges.
Federal Trade Commission. Retrieved 5 November 2014.

10.12 External links

HIV Antibody Assays - UCSF Medical Center
Complete List of Donor Screening Assays for Infectious Agents and HIV Diagnostic Assays - FDA
Fact sheets from the National Aids Trust (NAT)
in the UK:
General information on HIV testing - Types of
HIV test - Home testing
Bulk procurement of HIV test kits instructions from
the World Health Organization

Chapter 11

Prevention of HIV/AIDS
policies.

11.1 Prevention strategies

11.1.1 Pharmaceutical
Some commonly considered pharmaceutical interventions for the prevention of HIV include the use of the
following:
microbicides for sexually transmitted diseases
Know Aids No Aids road sign in Spiti Valley, Himachel
Pradesh, India, 2010

pre-exposure prophylaxis
post-exposure prophylaxis
HIV vaccines
circumcision (see also Circumcision and HIV)[1]
antiretroviral drugs to reduce viral load in the infected
condoms, and
low dead space syringes
Of these, the only universally medically proven method
for preventing the spread of HIV during sexual intercourse is the correct use of condoms, and condoms are
also the only method promoted by health authorities
worldwide. For HIV positive mothers wishing to prevent
the spread of HIV to their child during birth, antiretroviral drugs have been medically proven to reduce the likelihood of the spread of the infection. Scientists worldwide
are currently researching other prevention systems.

AIDS Clinic, McLeod Ganj, Himachel Pradesh, India, 2010

HIV prevention refers to practices done to prevent the

spread of HIV/AIDS. HIV prevention practices may be
done by individuals to protect their own health and the
health of those in their community, or may be instituted
by governments or other organizations as public health

Increased risk of contracting HIV often correlates with

infection by other diseases, particularly other sexually
transmitted infections. Medical professionals and scientists recommend treatment or prevention of other
infections such as herpes, hepatitis A, hepatitis B,
hepatitis C, human papillomavirus, syphilis, gonorrhea,
and tuberculosis as an indirect way to prevent the spread
of HIV infection. Often doctors treat these conditions
with pharmaceutical interventions.

93

94

CHAPTER 11. PREVENTION OF HIV/AIDS

As of September 2013, condoms are available inside

prisons in Canada, most of the European Union, Australia, Brazil, Indonesia, South Africa, and the US state of
Vermont (on September 17, 2013, the Californian Senate approved a bill for condom distribution inside the
states prisons, but the bill was not yet law at the time
of approval).[2]

11.1.2

Social strategies

In the mean time, research in health communication also

found that importance of advocating critical skills and informing available resources are higher for people with
lower social power, but not necessarily true for people
with more power. African American audiences need to
be educated about strategies they could take in order to
eciently manage themselves in health behaviors such as
mood control, management of drugs and proactive planning for sexual behaviors. However these things are not
as important for European-Americans.[7]

Social strategies do not require any drug or object to be

eective, but rather require persons to change their behavior in order to gain protection from HIV. Some social
strategies which people consider include the following:
sex education
LGBT sex education
needle-exchange programmes
safe injection sites
safe sex
serosorting
sexual abstinence
immigration regulation, and
Making it nancially rewarding to stay healthy[3]

11.1.4 Sexual contact

Consistent condom use reduces the risk of heterosexual
HIV transmission by approximately 80% over the longterm.[8] Where one partner of a couple is infected, consistent condom use results in rates of HIV infection for
the uninfected person of below 1% per year.[9] Some data
supports the equivalence of female condoms to latex condoms however the evidence is not denitive.[10] The use
of the spermicide nonoxynol-9 may increase the risk of
transmission due to the fact that it causes vaginal and
rectal irritation.[11] A vaginal gel containing tenofovir, a
reverse transcriptase inhibitor, when used immediately
before sex, reduce infection rates by approximately 40%
among African women.[12]

Each of these strategies has widely diering levels of ef- Circumcision in sub-Saharan Africa reduces the risk of
cacy, social acceptance and acceptance in the medical HIV infection in heterosexual men by between 38 perand scientic communities.
cent and 66 percent over two years.[13] Based on these
Populations which receive HIV testing are less likely to studies, the World Health Organization and UNAIDS
engage in behaviors with high risk of contracting HIV,[4] both recommended male circumcision as a method of
[14]
so HIV testing is almost always a part of any strategy to preventing female-to-male HIV transmission in 2007.
encourage people to change their behavior to become less Whether it protects against male-to-female transmission
is disputed[15][16] and whether it is of benet in developed
likely to contract HIV.
countries and among men who have sex with men is
Over 60 countries impose some form of travel restriction, undetermined.[17][18][19] For men who have sex with men
either for short or long term stays, for people infected with there is some evidence that the penetrative partner has a
HIV.[5]
lower chance of contracting HIV.[20] Some experts fear
that a lower perception of vulnerability among circumcised men may result in more sexual risk-taking behavior,
11.1.3 Advertising and campaigns
thus negating its preventive eects.[21] Women who have
female genital cutting have an increased risk
Persuasive messages delivered through health advertising undergone
[22]
of
HIV.
and social marketing campaigns which are designed to educate people about the danger of HIV/AIDS and simple
prevention strategies are also an important way of preventing HIV/AIDS. These persuasive messages have successfully increased peoples knowledges about HIV. More
importantly, information sent out through advertising and
social marketing also prove to be eective in promoting more favorable attitudes and intentions toward future
condom use even though they did not bring signicant
change in actual behaviors except those were targeting at
specic behavioral skills.[6][7]

Programs encouraging sexual abstinence do not appear

to aect subsequent HIV risk.[23] Evidence for a benet
from peer education is equally poor.[24] Comprehensive
sexual education provided at school may decrease high
risk behavior.[25] A substantial minority of young people continue to engage in high-risk practices despite
HIV/AIDS knowledge, underestimating their own risk of
becoming infected with HIV.[26] It is not known if treating other sexually transmitted infections is eective in
preventing HIV.[27]

11.1. PREVENTION STRATEGIES

11.1.5

95

Pre exposure

verse eects (for zidovudine ~70% including: nausea

24%, fatigue 22%, emotional distress 13%, headaches
Early treatment of HIV-infected people with antiretrovi- 9%).[38]
rals protected 96% of partners from infection.[28][29] Preexposure prophylaxis with a daily dose of the medications tenofovir with or without emtricitabine is eective 11.1.7 Follow-up care
in a number of groups including: men who have sex with
men, by couples where one is HIV positive, and by young Strategies to reduce recurrence rates of HIV have are be
successful in preventing reinfection. Treatment faciliheterosexuals in Africa.[12]
ties encourage those previously treated for HIV return to
Universal precautions within the health care environment ensure that the infection is being successfully managed.
are believed to be eective in decreasing the risk of New strategies to encouraging re-testing have been the
HIV.[30] Intravenous drug use is an important risk factor use of text messaging and email. These methods of reand harm reduction strategies such as needle-exchange call are now used along with phone calls and letters.[39]
programmes and opioid substitution therapy appear effective in decreasing this risk.[31]
Needle exchange programs (also known as syringe exchange programs) are eective in preventing HIV among
IDUs as well as in the broader community.[32] Pharmacy
sales of syringes and physician prescription of syringes
have been also found to reduce HIV risk.[33] Supervised
injection facilities are also understood to address HIV
risk in the most-at-risk populations.[34] Multiple legal and
attitudinal barriers limit the scale and coverage of these
harm reduction programs in the United States as well
as elsewhere around the world.[34]
The American Centers for Disease Control and Prevention (CDC) conducted a study in partnership with the
Thailand Ministry of Public Health to ascertain the effectiveness of providing people who inject drugs illicitly
with daily doses of the anti-retroviral drug Tenofovir as
a prevention measure. The results of the study were released in mid-June 2013 and revealed a 48.9% reduced
incidence of the virus among the group of subjects who
received the drug, in comparison to the control group
who received a placebo. The Principal Investigator of
the study stated in the Lancet medical journal: We now
know that pre-exposure prophylaxis can be a potentially
vital option for HIV prevention in people at very high risk
for infection, whether through sexual transmission or injecting drug use.[35]

11.1.6

Post exposure

A course of antiretrovirals administered within 48 to

72 hours after exposure to HIV positive blood or genital secretions is referred to as post-exposure prophylaxis.[12] The use of the single agent zidovudine reduces
the risk of subsequent HIV infection vefold following a needle stick injury.[12] Treatment is recommended
after sexual assault when the perpetrators is known to
be HIV positive but is controversial when their HIV
status is unknown.[36] Current treatment regimes typical use lopinavir/ritonavir and lamivudine/zidovudine
or emtricitabine/tenofovir and may decrease the risk
further.[12] The duration of treatment is usually four
weeks[37] and is associated with signicant rates of ad-

11.1.8 Mother-to-child
Programs to prevent the transmission of HIV from mothers to children can reduce rates of transmission by 9299%.[31][40] This primarily involves the use of a combination of antivirals during pregnancy and after birth
in the infant but also potentially include bottle feeding
rather than breastfeeding.[40][41] If replacement feeding
is acceptable, feasible, aordable, sustainable and safe
mothers should avoid breast-feeding their infants however exclusive breast-feeding is recommended during the
rst months of life if this is not the case.[42] If exclusive
breast feeding is carried out the provision of extended antiretroviral prophylaxis to the infant decreases the risk of
transmission.[43]

11.1.9 Vaccination
As of 2012 there is no eective vaccine for HIV or
AIDS.[44] A single trial of the vaccine RV 144 published
in 2009 found a partial ecacy rate of ~30% and has
stimulated optimism in the research community regarding developing a truly eective vaccine.[45] Further trials
of the vaccine are ongoing.[46][47]

11.1.10 Legal system

Laws criminalizing HIV transmission have not been
found an eective way to reduce HIV risk behavior, and
may actually do more harm than good. In the past, many
U.S. states criminalized the possession of needles without a prescription, even going so far as to arrest people as they leave private needle-exchange facilities.[48]
In jurisdictions where syringe prescription status presented a legal barrier to access, physician prescription
programs had shown promise in addressing risky injection behaviors.[49] Epidemiological research demonstrating that syringe access programs are both eective and
cost-eective helped change state and local laws relating
to needle-exchange program (NEP) operation as well as
the status of syringe possession more broadly.[50] As of

96

CHAPTER 11. PREVENTION OF HIV/AIDS

2006, 48 states in the United States authorized needle ex- somehow lead to many thousands of people worldwide
change in some form or allowed the purchase of sterile becoming infected with HIV.[60] In many countries leadsyringes without a prescription at pharmacies.[51]
ers and most of the general public denied both that AIDS
were
Removal of legal barriers to operation of NEPs and other and the risk behaviors which spread HIV existed
[60]
present
outside
of
concentrated
populations.
syringe access initiatives has been identied as an important part of a comprehensive approach to reducing HIV
transmission among injection drug users (IDUs).[50] Legal barriers include both law on the books and law on
the streets, i.e., the actual practices of law enforcement
ocers,[52][53] which may or may not reect the formal
law. Changes in syringe and drug control policy can be
ineective in reducing such barriers if police continue
to treat syringe possession as a crime or participation in
NEP as evidence of criminal activity. [54] Although most
NEPs in the US are now operating legally, many report
some form of police interference.[55]
Research elsewhere has shown similar misalignment between law on the books and law on the streets. For
example, in Kyrgyzstan, although sex work, syringe sales,
and possession of syringes are not criminalized and possession of a small amount of drug has been decriminalized, gaps remain between these policies and law
enforcement knowledge and practice.[56][57][58] To optimize public health eorts targeting vulnerable groups,
law enforcement personnel and public health policies and
practices should be closely aligned. Such alignment can
be improved through policy, training, and coordination
eorts.[58]

11.1.11

Quality in Prevention

The EU-wide Joint Action on Improving Quality in HIV

Prevention, is seeking to increase the eectiveness of
HIV prevention in Europe by using practical Quality Assurance (QA) and Quality Improvement (QI) tools.[59]

11.2 History
11.2.1

1980s

The Centers for Disease Control was the rst organization to recognize the pandemic which came to be called
AIDS.[60] Their announcement came on June 5, 1981
when one of their journals published an article reporting ve cases of pneumonia caused by Pneumocystis
jirovecii, all in gay men living in Los Angeles.[61][62]
In May 1983, scientists isolated a retrovirus which was
later called HIV from an AIDS patient in France.[63] At
this point the disease caused AIDS was proposed to be
caused by HIV, and people began to consider prevention
of HIV as a strategy for preventing AIDS.

In 1987 the United States FDA approved AZT as the rst

pharmaceutical treatment for AIDS.[64] Around the same
time ACT UP was formed, with one of the groups rst
goals being to nd a way to get access to pharmaceutical drugs to treat HIV.[65] When AZT was made publicly
available, it was extremely expensive and unaordable to
all but the most wealthy AIDS patients.[66] The availability of medicine but the lack of access to it sparked large
protests around FDA oces.[67][68]

11.2.2 From 2003

In 2003 there were reports that in Swaziland and
Botswana nearly 4 out of 10 people were HIV positive.[69]
Festus Mogae, president of Botswana, admitted huge infrastructure problems to the international community and
requested foreign intervention in the form of consulting
in health care setup and anti-retroviral drug distribution
programs.[70] and from this began to be personally involved in HIV issues worldwide. In Swaziland the government chose not to immediately address the problem
in the way that international health agencies advised and
many people died.[71] In world media, the governments
of African countries began to similarly be described as
participating in the eort to prevent HIV actively or less
actively.
There came to be international discussion about why
HIV rates in Africa were so high, because if the cause
were known then prevention strategies could be developed. Previously some researchers had suggested that
HIV in Africa was widespread because of unsafe medical practices which somehow transferred blood to patients through procedures such as vaccination, injection,
or reuse of equipment. In March 2003 the WHO released
a statement that almost all infections were, in fact, the result of unsafe practices in heterosexual intercourse.[72]
In response to the rising HIV rates, Cardinal Alfonso
Lpez Trujillo, speaking on behalf of the Vatican, said
that not only was the use of condoms immoral, but also
that condoms were ineective in preventing HIV.[73] The
cardinal was highly criticized by the world health community, who were trying to promote condom use as a way to
prevent the spread of HIV.[74]

In 2001 the United States began a War in Afghanistan related to ghting the Taliban. The Taliban, however, had
opposed local opium growers and the heroin trade; when
the government of Afghanistan fell during the war, opium
production was unchecked. By 2003, the world market
In the 1980s public policy makers and most of the pub- saw an increase in the available heroin supply, and in forlic could not understand that the overlap of sexual and mer Soviet states especially, there was an increase in HIV
needle-sharing networks with the general community had infection due to injection drug use. Eorts were renewed

11.3. SEE ALSO

97

to prevent HIV related to sharing needles.[75][76][77][78]

Since HIV-1 is never cleared by the immune system, removal of the virus is required in order to cure the disease.
The same technique could theoretically be used against a
variety of viruses. The research shows that these molecu11.2.3 From 2011
lar tools also hold promise as a therapeutic vaccine; cells
armed with the nuclease-RNA combination proved imIn July 2011, it was announced by the WHO and UNpervious to HIV infection.
AIDS that a once-daily antiretroviral tablet could significantly reduce the risk of HIV transmission in heterosexual couples.[79] These ndings were based on the results of two trials conducted in Kenya and Uganda, and 11.3 See also
Botswana.
Relationship between education and HIV/AIDS
The Partners PrEP (pre-exposure prophylaxis) trial was
funded by the Bill and Melinda Gates Foundation[80] and
AIDS education and training centers
conducted by the International Clinical Research Center
TeachAIDS
at the University of Washington. The trial followed 4758
heterosexual couples in Kenya and Uganda, in which
one individual was HIV positive and the other was HIV
negative.[79] The uninfected (HIV negative) partner was
given either a once-daily tenofovir tablet, a once-daily
combination tablet of tenofovir and emtricitabine, or a
placebo tablet containing no antiretroviral drug. These
couples also received counselling and had access to free
male and female condoms. In couples taking tenofovir
and tenofovir/emtricitabine, there was a 62% and 73%
decrease, respectively, in the number of HIV infections as
compared to couples who were receiving the placebo.[79]
A similar result was observed with the TDF2 trial, conducted by the United States Centers for Disease Control
in partnership with the Botswana Ministry of Health.[81]
The trial followed 1200 HIV negative men and women
in Francistown, Botswana, a city known to have one of
the worlds highest HIV infection rates.[81] Participants
received either a once-daily tenofovir/emtricitabine combination tablet or a placebo. In those taking the antiretroviral treatment, there was found to be a 63% decrease in
the risk of acquiring HIV, as compared to those receiving
the placebo.[79]
The HIV-1 virus has proved to be tenacious, inserting its
genome permanently into victims DNA, forcing patients
to take a lifelong drug regimen to control the virus and
prevent a fresh attack. Now, a team of Temple University
School of Medicine researchers have designed a way to
snip out the integrated HIV-1 genes for good.
This is one important step on the path toward a permanent cure for AIDS. This is the rst successful attempt to
eliminate latent HIV-1 virus from human cells.

11.4 References
[1] Nandra, Iqbal (28 March 2008). WHO and UNAIDS
announce recommendations from expert consultation on
male circumcision for HIV prevention. who.int. Retrieved 3 July 2011.
[2] Holly Richmond (18 September 2013). Everybody
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[3] Club 25 Pledge
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(1999). Eects of HIV counseling and testing on sexual risk behavior: a meta-analytic review of published research, 1985-1997. American Journal of Public Health
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[5] HIVTravel - Regulations on Entry, Stay, and Residence
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In a study published by the Proceedings of the National

[8] Crosby, R; Bounse, S (March 2012). Condom eectiveAcademy of Sciences (PNAS), Dr. Khalili and colleagues
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own gene repair machinery takes over, soldering the loose
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AS.; Navti, OB.; Akl, EA.; Lo, YR. (2011).
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[25] Ljubojevi, S; Lipozeni, J (2010). Sexually transmitted infections and adolescence.. Acta dermatovenerologica Croatica : ADC 18 (4): 30510. PMID 21251451.
[26] Patel VL, Yoskowitz NA, Kaufman DR, Shortlie EH
(2008). Discerning patterns of human immunodeciency virus risk in healthy young adults. Am J Med
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PMC 2597652. PMID 18724961.
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[29] Anglemyer, A; Rutherford, GW; Baggaley, RC;
Egger, M; Siegfried, N (2011-08-10). Antiretroviral therapy for prevention of HIV transmission
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PMID
21833973.
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Recommendations for prevention of HIV transmission
in health-care settings. MMWR 36 (Suppl 2): 1S18S.
PMID 3112554.
[31] Kurth, AE; Celum, C; Baeten, JM; Vermund, SH;
Wasserheit, JN (March 2011). Combination HIV
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20941553.
[32] World Health Organization. Eectiveness of Sterile Needle and Syringe Programming in Reducing
HIV/AIDS Among Injecting Drug Users (PDF). Evidence for Action Technical Papers. Retrieved 7 January
2012.

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[34] L Beletsky, CS Davis, ED Anderson, S Burris (2008).

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[46] U.S. Army Oce of the Surgeon General (March 21,

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[47] U.S. Army Oce of the Surgeon General (June 2, 2010).

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[49] GE Macalino, D Dhawan Sachdev, JD Rich, C Becker, LJ

Tan, L Beletsky and S Burris. (2009). A national physician survey on prescribing syringes as an HIV prevention
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September 2006. Retrieved 2006-06-10. Note: this article
contains a picture of the interior of a shooting gallery
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S., Vernick, J. S., Case, P.; et al. (2004). Addressing the
'Risk Environment' for Injection Drug Users: The Mysterious Case of the Missing Cop.. Milbank Quarterly 82:
125156. doi:10.1111/j.0887-378x.2004.00304.x. Retrieved 2012-07-05.

[42] WHO HIV and Infant Feeding Technical Consultation

Held on behalf of the Inter-agency Task Team (IATT)
on Prevention of HIV Infections in Pregnant Women,
Mothers and their Infants Consensus statement (PDF).
October 2527, 2006. Archived (PDF) from the original
on April 9, 2008. Retrieved March 12, 2008.

[53] Beletsky L, Burris S, Macalino GE. (2005). Attitudes

of Police Ocers Towards Syringe Access, Occupational Needle-Sticks, and Drug Use: A Qualitative
Study of One City Police Department in the United
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[43] Horvath, T; Madi, BC; Iuppa, IM; Kennedy, GE;

Rutherford, G; Read, JS (2009-01-21).
Interventions for preventing late postnatal mother-tochild transmission of HIV..
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[54] Beletsky L, Grau LE, White E, Bowman S, Heimer R.

(2011). The roles of law, client race and program
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towards humanization of its policy towards drug users.
[57] Eurasian Harm Reduction Network (2011). Implementation of the political declaration and plan of action
on international cooperation towards an integrated and
balanced strategy to counter the world drug problem.
Eurasian Harm Reduction Network.
[58] Beletsky L, Thomas R, Smelyanskaya M, et al. (2012).
Policy reform to shift the health and human rights environment for vulnerable groups: the case of Kyrgyzstans
Instruction 417. Journal of Health and Human Rights 14
(2): e1e15. PMID 23568946.
[59] http://www.qualityaction.eu/
[60] Michael H Merson, Jerey OMalley, David Serwadda,
Chantawipa Apisuk (6 August 2007). The history and
challenge of HIV prevention (PDF). The Lancet. online:
7. doi:10.1016/S0140-6736(08)60884-3. Retrieved 31
March 2011.
[61] Anonymous (1981). Pneumocystis pneumoniaLos
Angeles. Morbidity and Mortality Weekly Report (30):
25052.
[62] Sepkowitz, Kent A. (7 June 2001). AIDS The First 20
Years. NEJM (Massachusetts Medical Society) 344 (23):
176472. doi:10.1056/NEJM200106073442306. PMID
11396444. Retrieved 19 April 2011.
[63] F. Barr-Sinoussi; J. C. Chermann; F. Rey; M. T. Nugeyre
(20 May 1983). Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deciency Syndrome (AIDS)". Science (American Association for the Advancement of Science) 220 (4599): 868
871. doi:10.1126/science.6189183. JSTOR 1690359.
PMID 6189183.
[64] Brown, James (20 March 1987). AEGiS-FDA: Approval
of AZT. aegis.com. AIDS Education Global Information
System. Retrieved 2 July 2011.
[65] ACT UP 1987 Wall Street Action - List of Demands.
actupny.org. March 1987. Retrieved 2 July 2011.
[66] ACT UP/ NY Chronology 1989. actupny.org. 2003.
Retrieved 2 July 2011.
[67] Police Arrest AIDS Protesters Blocking Access to FDA
Oces. Los Angeles Times. 11 Oct 1988.

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[70] Boseley, Sarah (11 July 2003). Bush vows to join

Africas war on Aids. The Guardian (London: GMG).
ISSN 0261-3077. OCLC 60623878. Retrieved 2 July
2011.
[71] Bogus Aids cures ood Swaziland - News - Mail &
Guardian Online. mg.co.za. Mail & Guardian. 30 December 2003. Retrieved 2 July 2011.
[72] de Santis, Dominique (14 March 2003). Expert group
stresses that unsafe sex is primary mode of transmission
of HIV in Africa. who.int. World Health Organization.
Retrieved 2 July 2011.
[73] Johnston, B (14 October 2003). Cardinal wants health
warnings on 'unreliable' condoms. The Daily Telegraph. I
simply wished to remind the public, seconding the opinion
of a good number of experts, that when the condom is
employed as a contraceptive, it is not totally dependable,
and that the cases of pregnancy are not rare. In the case of
the AIDS virus, which is around 450 times smaller than
the sperm cell, the condoms latex material obviously gives
much less security.
[74] Stanford, Peter (22 April 2008). Obituary: Cardinal Alfonso Lpez Trujillo. The Guardian (London: GMG).
ISSN 0261-3077. OCLC 60623878. Retrieved 2 July
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[75] Partt, T. (2003). Drug addiction and HIV infection on
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[76] Grin, N.; Khoshnood, K. (2010). Opium Trade,
Insurgency, and HIV/AIDS in Afghanistan: Relationships and Regional Consequences. Asia-Pacic
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[77] Catherine A. Hankins , Samuel R. Friedman, Tariq Zafar and Steanie A. Strathdee (2002). Transmission and
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P. T.; Botros, B. A.; Sa, N.; Earhart, K. C. (2007).
HIV, Hepatitis C, and Hepatitis B Infections and Associated Risk Behavior in Injection Drug Users, Kabul,
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[68] Loth, Renee (12 October 1988). AIDS Protests close

FDA Headquarters. Boston Globe.

[80] HIV & AIDS Information :: The ecacy of PrEP - The

Partners PrEP trial. aidsmap.com. Retrieved 4 March
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[81] HIV & AIDS Information :: The ecacy of PrEP - The

TDF2 trial. aidsmap.com. 2012. Retrieved 4 March
2012.

11.5. EXTERNAL LINKS

11.5 External links

AVERTs layman guide to HIV prevention
UNAIDS operational guidelines for organizations
promoting HIV prevention
The US governments Centers for Disease Controls
Division of HIV and AIDS Prevention
CDC 2009 Compendium of Evidence-Based HIV
Prevention Interventions

101

Chapter 12

Management of HIV/AIDS
HAART redirects here. For UK estate agency Haart, several more NRTIs were developed but even in combisee Spicerhaart.
nation were unable to suppress the virus for long periods of time and patients still inevitably died.[7] To disThe management of HIV/AIDS normally includes the tinguish from this early anti-retroviral therapy (ART),
the term highly active anti-retroviral therapy (HAART)
use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretro- was introduced. In 1996 by sequential publications in
The New England Journal of Medicine by Hammer and
viral agents that act on dierent stages of the HIV life[8]
[9]
cycle. The use of multiple drugs that act on dierent colleagues and Gulick and coinvestigators illustrating the substantial benet of combining 2 NRTIs with a
viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patients total bur- new class of anti-retrovirals, protease inhibitors, namely
den of HIV, maintains function of the immune system, indinavir. This concept of 3-drug therapy was quickly inand prevents opportunistic infections that often lead to corporated into clinical practice and rapidly showed impressive benet with a 60% to 80% decline in rates of
death.[1]
AIDS, death, and hospitalization.[1]
Treatment has been so successful that in many parts of
the world, HIV has become a chronic condition in which
progression to AIDS is increasingly rare. Anthony Fauci,
head of the United States National Institute of Allergy 12.2 Classes of drugs
and Infectious Diseases, has written, With collective
and resolute action now and a steadfast commitment for
years to come, an AIDS-free generation is indeed within
reach. In the same paper, he noted that an estimated
700,000 lives were saved in 2010 alone by antiretroviral therapy.[2] As another commentary in The Lancet
noted, Rather than dealing with acute and potentially
life-threatening complications, clinicians are now confronted with managing a chronic disease that in the absence of a cure will persist for many decades.[3]
The United States Department of Health and Human
Services and the World Health Organization[4] recommend oering antiretroviral treatment to all patients with
HIV.[5] Because of the complexity of selecting and following a regimen, the potential for side eects, and the
importance of taking medications regularly to prevent Schematic description of the mechanism of the four classes of
viral resistance, such organizations emphasize the impor- currently available antiretroviral drugs against HIV
tance of involving patients in therapy choices and recommend analyzing the risks and the potential benets.[5]
There are ve classes of drugs, which are usually used
in combination, to treat HIV infection. Use of these
drugs in combination can be termed anti-retroviral therapy (ART), combination anti-retroviral therapy (cART)
12.1 History
or highly active anti-retroviral therapy (HAART). Antiretroviral (ARV) drugs are broadly classied by the phase
The rst eective therapy against HIV was the nucleoside of the retrovirus life-cycle that the drug inhibits. Typireverse transcriptase inhibitor (NRTI) zidovudine (AZT). cal combinations include 2 NRTIs as a backbone along
It was approved by the US FDA in 1987.[6] Subsequently with 1 NNRTI, PI or INSTI as a base.[5]
102

12.3. COMBINATION THERAPY

Entry inhibitors (or fusion inhibitors) interfere with
binding, fusion and entry of HIV-1 to the host cell
by blocking one of several targets. Maraviroc and
enfuvirtide are the two currently available agents in
this class. Maraviroc works by targeting CCR5, a
co-receptor located on human helper T-cells. Caution should be used when administering this drug
however due to a possible shift in tropism which allows HIV to target an alternative co-receptor such
as CXCR4. In rare cases, individuals may have a
mutation in the CCR5 delta gene which results in
a nonfunctional CCR5 co-receptor and in turn, a
means of resistance or slow progression of the disease. However, as mentioned previously, this can be
overcome if an HIV variant that targets CXCR4 becomes dominant.[10] To prevent fusion of the virus
with the host membrane, enfuvirtide can be used.
Enfuvirtide is a peptide drug that must be injected
and acts by interacting with the N-terminal heptad
repeat of gp41 of HIV to form an inactive hetero
six-helix bundle, therefore preventing infection of
host cells.[11]
Nucleoside reverse transcriptase inhibitors (NRTI)
and nucleotide reverse transcriptase inhibitors
(NtRTI) are nucleoside and nucleotide analogues
which inhibit reverse transcription. HIV is an RNA
virus and hence unable to become integrated into
the DNA in the nucleus of the human cell; it must
be reverse transcribed into DNA. Since the conversion of RNA to DNA is not done in the mammalian cell it is performed by a viral protein which
makes it a selective target for inhibition. NRTIs are
chain terminators such that once incorporated, work
by preventing other nucleosides from also being incorporated into the DNA chain because of the absence of a 3 OH group. Both act as competitive
substrate inhibitors. Examples of currently used
NRTIs include zidovudine, abacavir, lamivudine,
emtricitabine, and tenofovir.[12]
Non-Nucleoside reverse transcriptase inhibitors
(NNRTI) inhibit reverse transcriptase by binding
to an allosteric site of the enzyme; NNRTIs act
as non-competitive inhibitors of reverse transcriptase. NNRTIs aect the handling of substrate (nucleotides) by reverse transcriptase by binding near
the active site. NNRTIs can be further classied into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and
efavirenz. 2nd generation NNRTIs are etravirine
and rilpivirine.[12] HIV-2 is naturally resistant to
NNRTIs.[13]
Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit
the viral enzyme integrase, which is responsible for
integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors

103
currently under clinical trial, and raltegravir became
the rst to receive FDA approval in October 2007.
Raltegravir has two metal binding groups that compete for substrate with two Mg2+ ions at the metal
binding site of integrase. As of early 2014, two
other clinically approved integrase inhibitors are
elvitegravir and dolutegravir.[14]
Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon
budding from the host membrane. Particularly,
these drugs prevent the cleavage of gag and gag/pol
precursor proteins.[15] Virus particles produced
in the presence of protease inhibitors are defective and mostly non-infectious. Examples of
HIV protease inhibitors are Lopinavir, Indinavir,
Nelnavir, Amprenavir and Ritonavir. Darunavir
and atazanavir are currently recommended as rst
line therapy choices.[5] Maturation inhibitors have a
similar eect by binding to gag, but development of
two experimental drugs in this class, Bevirimat and
Vivecon, was halted in 2010.[16] Resistance to some
protease inhibitors is high. Second generation drugs
have been developed that are eective against otherwise resistant HIV variants.[15]

12.3 Combination therapy

The life cycle of HIV can be as short as about 1.5 days
from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other
cells.[17] HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse
transcription. Its short life-cycle and high error rate cause
the virus to mutate very rapidly, resulting in a high genetic variability of HIV. Most of the mutations either are
inferior to the parent virus (often lacking the ability to
reproduce at all) or convey no advantage, but some of
them have a natural selection superiority to their parent
and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more
active copies of the virus, the greater the possibility that
one resistant to antiretroviral drugs will be made.[18]
When antiretroviral drugs are used improperly, multidrug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes
were available (pre-1997), the reverse transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine,
and lamivudine were used serially or in combination
leading to the development of multi-drug resistant mutations.<ref name= pmid8896496 '>Schmit, JC; Cogniaux, J; Hermans, P; Van Vaeck, C; et al. (1996).
Multiple drug resistance to nucleoside analogues and
nonnucleoside reverse transcriptase inhibitors in an eciently replicating human immunodeciency virus type 1
patient strain (PDF). The Journal of Infectious Diseases

104

CHAPTER 12. MANAGEMENT OF HIV/AIDS

174 (5): 9628. doi:10.1093/infdis/174.5.962. PMID In April 1995, Merck and the National Institute of Al8896496.</ref>
lergy and Infectious Diseases began recruiting patients
Antiretroviral combination therapy defends against resis- for a trial examining the eects of a three drug combinaprotease inhibitor indinavir and two nucleoside
tance by suppressing HIV replication as much as possible, tion of the
[9]
analogs.
illustrating the substantial benet of combinthus reducing the potential pool of spontaneous resistance
ing
2
NRTIs
with a new class of anti-retrovirals, protease
[18]
mutations.
inhibitors, namely indinavir. Later that year David Ho
Combinations of antiretrovirals create multiple obstacles became an advocate of this hit hard, hit early approach
to HIV replication to keep the number of ospring low with aggressive treatment with multiple antiretrovirals
and reduce the possibility of a superior mutation. If a early in the course of the infection.[27] Later reviews in
mutation that conveys resistance to one of the drugs be- the late 90s and early 2000s noted that this approach of
ing taken arises, the other drugs continue to suppress re- hit hard, hit early ran signicant risks of increasing
production of that mutation. With rare exceptions, no side eects and development of multidrug resistance, and
individual antiretroviral drug has been demonstrated to this approach was largely abandoned. The only consensus
suppress an HIV infection for long; these agents must be was on treating patients with advanced immunosupprestaken in combinations in order to have a lasting eect. sion (CD4 counts less than 350/L).[28] Treatment with
As a result, the standard of care is to use combinations antiretrovirals was expensive at the time, ranging from
of antiretroviral drugs.[5] Combinations usually consist $10,000 to $15,000 a year.[29]
of three drugs from at least two dierent classes.[5] This
three drug combination is commonly known as a triple The timing of when to start therapy has continued to
cocktail.[19] Combinations of antiretrovirals are subject be a core controversy within the medical community,
studies have led to more clarity. The NAto positive and negative synergies, which limits the num- though recent
[30]
ACCORD
study observed patients who started anber of useful combinations.
tiretroviral therapy either at a CD4 count of less than 500
In recent years, drug companies have worked together to versus less than 350 and showed that patients who started
combine these complex regimens into simpler formulas, ART at lower CD4 counts had a 69% increase in the risk
termed xed-dose combinations.[20] For instance, there of death.[31] In 2015 the START[32] and TEMPRANO[33]
are now several options that combine 3 drugs into one studies both showed that patients lived longer if they
pill taken once daily.[21][22][23] This greatly increases the started antiretrovirals at the time of their diagnosis, rather
ease with which they can be taken, which in turn in- than waiting for their CD4 counts to drop to a specied
creases the consistency with which medication is taken level.
(adherence),[24] and thus their eectiveness over the longterm. Not taking anti-retrovirals regularly is a cause of Other arguments for starting therapy earlier are that peoshown to have less
resistance development in people who have started tak- ple who start therapy later have been
[34]
recovery
of
their
immune
systems,
and higher CD4
[25]
ing them previously.
Patients who take medications
[35]
counts
are
associated
with
less
cancer.
regularly can stay on one regimen without developing
resistance.[25] This greatly increases life expectancy and
leaves more drugs available to the individual should the Treatment as prevention
need arise.

12.3.1

Fixed-dose combinations

Fixed dose combinations are multiple antiretroviral drugs

combined into a single pill.

12.4 Treatment guidelines

12.4.1

Initiation of antiretroviral therapy

Antiretroviral drug treatment guidelines have changed

over time. Before 1987, no antiretroviral drugs were
available and treatment consisted of treating complications from opportunistic infections and malignancies. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4
counts should be treated, but no consensus formed as to
whether to treat patients with high CD4 counts.[26]

A separate argument for starting antiretroviral therapy

that has gained more prominence is its eect on HIV
transmission. ART reduces the amount of virus in the
blood and genital secretions.[36][37] This has been shown
to lead to dramatically reduced transmission of HIV when
one partner with a suppressed viral load (<50 copies/ml)
has sex with a partner who is HIV negative. In clinical
trial HPTN 052, 1763 serodiscordant heterosexual couples in 9 countries were planned to be followed for at
least 10 years, with both groups receiving education on
preventing HIV transmission and condoms, but only one
group getting ART. The study was stopped early for ethical reasons when it became clear that antiviral treatment provided signicant protection. Of the 28 couples where cross-infection had occurred, all but one had
taken place in the control group consistent with a 96%
reduction in risk of transmission while on ART.[38] The
term treatment as prevention has been used for the
concept of treating patients with HIV to help prevent
the spread of HIV.[39] In 2011, the journal Science gave

12.4. TREATMENT GUIDELINES

the Breakthrough of the Year award to treatment as
prevention.[40]

105
therapy on the basis of clinical and/or psychosocial
factors.

In summary, as the WHO HIV treatment guidelines state,

The ARV regimens now available, even in the poorest The newest World Health Organization guidelines (dated
[4]
countries, are safer, simpler, more ecacious and more September 30, 2015) now agree and state:
[41]
aordable than ever before.
Antiretroviral therapy (ART) should be initiated in
There is a consensus among experts that, once initiated,
everyone living with HIV at any CD4 cell count
antiretroviral therapy should never be stopped. This is
because the selection pressure of incomplete suppression
of viral replication in the presence of drug therapy causes
the more drug sensitive strains to be selectively inhibited.
This allows the drug resistant strains to become dominant.
This in turn makes it harder to treat the infected individual as well as anyone else they infect.[5] One trial where
ART therapy was periodically stopped had higher rates of
opportunistic infections, cancers, heart attacks and death
in patients who interrupted their ART.[42][43]

12.4.2

Guideline Sources

There are several treatment guidelines for HIV-1 infected

adults in the developed world (that is, those countries with
access to all or most therapies and laboratory tests). In
the United States there are both the International AIDS
Society-USA (IAS-USA) (a 501(c)(3) not-for-prot organization in the USA)[44] as well as the US governments
Department of Health and Human Services guidelines.[5]
In Europe there are the European AIDS Clinical Society
guidelines.[45]

Baseline resistance
Baseline resistance is the presence of resistance mutations in patients who have never been treated before for
HIV. In countries with a high rate of baseline resistance,
resistance testing is recommended before starting treatment; or, if the initiation of treatment is urgent, then a
best guess treatment regimen should be started, which
is then modied on the basis of resistance testing.[13]
In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level
resistance to stavudine + lamivudine + nevirapine.[46]
In the US, 10.8% of one cohort of patients who had
never been on ART before had at least one resistance
mutation in 2005.[47] Various surveys in dierent parts
of the world have shown increasing or stable rates of
baseline resistance as the era of eective HIV therapy
continues.[48][49][50][51] With baseline resistance testing,
a combination of antiretrovirals that are likely to be effective can be customized for each patient.

For resource limited countries, most national guidelines closely follow the World Health Organization
12.4.3
guidelines.[4]

Regimens

Most current HAART regimens consist of three drugs: 2

NRTIs (backbone)+ a PI/NNRTI/INSTI (base). Initial regimens use rst-line drugs with a high ecacy
The current guidelines use new criteria to consider start- and low side-eect prole.
ing HAART, as described below. However, there re- The US DHHS preferred initial regimens for adults and
main a range of views on this subject and the decision adolescents in the United States, as of April 2015, are:[5]
of whether to commence treatment ultimately rests with
the patient and his or her doctor.
tenofovir/emtricitabine and raltegravir (an integrase
Current US DHHS guidelines (published April 8, 2015)
inhibitor)
state:
tenofovir/emtricitabine and dolutegravir (an integrase inhibitor)
Antiretroviral therapy (ART) is recommended for
all HIV-infected individuals to reduce the risk of
abacavir/lamivudine (two NRTIs) and dolutegravir
disease progression.
for patients who have been tested negative for the
Current guidelines

ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
Patients starting ART should be willing and able
to commit to treatment and understand the benets
and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and
providers, on a case-by-case basis, may elect to defer

HLA-B*5701 gene allele

tenofovir/emtricitabine, elvitegravir (an integrase
inhibitor) and cobicistat (inhibiting metabolism of
the former) in patients with good kidney function
(gfr > 70)
tenofovir/emtricitabine, ritonavir, and darunavir
(both latter are protease inhibitors)

106

CHAPTER 12. MANAGEMENT OF HIV/AIDS

In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450
enzymes and boost the levels of other protease inhibitors, rather than for its direct antiviral eect. This
boosting eect allows them to be taken less frequently
throughout the day.[52] Cobicistat is used with elvitegravir
for a similar eect but does not have any direct antiviral
eect itself.[53]

As for which antiretrovirals to use, this is complicated by

the fact that many children who are born to mothers with
HIV are given a single dose of nevirapine (an NNRTI) at
the time of birth to prevent transmission. If this fails it can
lead to NNRTI resistance.[58] Also, a large study in Africa
and India found that a PI based regimen was superior to an
NNRTI based regimen in children less than 3 years who
had never been exposed to NNRTIs in the past.[59] Thus
the WHO recommends PI based regimens for children
The WHO preferred initial regimen for adults and adoless than 3.
[41]
lescents as of June 30, 2013 is:
The WHO recommends for children less than 3 years:[41]
tenofovir + lamivudine (or emtricitabine) +
efavirenz

12.4.4

Special populations

Acute infection
In the rst 6 months after infection HIV viral loads tend
to be elevated and people are more often symptomatic
than in later latent phases of HIV disease. There may
be special benets to starting antiretroviral therapy early
during this acute phase, including lowering the viral setpoint or baseline viral load, reduce the mutation rate of
the virus, and reduce the size of the viral reservoir (See
section below on viral reservoirs).[5] The SPARTAC trial
compared 48 weeks of ART vs 12 weeks vs no treatment
in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below
350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped.[54] Since
viral loads are usually very high during acute infection,
this period carries an estimated 26 times higher risk of
transmission.[55] By treating acutely infected patients, it
is presumed that it could have a signicant impact on decreasing overall HIV transmission rates since lower viral
loads are associated with lower risk of transmission (See
section on treatment as prevention). However an overall benet has not been proven and has to be balanced
with the risks of HIV treatment. Therapy during acute
infection carries a grade BII recommendation from the
US DHHS.[5]
Children
HIV can be especially harmful to infants and children,
with one study in Africa showing that 52% of untreated
children born with HIV had died by age 2.[56] By ve
years old, the risk of disease and death from HIV starts
to approach that of young adults. The WHO recommends treating all children less than 5 years old, and
starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml.[41] DHHS guidelines are
more complicated but recommend starting all children
less than 12 months old and children of any age who have
symptoms.[57]

abacavir (or zidovudine) + lamivudine + lopinivir +

ritonivir
and for children 3 years to less than 10 years and adolescents <35 kilograms:
abacavir + lamivudine + efavirenz
US DHHS guidelines are similar but include PI based options for children > 3 years old.[57]
A systematic review assessed the eects and safety of
abacavir-containing regimens as rst-line therapy for
children between 1 month and 18 years of age when compared to regimens with other NRTIs.[60] This review included two trials and two observational studies with almost eleven thousand HIV infected children and adolescents. They measured virologic suppression, death and
adverse events. The authors found that there is no meaningful dierence between abacavir-containing regimens
and other NRTI-containing regimens. The evidence if of
low to moderate quality and therefore it is likely that future research may change these ndings.
Pregnant women
Main articles: HIV and pregnancy and Breastfeeding by
HIV infected mothers
The goals of treatment for pregnant women include the
same benets to the mother as in other infected adults as
well as prevention of transmission to her child. The risk
of transmission from mother to child is proportional to
the plasma viral load of the mother. Untreated mothers
with a viral load >100,000 copies/ml have a transmission
risk of over 50%.[61] The risk when viral loads are < 1000
copies/ml are less than 1%.[62] ART for mothers both before and during delivery and to mothers and infants after
delivery are recommended to substantially reduce the risk
of transmission.[63] The mode of delivery is also important, with a planned Caesarian section having a lower risk
than vaginal delivery or emergency Caesarian section.[64]
HIV can also be detected in breast milk of infected mothers and transmitted through breast feeding.[65] The WHO

12.6. RESPONSE TO THERAPY

107

balances the low risk of transmission through breast feed- 12.6 Response to therapy
ing from women who are on ART with the benets of
breastfeeding against diarrhea, prneumonia and malnutrition. It also strongly recommends that breastfeeding in- 12.6.1 Virologic response
fants receive prophylactic ART.[41] In the US, the DHHS
recommends against women with HIV breastfeeding.[63] Suppressing the viral load to undetectable levels (<50
copies per ml) is the primary goal of ART.[52] This
should happen by 24 weeks after starting combination
Older adults
therapy.[44] Viral load monitoring is the most important
predictor of response to treatment with ART.[79] Levels
With improvements in HIV therapy, several studies now higher than 200 copies per ml is considered virologic failestimate that patients on treatment in high-income coun- ure, and should prompt further testing for potential viral
tries can expect a normal life expectancy.[66][67] This resistance.[5] Lack of viral load suppression on ART is
means that a higher proportion of people living with HIV termed virologic failure.
are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data
that older people with HIV have a blunted CD4 response
to therapy but are more likely to achieve undetectable vi- 12.6.2 Immunologic response
ral levels.[68] However, not all studies have seen a difference in response to therapy.[69] Current guidelines do CD4 cell counts are another key measure of immune stanot have separate treatment recommendations for older tus and ART eectiveness.[44] CD4 counts should rise 50
adults, but it is important to take into account that older to 100 cells per ml in the rst year of therapy.[52] There
patients are more likely to be on multiple non-HIV med- can be substantial uctuation in CD4 counts of up to 25%
ications and consider drug interactions with any poten- based on the time of day or concominant infections.[80]
tial HIV medications.[70] There are also increased rates In one long term study, the majority of increase in CD4
of HIV associated non-AIDS conditions (HANA) such cell counts was in the rst two years after starting ART
as heart disease, liver disease and dementia that are mul- with little increase afterwards. This study also found that
tifactorial complications from HIV, associated behaviors, patients who began ART at lower CD4 counts contincoinfections like hepatitis B, hepatitis C, and human pa- ued to have lower CD4 counts than those who started at
pilloma virus (HPV) as well as HIV treatment.[70]
higher CD4 counts.[81] When viral suppression on ART
is achieved but without a corresponding increase in CD4
counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse out12.5 Concerns
comes, there is no consensus on how to adjust therapy
There are several concerns about antiretroviral regimens to immunologic failure and whether switching therapy is
benecial. DHHS guidelines do not recommend switchthat should be addressed before initiating:
ing an otherwise suppressive regimen.[5][82]
Intolerance: The drugs can have serious side-eects
which can lead to harm as well as keep patients from
taking their medications regularly.

12.7 Salvage therapy

Resistance: Not taking medication consistently

can lead to low blood levels that foster drug In patients who have persistently detectable viral loads
resistance.[71]
while taking ART, tests can be done to investigate
Cost: The WHO maintains a database of world whether there is drug resistance. Most commonly a
ART costs[72] which have dropped dramatically in genotype is sequenced which can be compared with
and resistance
recent years as more rst line drugs have gone o- databases of other HIV viral genotypes
[83]
If there is exproles
to
predict
response
to
therapy.
[73]
patent. A one pill, once a day combination thertensive
resistance
a
phenotypic
test
of
a
patients
virus
apy has been introduced in South Africa for as little
against
a
range
of
drug
concentrations
can
be
performed,
[74]
One recent study
as $10 per patient per month.
estimated an overall cost savings to ART therapy in but is expensive and can[5]take several weeks, so genotypes
South Africa given reduced transmission.[75] In the are generally preferred. Using information from a genoUnited States, new on-patent regimens can cost up type or phenotype, a regimen of 3 drugs from at least 2
classes is constructed that will have the highest probabilto $28,500 per patient, per year.[76][77]
ity of suppressing the virus. If a regimen cannot be con Public health: Individuals who fail to use antiretro- structed from recommended rst line agents it is termed
virals as directed can develop multi-drug resistant salvage therapy, and when 6 or more drugs are needed it
is termed mega-HAART.[84]
strains which can be passed onto others.[78]

108

CHAPTER 12. MANAGEMENT OF HIV/AIDS

12.8 Structured treatment inter- 12.10 HIV Postexposure Prophyruptions

laxis (PEP)
Drug holidays (or structured treatment interruptions)
are intentional discontinuations of antiretroviral drug
treatment. As mentioned above, randomized controlled
studies of structured treatment interruptions have shown
higher rates of opportunistic infections, cancers, heart attacks and death in patients who took drug holidays.[42][43]
With the exception of post exposure prophylaxis, current
treatment guidelines do not call for the interruption of
drug therapy once it has been initiated.[5][41][44]

12.9 Adverse eects

Each class and individual antiretroviral carries unique
risks of adverse side eects.

12.9.1

NRTIs

The NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and
lipoatrophy.[52] Current rst line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely
to cause mitochondrial dysfunction.[85][86]

12.9.2

When people are exposed to HIV-positive infectious

bodily uids either through skin puncture, contact with
mucous membranes or contact with damaged skin they
are at risk for acquiring HIV. Pooled estimates give a risk
of transmission with puncture exposures of 0.3%[90] and
mucous membrane exposures 0.63%.[91] United States
guidelines state that feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered
potentially infectious unless they are visibly bloody.[92]
Given the rare nature of these events, rigorous study of
the protective abilities of antiretrovirals are limited but
do suggest that taking antiretrovirals afterwards can prevent transmission.[93] It is unknown if three medications
are better than two. The sooner after exposure that ART
is started the better, but after what period they become
ineective is unknown, with the US Public Health Service Guidelines recommending starting prophylaxis up to
a week after exposure.[92] They also recommend treating for a duration of four weeks based on animal studies. Their recommended regimen is emtricitabine + tenofovir + raltegravir (an INSTI). The rationale for this regimen is that it is tolerable, potent, and conveniently administered, and it has been associated with minimal drug
interactions.[92] People who are exposed to HIV should
have follow up HIV testing at six, 12, and 24 weeks.

NNRTIs

NNRTIs are generally safe and well tolerated. The

main reason for discontinuation of efavirenz is 12.11 Pregnancy planning
neuro-psychiatric eects including suicidal ideation.
Nevirapine can cause severe hepatotoxicity, especially in
Further information: HIV and pregnancy
women with high CD4 counts.[87]

12.9.3

Protease inhibitors

Protease inhibitors (PIs) are often given with ritonavir,

a strong inhibitor of cytochrome P450 enzymes, leading
to numerous drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and elevated risk of heart attack.[88]

12.9.4

Integrase inhibitors

Integrase inhibitors (INSTIs) are among the best tolerated

of the antiretrovirals with excellent short and medium
term outcomes. Given their relatively new development
there is less long term safety data. They are associated
with an increase in creatinine kinase levels and rarely
myopathy.[89]

Women with HIV have been shown to have decreased fertility which can aect available reproductive options.[94]
In cases where the woman is HIV negative and the man is
HIV positive, the primary assisted reproductive method
used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man
has achieved an undetectable plasma viral load.[95] In
the past there have been cases of HIV transmission
to an HIV-negative partner through processed articial
insemination,[96] but a large modern series in which followed 741 couples where the man had a stable viral load
and semen samples were tested for HIV-1, there were no
cases of HIV transmission.[97]
For cases where the woman is HIV positive and the man
is HIV negative, the usual method is articial insemination.[95] With appropriate treatment the risk of motherto-child infection can be reduced to below 1%.[98]

12.13. SEE ALSO

12.12 Towards a cure

People living with HIV can currently expect to live a
normal life span if able to achieve durable viral suppression on combination antiretroviral therapy. However
this requires lifelong medication and will still suer from
higher rates of cardiovascular, renal, liver and neurologic
disease.[99] This has prompted further research towards a
cure for HIV.

12.12.1

Berlin patient

So far only one adult (the so-called "Berlin patient") has

been potentially cured and has been o of treatment since
2006 with no detectable virus.[100] This was achieved
through two bone marrow transplants that replaced his
immune system with a donors that did not have the CCR5
cell surface receptor, which is needed for some variants
of HIV to enter a cell.[101] Bone marrow transplants carry
their own signicant risks including potential death and
was only attempted because it was necessary to treat a
blood cancer he had. Attempts to replicate this have
not been successful and given the risks, expense and rarity of CCR5 negative donors, bone marrow transplant is
not seen as a mainstream option.[99] It has inspired research into other methods to try to block CCR5 expression through gene therapy. A zinc-nger nuclease has
been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while
o antiretroviral treatment.[102]

12.12.2

Viral reservoirs

The main obstacle to conventional antiretroviral therapy

eliminating HIV infection is that HIV is able to integrate itself into the DNA of host cells and rest in a latent
state, while antiretrovirals only attack actively replicating
HIV. The cells in which HIV lays dormant are called the
viral reservoir, and one of the main sources is thought
to be central memory and transitional memory CD4+
T cells.[103] Recent reports of the cure of HIV in two
infants[104] are presumably due to the fact that treatment
was initiated within hours of infection, preventing HIV
from establishing a deep reservoir.[105] Currently there is
work being done to try and activate reservoir cells into
replication so that the virus is forced out of latency and
can be attacked by antiretrovirals and the host immune
system. Targets include histone deacetylase (HDAC)
which represses transcription and if inhibited can lead to
increased cell activation. The HDAC inhibitors valproic
acid and vorinostat have been used in human trials with
only preliminary results so far.[106][107]

109

12.12.3 Immune activation

Even with all latent virus deactivated, it is thought
that a vigorous immune response will need to be induced to clear all the remaining infected cells.[99] Current
strategies include using cytokines to restore CD4+ cell
counts as well as therapeutic vaccines to prime immune
responses.[108] One such candidate vaccine is Tat Oyi, developed by Biosantech.[109] This vaccine is based on the
HIV protein tat. A brief report of their phase I/II clinical
trial reported it was safe and well tolerated in 48 HIVpositive patients.[110] Animal models have shown the generation of neutralizing antibodies and lower levels of HIV
viremia.[111]

12.13 See also

Antiviral drug
Discovery and Development of HIV Protease Inhibitors
Discovery and Development of Non-Nucleoside Reverse Transcriptase Inhibitors
Discovery and development of nucleoside and nucleotide reverse transcriptase inhibitors

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doi:10.1016/S0140-6736(04)17140-7.

[45] EACS Guidelines. European AIDS Clinical Society

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[57] Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (PDF). US Department of Health
and Human Services. February 12, 2014. pp. 5061.
Retrieved April 11, 2014.

[46] UK Group on Transmitted HIV Drug Resistance; Cane,

P; Chrystie, I; Dunn, D; et al. (2005). Time trends
in primary resistance to HIV drugs in the United Kingdom: Multicentre observational study. BMJ 331 (7529):
136871. doi:10.1136/bmj.38665.534595.55. PMC
1309643. PMID 16299012.
[47] Prevalence of antiretroviral drug resistance mutations in
chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation
of antiretroviral therapy. Clinical Infectious Diseases 40
(3): 46874. Feb 1, 2005. doi:10.1086/427212. PMID
15668873.
[48] National sentinel surveillance of transmitted drug resistance in antiretroviral-naive chronically HIV-infected
patients in France over a decade: 2001-2011. J Antimicrob Chemother 68 (11): 262631. Nov 2013.
doi:10.1093/jac/dkt238. PMID 23798669.

[58] Response to Nonnucleoside Reverse Transcriptase

Inhibitor-Based Therapy in HIV-Infected Children with
Perinatal Exposure to Single-Dose Nevirapine. AIDS
Research and Human Retroviruses 25 (10): 989996.
October 2009. doi:10.1089/aid.2009.0054.
[59] Nevirapine versus Ritonavir-Boosted Lopinavir for HIVInfected Children. New England Journal of Medicine 366
(25): 23802389. 2012. doi:10.1056/NEJMoa1113249.
[60] Adetokunboh, Olatunji O.; Schoonees, Anel; Balogun,
Tolulope A.; Wiysonge, Charles S. (26 October 2015).
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and meta-analysis. BMC Infectious Diseases 15 (1).
doi:10.1186/s12879-015-1183-6.

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[61] Maternal Levels of Plasma Human Immunodeciency Virus Type 1 RNA and the Risk of Perinatal
Transmission. NEJM 341 (6): 394402. 1999.
doi:10.1056/NEJM199908053410602.
[62] Mother-to-Child Transmission of HIV Infection in the
Era of Highly Active Antiretroviral Therapy. Clin Infect
Dis. 40 (3): 458465. 02/01/2005. doi:10.1086/427287.
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[63] Recommendations for Use of Antiretroviral Drugs in
Pregnant HIV-1-Infected Women for Maternal Health
and Interventions to Reduce Perinatal HIV Transmission
in the United States (PDF). US DHHS. March 28, 2014.
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[64] Mother-to-Child Transmission of HIV Infection in the
Era of Highly Active Antiretroviral Therapy. Clin Infect
Dis 40 (3): 458465. 02/01/2005. doi:10.1086/427287.
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[65] Longitudinal analysis of human immunodeciency virus
type 1 RNA in breast milk and of its relationship to
infant infection and maternal disease. The Journal of
infectious diseases 187 (5): 741747. Mar 1, 2003.
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[66] Impact on life expectancy of HIV-1 positive individuals
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[67] Life expectancy living with HIV: recent estimates and future implications..
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doi:10.1097/QCO.0b013e32835ba6b1.
[68] Older age and the response to and tolerability of antiretroviral therapy. Arch Intern Med 167 (7): 684. April
9, 2007. doi:10.1001/archinte.167.7.684.
[69] Virologic and immunologic response to HAART, by age
and regimen class. AIDS 24 (16): 24692479. October
2010. doi:10.1097/QAD.0b013e32833e6d14.
[70] Management of human immunodeciency virus infection in advanced age. JAMA 309 (13): 1397. April 3,
2013. doi:10.1001/jama.2013.2963.
[71] Antiretroviral medication adherence and the development of class-specic antiretroviral resistance. AIDS 23 (9): 10351046. Jun 1, 2009.
doi:10.1097/QAD.0b013e32832ba8ec.
[72] Global Price Reporting Mechanism for HIV, tuberculosis and malaria. World Health Organization. Retrieved
2014-04-11.
[73] Antiretroviral Drug Prices. Avert. Retrieved 2014-0412.
[74] New one-pill, $10-per-month anti-retroviral AIDS treatment debuts in South Africa. The Raw Story. Agence
France-Presse. 4/8/2013. Retrieved 2014-04-14. Check
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[75] Cost-Eectiveness of HIV Treatment as Prevention in

Serodiscordant Couples. NEJM 369 (18): 17151725.
2013. doi:10.1056/NEJMsa1214720.
[76] Horn, Tim (August 28, 2012). Activists Protest Stribilds
$28,500 Price Tag. AIDSMeds. Retrieved 2014-04-11.
[77] Stribild. GoodRx. Retrieved 2014-04-11.
[78] Beardsley, T (1998).
Coping with HIVs ethical dilemmas. Scientic American 279 (1): 106
7. doi:10.1038/scienticamerican0798-106. PMID
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[79] The use of plasma HIV RNA as a study endpoint in ecacy trials of antiretroviral drugs. AIDS 13 (7): 797804.
May 7, 1999. doi:10.1097/00002030-199905070-00008.
PMID 10357378.
[80] Within-Subject Variation in CD4 Lymphocyte
Count in Asymptomatic Human Immunodeciency
Virus Infection: Implications for Patient Monitoring. J Infect Dis. 169 (1): 2836. 1994-01-01.
doi:10.1093/infdis/169.1.28.
[81] Long-term increase in CD4+ T-cell counts during
combination antiretroviral therapy for HIV-1 infection. AIDS 24 (12): 18671876. Jul 31, 2010.
doi:10.1097/QAD.0b013e32833adbcf.
[82] The Absence of CD4+ T Cell Count Recovery Despite
Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy: Clinical Risk, Immunological Gaps,
and Therapeutic Options. Clin Infect Dis. 48 (3): 328
337. 02/01/2009. doi:10.1086/695852. Check date values in: |date= (help)
[83] Stanford University HIV Drug Resistance Database.
Retrieved 2014-04-13.
[84] HIV drug susceptibility and treatment response to megaHAART regimen in patients from the Frankfurt HIV
cohort.. Antivir Ther 5 (1): 4955. 2000. PMID
10846593.
[85] Toxicity of antiviral nucleoside analogs and the
human mitochondrial DNA polymerase.
J Biol
Chem 276 (44):
4084757.
November 2001.
doi:10.1074/jbc.M106743200. PMID 11526116.
[86] Assessment of mitochondrial toxicity in human cells
treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors.. Antimicrob
Agents Chemother 46 (3): 71623. March 2002.
doi:10.1128/aac.46.3.716-723.2002.
PMC 127499.
PMID 11850253.
[87] Non-nucleoside reverse transcriptase inhibitors: a review
on pharmacokinetics, pharmacodynamics, safety and tolerability. J Int AIDS Soc. 16 (1): 114. 2013.
doi:10.7448/ias.16.1.18567. PMC 3764307. PMID
24008177.
[88] Protease inhibitor-based regimens for HIV therapy:
safety and ecacy.. J Acquir Immune Dec Syndr. 45
Suppl 1 (Supplement 1): S513; quiz S2831. June
2007. doi:10.1097/QAI.0b013e3180600709. PMID
17525691.

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113

[89] Tolerability of HIV integrase inhibitors.

Curr [103] HIV reservoir size and persistence are driven by T cell
Opin HIV AIDS. 7 (5): 4228. September 2012.
survival and homeostatic proliferation. Nat Med 15 (8):
doi:10.1097/COH.0b013e328356682a.
PMID
893900. August 2009. doi:10.1038/nm.1972.
22886031.
[104] McNeil, Donald (3/5/2014). Early Treatment Is Found
to Clear H.I.V. in a 2nd Baby. New York Times. Re[90] Bell, D M (May 19, 1997). Occupational risk of human
trieved 2014-04-14. Check date values in: |date= (help)
immunodeciency virus infection in healthcare workers: an overview. Am. J. Med. 102 (5B): 915.
doi:10.1016/s0002-9343(97)89441-7. PMID 9845490. [105] Absence of Detectable HIV-1 Viremia after Treatment
Cessation in an Infant. NEJM 369 (19): 18281835.
11/7/2013. doi:10.1056/NEJMoa1302976. Check date
[91] The risk of occupational human immunodeciency virus
values in: |date= (help)
infection in health care workers: Italian multicenter
study. Arch Intern Med 153 (12): 1451. June 28, 1993.
[106] Antiretroviral Intensication and Valproic Acid Lack
doi:10.1001/archinte.1993.00410120035005.
Sustained Eect on Residual HIV-1 Viremia or Resting
CD4+ Cell Infection. PLoS ONE 5 (2): e9390. 2010-2[92] Updated US Public Health Service Guidelines for the
23. doi:10.1371/journal.pone.0009390. PMC 2826423.
Management of Occupational Exposures to Human ImPMID 20186346. Check date values in: |date= (help)
munodeciency Virus and Recommendations for Postexposure Prophylaxis. Infection Control and Hospital Epidemiology 34 (9): 87592. September 1, 2013. [107] Administration of vorinostat disrupts HIV-1 latency in
patients on antiretroviral therapy. Nature 487 (7408):
doi:10.1086/672271. PMID 23917901.
482485. 2012-07-26. doi:10.1038/nature11286.
[93] A CaseControl Study of HIV Seroconversion
in Health Care Workers after Percutaneous Ex- [108] Immune interventions in HIV infection. Immunol Rev
254 (1): 355371. 7/1/2013. doi:10.1111/imr.12083.
posure.
NEJM 337 (21): 148590.
1997.
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doi:10.1056/NEJM199711203372101. PMID 9366579.
[94] Decreased fertility among HIV-1-infected women at- [109] Programs TAT Vaccin VIH | BIOSANTECH SA ".
www.biosantech.org. Retrieved 2015-10-27.
tending antenatal clinics in three African cities. J. Acquir. Immune Dec. Syndr. 25 (4): 34552. Dec 1, [110] Tat Oyi-based candidate therapeutic vaccine: a suc2000. doi:10.1097/00126334-200012010-00008. PMID
cessful phase 1 clinical trial in HIV-1 infected pa11114835.
tients | Retroviruses-2015 | OMICS International. retrovirus.conferenceseries.com. Retrieved 2015-10-27.
[95] Savasi, V; Mandia, L; Laoreti, A; Cetin, I (2012).
Reproductive assistance in HIV serodiscordant cou- [111] Watkins, Jennifer D.; Lancelot, Sophie; Campbell, Grant
ples. Human Reproduction Update 19 (2): 13650.
R.; Esquieu, Didier; de Mareuil, Jean; Opi, Sandrine;
doi:10.1093/humupd/dms046. PMID 23146867.
Annappa, Sylvie; Salles, Jean-Pierre; Loret, Erwann P.
[96] HIV-1 infection and articial insemination with processed semen. MMWR 39 (15): 249, 2556. Apr 20,
1990. PMID 2109169.
[97] Safety of sperm washing and ART outcome in 741 HIV1-serodiscordant couples. Hum. Reprod. 22 (3): 772
777. 03/01/2007. doi:10.1093/humrep/del422. Check
date values in: |date= (help)
[98] Coutsoudis, A; Kwaan, L; Thomson, M (2010). Prevention of vertical transmission of HIV-1 in resource-limited
settings. Expert Review of Anti-infective Therapy 8 (10):
116375. doi:10.1586/eri.10.94. PMID 20954881.
[99] HIV cure research:
Advances and prospects.
Virology.
454-455:
340352.
April 2014.
doi:10.1016/j.virol.2014.02.021.
[100] Rosenberg, Tina (May 29, 2011). The Man Who Had
HIV and Now Does Not. New York Magazine. Retrieved
2014-04-12.
[101] Long-Term Control of HIV by CCR5 Delta32/Delta32
Stem-Cell Transplantation. NEJM 360 (7): 6928.
2009. doi:10.1056/NEJMoa0802905. PMID 19213682.
[102] Gene Editing of CCR5 in Autologous CD4 T Cells of
Persons Infected with HIV. NEJM 370 (10): 90110.
2014. doi:10.1056/NEJMoa1300662. PMID 24597865.

(2006-01-01). Reservoir cells no longer detectable after

a heterologous SHIV challenge with the synthetic HIV-1
Tat Oyi vaccine. Retrovirology 3: 8. doi:10.1186/17424690-3-8. ISSN 1742-4690. PMC 1434768. PMID
16441880.

12.15 External links

AIDSinfo - Comprehensive resource for HIV/AIDS
treatment and clinical trial information from the U.
S. Department of Health and Human Services
ASHM - Australian Commentary on HHS Guidelines for the use of Antiretroviral Agents in HIV-1Infected Adults and Adolescents
Origins of antiretroviral combination therapy
Viral Load research papers, including eectiveness
of HAART on reducing viral load
Current status of gene therapy strategies to treat
HIV/AIDS

Chapter 13

Epidemiology of HIV/AIDS
HIV/AIDS is a global pandemic.[1] As of 2012, approximately 35.3 million people are living with HIV
globally.[2] Of these, approximately 17.2 million are men,
16.8 million are women and 3.4 million are less than 15
years old.[3] There were about 1.8 million deaths from
AIDS in 2010, down from 2.2 million in 2005.[3]
Sub-Saharan Africa is the region most aected. In 2010,
an estimated 68% (22.9 million) of all HIV cases and
66% of all deaths (1.2 million) occurred in this region.[4]
This means that about 5% of the adult population in
this area is infected.[5] Here, in contrast to other regions,
women compose nearly 60% of cases.[4] South Africa has
the largest population of people with HIV of any country
in the world, at 5.9 million.[4]

AIDS and HIV prevalence 2009

No data
< 0.1%
0.1 - 0.5%
0.5 - 1%
1 - 5%
5 - 15%
15 - 50%

South & South East Asia (a region with about 2 billion

people as of 2010, over 30% of the global population)
has an estimated 4 million cases (12% of all people living with HIV), with about 250,000 deaths in 2010.[5] Approximately 2.5 million of these cases are in India, where
however the prevalence is only about 0.3% (somewhat
higher than that found in Western and Central Europe or
Canada).[4] Prevalence is lowest in East Asia at 0.1%.[5]

Disability-adjusted life year for HIV and AIDS per 100,000

inhabitants
no data
10
1025
2550
50100
100500
5001000
10002500
25005000
50007500
7500-10000
10000-50000
50000

In 2008 approximately 1.2 million people in the United

States had HIV; 20% did not realize that they were
infected.[6] Over the 10-year period from 1999-2008 it
resulted in about 17,500 deaths per year.[6] In the United
Kingdom, as of 2009, there were approximately 86,500
cases and 516 deaths.[7] In Australia, as of 2009, there
were about 21,171 cases and around 23 deaths.[8] In
Canada as of 2008 there were about 65,000 cases and
53 deaths.[9]
A reconstruction of its genetic history shows that the HIV
pandemic almost certainly originated in Kinshasa, the
capital of the Democratic Republic of the Congo, around
1920.[10] AIDS was rst recognized in 1981 and by 2009
had caused nearly 30 million deaths.[11]

13.1 By region
See also: List of countries by HIV/AIDS adult prevalence
rate

114

13.1. BY REGION

115

The pandemic is not homogeneous within regions, with

some countries more aicted than others. Even at the
country level, there are wide variations in infection levels between dierent areas. The number of people infected with HIV continues to rise in most parts of the
world, despite the implementation of prevention strategies, Sub-Saharan Africa being by far the worst-aected
region, with an estimated 22.9 million at the end of 2010,
68% of the global total.[12]

Life expectancy in years

70
World

South and South East Asia have an estimated 12% of

the global total.[13] The rate of new infections has fallen
slightly since 2005 after a more rapid decline between
1997 and 2005.[12] Annual AIDS deaths have been continually declining since 2005 as antiretroviral therapy has
become more widely available.

40

Botswana
South Africa
Kenya

60
Swaziland
50

Uganda
Zimbabwe
Sub-Saharan Africa

30

20

13.1.1

Sub-Saharan Africa
10

0
1960

1970

1980

1990

2000

2010

Graphs of life expectancy at birth for some sub-Saharan countries showing the fall in the 1990s primarily due to the AIDS
pandemic.[14]

less aected by the pandemic. Several countries reportedly have prevalence rates around 2 to 3%, and no country
has rates above 10%. In Nigeria and Cte d'Ivoire, two
of the regions most populous countries, between 5 and
7% of adults are reported to carry the virus.
Across Sub-Saharan Africa, more women are infected
with HIV than men, with 13 women infected for every
10 infected men. This gender gap continues to grow.
Throughout the region, women are being infected with
HIV at earlier ages than men. The dierences in infecEstimated HIV infection in Africa in 2011.
tion levels between women and men are most pronounced
among young people (aged 1524 years). In this age
group, there are 36 women infected with HIV for every
Main article: HIV/AIDS in Africa
10 men. The widespread prevalence of sexually transmitted
diseases, the practice of scarication, unsafe blood
Sub-Saharan Africa remains the hardest-hit region. HIV
transfusions,
and the poor state of hygiene and nutrition
infection is becoming endemic in sub-Saharan Africa,
in
some
areas
may all be facilitating factors in the transwhich is home to just over 12% of the worlds populamission
of
HIV-1
(Bentwich et al., 1995).
[12]
tion but two-thirds of all people infected with HIV.
The adult HIV prevalence rate is 5.0% and between 21.6 Mother-to-child transmission is another contributing facmillion and 24.1 million total are aected.[12] However, tor in the transmission of HIV-1 in developing nations.
the actual prevalence varies between regions. Presently, Due to a lack of testing, a shortage in antenatal theraSouthern Africa is the hardest hit region, with adult preva- pies and through the feeding of contaminated breast milk,
lence rates exceeding 20% in most countries in the region, 590,000 infants born in developing countries are infected
and 30% in Swaziland and Botswana.
with HIV-1 per year. In 2000, the World Health OrganiEastern Africa also experiences relatively high levels of zation estimated that 25% of the units of blood transfused
prevalence with estimates above 10% in some countries, in Africa were not tested for HIV, and that 10% of HIV
although there are signs that the pandemic is declining in infections in Africa were transmitted via blood.
this region. West Africa on the other hand has been much Poor economic conditions (leading to the use of dirty nee-

116

CHAPTER 13. EPIDEMIOLOGY OF HIV/AIDS

dles in healthcare clinics) and lack of sex education contribute to high rates of infection. In some African countries, 25% or more of the working adult population is
HIV-positive. Poor economic conditions caused by slow
onset-emergencies, such as drought, or rapid onset natural disasters and conict can result in young women and
girls being forced into using sex as a survival strategy.[15]
Worse still, research indicates that as emergencies, such
as drought, take their toll and the number of potential
'clients decreases, women are forced by clients to accept
greater risks, such as not using contraceptives.[15]

(480,000) occur in this region than in any other except

sub-Saharan Africa. The geographical size and human
diversity of South and South-East Asia have resulted in
HIV epidemics diering across the region. The AIDS
picture in South Asia is dominated by the epidemic in India.
In South and Southeast Asia, the HIV epidemic remains
largely concentrated in injecting drug users, men who
have sex with men, sex workers, and clients of sex workers and their immediate sexual partners.[20] In the Philippines, in particular, sexual contact between males comprise the majority of new infections. An HIV surveillance
study conducted by Dr. Louie Mar Gangcuangco and colleagues from the University of the Philippines-Philippine
General Hospital showed that out of 406 MSM tested for
HIV in Metro Manila, HIV prevalence was 11.8% (95%
condence interval: 8.7- 15.0).[21][22]

AIDS-denialist policies have impeded the creation of effective programs for distribution of antiretroviral drugs.
Denialist policies by former South African President
Thabo Mbeki's administration led to several hundred
thousand unnecessary deaths.[16][17] UNAIDS estimates
that in 2005 there were 5.5 million people in South Africa
infected with HIV 12.4% of the population. This was Migrants, in particular, are vulnerable and 67% of those
an increase of 200,000 people since 2003.
infected in Bangladesh and 41% in Nepal are migrants reAlthough HIV infection rates are much lower in Nigeria turning from India.[20] This is in part due to human trafthan in other African countries, the size of Nigerias pop- cking and exploitation, but also because even those miulation meant that by the end of 2003, there were an es- grants who willingly go to India in search of work are oftimated 3.6 million people infected. On the other hand, ten afraid to access state health services due to concerns
Uganda, Zambia, Senegal, and most recently Botswana over their immigration status.[20]
have begun intervention and educational measures to slow
the spread of HIV, and Uganda has succeeded in actually
13.1.4 East Asia
reducing its HIV infection rate.
Main article: HIV/AIDS in Asia

13.1.2

Middle East and North Africa

The national HIV prevalence levels in East Asia is 0.1% in

the adult (1549) group. However, due to the large populations of many East Asian nations, this low national HIV
prevalence still means that large numbers of people are infected with HIV. The picture in this region is dominated
by China. Much of the current spread of HIV in China
is through injecting drug use and paid sex. In China, the
Approximately 500,000 people are living with HIV number was estimated at between 430,000 and 1.5 milin the MENA region. This number is estimated at lion by independent researchers, with some estimates go470,000 (350,000570,000) without Afghanistan and ing much higher.
Pakistan (which are not considered by UNAIDS geoIn the rural areas of China, where large numbers of
graphic denition as part of MENA region), and reaches
farmers, especially in Henan province, participated in
580,000 (430,000810,000) if Pakistan and Afghanistan
unclean blood transfusions; estimates of those infected
are included.[18]
are in the tens of thousands. In Japan, just over half
Despite the low prevalence of HIV/AIDS in the MENA of HIV/AIDS cases are ocially recorded as occurring
region, there are epidemics among vulnerable groups. As amongst homosexual men, with the remainder occurring
of 2012, the prevalence of HIV among men who have sex amongst heterosexuals and also via drug abuse, in the
with men in Egypt is estimated to be 5.0%9.9%.[19]
womb or unknown means.
HIV/AIDS prevalence in the Middle East and North
Africa is around 0.2% (0.10.7%), with between 230,000
and 1.4 million people infected. Among young people
1524 years of age, 0.3% of women [0.10.8%] and
0.17% of men [0.10.3%] were living with HIV infection by the end of 2004.

13.1.3

South and South-East Asia

Main article: HIV/AIDS in Asia

13.1.5 Americas
Caribbean

The HIV prevalence rate in South and South-East Asia Main article: HIV/AIDS in the Caribbean
is less than 0.35 percent, with total of 4.2 4.7 million adults and children infected. More AIDS deaths The Caribbean is the second-most aected region in the

13.1. BY REGION
world.[12] Among adults aged 1544, AIDS has become
the leading cause of death. The regions adult prevalence rate is 0.9%.[12] with national rates ranging up to
2.7%.[23] HIV transmission occurs largely through heterosexual intercourse, with two-thirds of AIDS cases in
this region attributed to this route. Sex between men is
also a signicant route of transmission, even though it is
heavily stigmatised and illegal in many areas. HIV transmission through injecting drug use remains rare, except
in Bermuda and Puerto Rico.
Central and South America
Main article: HIV/AIDS in Latin America

117
men today, including Michael Majeski, who believes
meth is the catalyst for at least 80% of seroconversions currently occurring across the United States, and
Tony Zimbardi, who calls methamphetamine the number
one cause of HIV transmission, and says that high rates
of new HIV infection are not being found among noncrystal users. In addition, various HIV and STD clinics across the United States report anecdotal evidence
that 75% of new HIV seroconversions they deal with
are methamphetamine-related; indeed, in Los Angeles,
methamphetamine is regarded as the main cause of HIV
seroconversion among gay men in their late thirties.[26]
The chemical methamphetamine, in and of itself, cannot infect someone with HIV.

Washington, D.C., the nations capital, also has the nations highest rate of infection, at 3%. This rate is comIn these regions of the American continent, only parable to what is seen in west Africa, and is considered
Guatemala and Honduras have national HIV prevalence a severe epidemic.[27]
of over 1%. In these countries, HIV-infected men outIn Canada, nearly 60,000 people were living with
number HIV-infected women by roughly 3:1.
HIV/AIDS in 2005.[28] The HIV-positive population continues to increase in Canada, with the greatest increases
amongst aboriginal Canadians.[29] As in Western Europe,
United States and Canada
the death rate from AIDS in North America fell sharply
with the introduction of combination AIDS therapies
Main articles: HIV/AIDS in the United States and
(HAART).
HIV/AIDS in Canada
In the United States, young African-American women are
also at high risk for HIV infection.[30] African AmeriThe adult prevalence rate in this region is 0.7% with
cans make up 10% of the population but about half of
over 1 million people currently infected with HIV. In the
the HIV/AIDS cases nationwide.[31] This is due in part
United States from 20012005, the highest transmission
to a lack of information about AIDS and a perception
risk behaviors were sex between men (4049% of new
that they are not vulnerable, as well as to limited access
cases) and high risk heterosexual sex (3235% of new
to health-care resources and a higher likelihood of sexcases).[24] Currently, rates of HIV infection in the US are
ual contact with at-risk male sexual partners.[32] There
highest in the eastern and southern regions, with the exare also geographic disparities in AIDS prevalence in
ception of California. Currently, 35,00040,000 new inthe United States, where it is most common in the large
fections occur in the USA every year. AIDS is one of
metropolitan areas of the East Coast and California and
the top three causes of death for African American men
in urban areas of the Deep South.[33] Rates are lower in
aged 2554 and for African American women aged 35
Utah, Texas, and Northern Florida.[33]
44 years in the United States of America. In the United
States, African Americans make up about 48% of the to- Since 1985, the incidence of HIV infection among
tal HIV-positive population and make up more than half women has been steadily increasing. It is currently esof new HIV cases, despite making up only 12% of the timated that at least 27% of new HIV infections are
population. The main route of transmission for women in women.[34] There has been increasing concern for
is through unprotected heterosexual sex. African Ameri- the concurrency of violence surrounding women infected
can women are 19 times more likely to contract HIV than with HIV. In 2012, a meta-analysis showed that the
rates of psychological trauma, including Intimate Partother women.[25]
ner Violence and PTSD in HIV positive women were
In the United States in particular, a new wave of infection
more than ve times and twice the national averages,
is being blamed on the use of methamphetamine, known
respectively.[35] In 2013, the White House commissioned
as crystal meth. Research presented at the 12th Annual
an Interagency Federal Working Group to address the inRetrovirus Conference in Boston in February 2005 contersection of violence and women infected with HIV.[36]
cluded that using crystal meth or cocaine is the biggest
single risk factor for becoming HIV+ among US gay men, A review of studies containing data regarding the
contributing 29% of the overall risk of becoming positive prevalence of HIV in transgender women found that
and 28% of the overall risk of being the receptive partner nearly 11.8% self-reported that they were infected with
HIV.[37] In the National Transgender Discrimination Surin anal sex.[26]
vey, 20.23% of black respondents reported being HIVIn addition, several renowned clinical psychologists now
positive, with an additional 10% reporting that they were
cite methamphetamine as the biggest problem facing gay

118

CHAPTER 13. EPIDEMIOLOGY OF HIV/AIDS

unaware of their status.[38]

13.1.6

Eastern Europe and Central Asia

dence of antiretroviral drug resistance among some newly

HIV-infected individuals in this region.

13.1.8 Oceania

Main article: HIV/AIDS in Eastern Europe and Central

Main articles: HIV/AIDS in Australia and HIV/AIDS in
Asia
Papua New Guinea
There is growing concern about a rapidly growing epidemic in Eastern Europe and Central Asia, where an estimated 1.233.7 million people were infected as of December 2011, though the adult (1549) prevalence rate
is low (1.1%). The rate of HIV infections began to grow
rapidly from the mid-1990s, due to social and economic
collapse, increased levels of intravenous drug use and increased numbers of prostitutes. By 2010 the number of
reported cases in Russia was over 450,000 according to
the World Health Organization, up from 15,000 in 1995
and 190,000 in 2002; some estimates claim the real number is up to eight times higher, well over 2 million. There
are predictions that the infection rate in Russia will continue to rise quickly, since education there about AIDS is
almost non-existent.[39]
Ukraine and Estonia also have growing numbers of infected people, with estimates of 650,000 and 4,400 respectively in 2011. The disease is now ocially epidemic
in this region, which means that prevention strategies may
not be able to halt and reverse its spread. Also, transmission of HIV is increasing through sexual contact and drug
use among the young (<30 years). Indeed, over 84% of
current AIDS cases in this region occur in non-drug-using
heterosexuals less than 26 years of age.

13.1.7

There is a very large range of national situations regarding

AIDS and HIV in this region. This is due, in part, to the
large distances between the islands of Oceania. The wide
range of development in the region also plays an important role. The prevalence is estimated at between 0.2%
and 0.7%, with between 45,000 and 120,000 adults and
children currently infected with HIV.
Papua New Guinea has one of the most serious AIDS epidemics in the region. According to UNAIDS, HIV cases
in the country have been increasing at a rate of 30 percent
annually since 1997, and the countrys HIV prevalence
rate in late 2006 was 1.3%.[40]

13.2 AIDS and society

In June 2001, the United Nations held a Special General Assembly to intensify international action to ght the
HIV/AIDS epidemic as a global health issue, and to mobilize the resources needed towards this aim, labelling the
situation a global crisis.[41]
Regarding the social eects of the HIV/AIDS pandemic,
some sociologists suggest that AIDS has caused a profound re-medicalization of sexuality".[42][43]

Western Europe

Social factors also inuence HIV/AIDS. A 2003 study

states that HIV and AIDS are less prevalent in Muslim
Main article: HIV/AIDS in Western Europe
populations and speculates that this may be due to the
eect of several Islamic tenets, such as the avoidance
In most countries of Western Europe, AIDS cases have of extramarital aairs and the benets arising from
[44]
fallen to levels not seen since the original outbreak; many circumcision".
attribute this trend to aggressive educational campaigns,
screening of blood transfusions and increased use of condoms. Also, the death rate from AIDS in Western Europe 13.3 See also
has fallen sharply, as new AIDS therapies have proven to
be an eective (though expensive) means of suppressing
List of countries by HIV/AIDS adult prevalence rate
HIV.
In this area, the routes of transmission of HIV is diverse,
including paid sex, injecting drug use, mother to child,
male with male sex and heterosexual sex. However, many
new infections in this region occur through contact with
HIV-infected individuals from other regions. The adult
(1549) prevalence in this region is 0.3% with between
570,000 and 890,000 people currently infected with HIV
infection. Due to the availability of antiretroviral therapy,
AIDS deaths have stayed low since the lows of the late
1990s. However, in some countries, a large share of HIV
infections remain undiagnosed and there is worrying evi-

13.4 Notes
[1] Cohen, MS; Hellmann, N; Levy, JA; DeCock, K; Lange,
J (April 2008). The spread, treatment, and prevention of HIV-1: evolution of a global pandemic.
The Journal of Clinical Investigation 118 (4): 1244
54. doi:10.1172/JCI34706. PMC 2276790. PMID
18382737. Retrieved 17 September 2012.
[2] Fact Sheet. UNAIDS.org. 2013. Retrieved 4 December
2013.

13.4. NOTES

[3] UNAIDS 2011 pg. 1-10

[4] UNAIDS 2011 pg. 20-30
[5] UNAIDS 2011 pg. 40-50
[6] Centers for Disease Control and Prevention, (CDC) (3 Jun
2011). HIV surveillance--United States, 1981-2008..
MMWR. Morbidity and mortality weekly report 60 (21):
68993. PMID 21637182.
[7] Health Protection Agency (2010). HIV in the United Kingdom: 2010 Report.
[8] Benson, Kate (19 October 2010). HIV rate rising but
other infections less common. The Sydney Morning Herald. Retrieved 19 October 2010.
[9] Surveillance; riques, Risk Assessment Division = Le VIH
et le sida au Canada: rapport de surveillance en date
du 31 dcembre 2009 / Division de la surveillance et
de l'valuation des (2010). HIV and AIDS in Canada :
surveillance report to December 31, 2009 (PDF). Ottawa:
Public Health Agency of Canada, Centre for Communicable Diseases and Infection Control, Surveillance and Risk
Assessment Division. ISBN 978-1-100-52141-1.
[10] HIV pandemics origins located. University of Oxford.
3 October 2014. Retrieved 5 October 2014.
[11] Global Report Fact Sheet (PDF). UNAIDS. 2010.
[12] UNAIDS World Aids Day Report (PDF). publisher.
2011. Retrieved 12 March 2014. The ranges dene the
boundaries within which the actual numbers lie, based on
the best available information.
[13] UNAIDS, WHO (2007). 2007 AIDS epidemic update
(PDF). Archived (PDF) from the original on 27 May
2008. Retrieved 2008-05-26.
[14] Life expectancy at birth, total (years)". worldbank.org.
[15] Samuels, Fiona (2009) HIV and emergencies: one size
does not t all London: Overseas Development Institute
[16] Chigwedere P, Seage GR, Gruskin S, Lee TH, Essex
M (October 2008). Estimating the Lost Benets of
Antiretroviral Drug Use in South Africa. Journal of
acquired immune deciency syndromes (1999) 49 (4):
410415. doi:10.1097/QAI.0b013e31818a6cd5. PMID
18931626. Lay summary.
[17] Nattrass N (February 2008). Estimating the Lost Benets of Antiretroviral Drug Use in South Africa. African
Aairs 107 (427): 15776. doi:10.1093/afraf/adm087.
[18] UNAIDS Middle East and North Africa Regional Report
on AIDS 2011 (PDF). Retrieved 2014-12-16.
[19] HIV in the Middle East: Low Prevalence but Not Low
Risk. pbr.org. Population Reference Bureau. Retrieved
24 August 2014.
[20] Fiona Samuels and Sanju Wagle 2011. Population mobility and HIV and AIDS: review of laws, policies and
treaties between Bangladesh, Nepal and India. London:
Overseas Development Institute

119

[21] Gangcuangco LM, Tan ML, Berba RP. Prevalence and

risk factors for HIV infection among men having sex with
men in Metro Manila, Philippines. Southeast Asian Journal of Tropical Medicine and Public Health 2013 Sep;
44(5) 810-816. http://www.tm.mahidol.ac.th/seameo/
2013-44-5/10-5743-12.pdf
[22] Gangcuangco, et al. http://www.iasociety.org/Abstracts/
A200739361.aspx
[23] UNAIDS, WHO (2005). AIDS epidemic update 2005.
[24] Cases of HIV infection and AIDS in the United States
and Dependent Areas, 2005. Centers for Disease Control
and Prevention. June 2007. Retrieved 2010-12-27.
[25] Kaiser Daily HIV/AIDS Report Summarizes Opinion
Pieces on U.S. AIDS Epidemic. The Body The Complete HIV/AIDS Resource. 20 June 2005. Retrieved
2010-12-27.
[26] Life or Meth. Retrieved 2010-12-27.
[27] AIDS epidemic in Washington D.C.
[28] The State of the HIV/AIDS Pandemic. Public Health
Agency of Canada. Archived from the original on 4 January 2010. Retrieved 2010-01-05.
[29] CBC News In Depth AIDS. CBC.ca. 1 December
2008. Archived from the original on 4 December 2008.
Retrieved 2008-12-01.
[30] Report: Black U.S. AIDS rates rival some African nations. cnn.com.
[31] "DTL&feed=rss. news_politics White House summit on
AIDS' impact on black men". San Francisco Chronicle. 3
June 2010.
[32] Arya M, Behforouz HL, and Viswanath K (9 March
2009). African American Women and HIV/AIDS: A
National Call for Targeted Health Communication Strategies to Address a Disparity. The AIDS Reader 19 (2).
[33] http://www.cdc.gov/hiv/topics/surveillance/resources/
reports/2005report/pdf/2005SurveillanceReport.pdf
[34] CDC. HIV/AIDS Surveillance Report, 2005. Vol. 17.
Rev ed. Atlanta: US Department of Health and Human
Services, CDC: 2007:146. Available at http://www.cdc.
gov/hiv/topics/surveillance/resources/reports/. Accessed
28 June 2007.
[35] Machtinger EL, Wilson TC, Haberer JE, Weiss DS. Psychological trauma and PTSD in HIV-positive women:
a meta-analysis. AIDS Behav. 2012 Nov;16(8):2091100. doi: 10.1007/s10461-011-0127-4. http://www.
medscape.com/viewarticle/773935
[36] http://www.whitehouse.gov/sites/default/files/docs/
vaw-hiv_working_group_report_final_-_9-6-$-$2013.
pdf
[37] Estimating HIV Prevalence and Risk Behaviors of Transgender Persons in the United States: A Systematic Review. AIDS and Behavior.

120

[38] Injustice at Every Turn: A Look at Black Respondents in

the National Transgender Discrimination Survey (PDF).
National Black Justice Coalition, National Center for
Transgender Equality, and National Gay and Lesbian Task
Force. Retrieved April 7, 2015.
[39] Center for Strategic and International Studies. http://csis.
org/program/hivaids
[40] Health Prole: Papua New Guinea. United States Agency
for International Development (September 2008). Accessed 20 March 2009.
[41] United Nations Special Session on HIV/AIDS. New
York, 2527 June 2001 - http://www.un.org/ga/aids/
conference.html
[42] Aggleton, Peter; Parker, Richard Bordeaux; Barbosa,
Regina Maria (2000). Framing the sexual subject: the politics of gender, sexuality, and power. Berkeley: University
of California Press. ISBN 0-520-21838-8. p.3
[43] Vance, Carole S. (1991). Anthropology Rediscovers Sexuality: A Theoretical Comment. Social Science and Medicine 33 (8): 875884. doi:10.1016/02779536(91)90259-F. PMID 1745914.
[44] Gray, Peter B. (Harvard University) (May 2004). HIV
and Islam: is HIV prevalence lower among Muslims?". Social Science & Medicine 58 (9): 17516.
doi:10.1016/S0277-9536(03)00367-8. PMID 14990375.

References
Joint United Nations Programme on HIV/AIDS (UNAIDS) (2011). Global HIV/AIDS Response, Epidemic update and health sector progress towards universal access
(PDF). Joint United Nations Programme on HIV/AIDS.

13.5 Further reading

Global report with AIDS info database from
UNAIDS
Global, regional and national proles from
AVERT.org
The River: A Journey to the Source of HIV and AIDS
Edward Hooper (1999) ISBN 978-0-316-37261-9
IASSTD & AIDS Indian Association for the Study
of Sexually Transmitted Diseases & AIDS
AIDS.gov The U.S. Federal Domestic HIV/AIDS
Resource

CHAPTER 13. EPIDEMIOLOGY OF HIV/AIDS

Chapter 14

HIV/AIDS research
14.1 Transmission
See also: Circumcision and HIV
A body of scientic evidence has shown that men who are
circumcised are less likely to contract HIV than men who
are uncircumcized.[2] Research published in 2014, concludes that the sex hormones estrogen and progesterone
selectively impact HIV transmission.[3]

Scanning electron micrograph of HIV-1, colored green, budding

from a cultured lymphocyte.

14.1.1 Pre- and post-exposure prophylaxis

Main articles: Pre-exposure prophylaxis and Postexposure prophylaxis
Pre-exposure prophylaxis refers to the practice of taking some drugs before being exposed to HIV infection,
and having a decreased chance of contracting HIV as a result of taking that drug. Post-exposure prophylaxis refers
to taking some drugs quickly after being exposed to HIV,
while the virus is in a persons body but before the virus
has established itself. In both cases, the drugs would be
the same as those used to treat persons with HIV, and the
intent of taking the drugs would be to eradicate the virus
before the person becomes irreversibly infected.
Post-exposure prophylaxis is recommended in anticipated cases of HIV exposure, such as if a nurse somehow
Diagram of HIV
has blood-to-blood contact with a patient in the course
of work, or if someone without HIV requests the drugs
immediately after having unprotected sex with a person
who might have HIV. Pre-exposure prophylaxis is someHIV/AIDS research includes all medical research that times an option for HIV-negative persons who feel that
attempts to prevent, treat, or cure HIV/AIDS, as well as they are at increased risk of HIV infection, such as an
fundamental research about the nature of HIV as an in- HIV-negative person in a serodiscordant relationship with
fectious agent and AIDS as the disease caused by HIV.
an HIV-positive partner.
Examples of particular HIV/AIDS research include, drug Current research in these agents include drug developdevelopment, HIV vaccines, pre-exposure prophylaxis, or ment, ecacy testing, and practice recommendations for
post-exposure prophylaxis.[1]
using drugs for HIV prevention.
121

122

14.2 Within-host dynamics

The within-host dynamics of HIV infections include the
spread of the virus in vivo, the establishment of latency,
the eects of immune response on the virus etc.[4][5] Early
studies used simple models and only considered the cellfree spreading of HIV, in which virus particles bud from
an infected T cell, enter the blood/extracellular uid and
then infect another T cell.[5] A 2015 study[4] proposes a
more realistic HIV dynamics model that also incorporates
the viruss cell-to-cell spreading mechanism, where the
virus is direct transited from one cell to another, the T cell
activation, the cellular immune response, and the immune
exhaustion as the infection progresses.[4]

CHAPTER 14. HIV/AIDS RESEARCH

14.5 Age acceleration eects due to

HIV-1 infection
Infection with the Human Immunodeciency Virus-1
(HIV) is associated with clinical symptoms of accelerated
aging, as evidenced by increased incidence and diversity
of age-related illnesses at relatively young ages. A significant age acceleration eect could be detected in brain
(7.4 years) and blood (5.2 years) tissue due to HIV-1 infection [8] with the help of a biomarker of aging, which is
known as epigenetic clock.

14.6 Long-term nonprogressor

A long-term nonprogressor is a person who is infected
with HIV, but whose body, for whatever reason, naturally
controls the virus so that the infection does not progress
to the AIDS stage. Such persons are of great interest to
See also: Structure and genome of HIV and Subtypes of
researchers, who feel that a study of their physiologies
HIV
could provide a more in-depth understanding of the virus
and disease.
A 2014 study with SIV, found that the virus initially establishes a reservoir in the gut. The virus infection provokes an inammatory response of paneth cells in the
intestine, and helps to spread the virus by causing tissue damage. The ndings oer new pointers for poten- 14.7 HIV vaccine
tial future treatments, testing (biomarkers), and helps to
explain the virus resistance to antiviral therapies. The
study also identied the bacteria strain Lactobacillus Main article: HIV vaccine
plantarum, which reversed damage by rapidly reducing
IL-1 (Interleukin-1 beta).[6] Seeding of HIV in the body An HIV vaccine is a vaccine which would be given to a
begins within a few days, during the acute phase of HIV person who does not have HIV, and then subsequently
infection.[7]
if that vaccinated person were exposed to HIV, then the
vaccine would protect that person and reduce the likelihood that the person would become infected by HIV.
Currently, no eective HIV vaccine exists. Various HIV
vaccines have been tested in clinical trials almost since
the discovery of HIV.

14.3 Virus characteristics

14.4 Management of HIV/AIDS

Only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus
Main article: Management of HIV/AIDS
being aordable for developing countries, and would
not require daily treatment.[9] However, after over 20
research, HIV-1 remains a dicult target for a
Research to improve current treatments includes decreas- years of[9][10]
vaccine.
ing side eects of current drugs, further simplifying drug
regimens to improve adherence, and determining better In 2003 a clinical trial in Thailand tested an HIV vaccine
sequences of regimens to manage drug resistance. There called RV 144. In 2009, the researchers reported that
are variations in the health community in recommenda- this vaccine showed some ecacy in protecting recipients
tions on what treatment doctors should recommend for from HIV infection. Results of this trial give the rst suppeople with HIV. One question, for example, is deter- porting evidence of any vaccine being eective in lowermining when a doctor should recommend that a patient ing the risk of contracting HIV. Another possible vaccine
take antiretroviral drugs and what drugs a doctor may rec- comes from a novel gene therapy that alters the CCR5
ommend. This eld also includes the development of an- co-receptor permanently, preventing HIV from entering
cells.[11] Other vaccine trials continue worldwide.
tiretroviral drugs.

14.10. IMMUNOMODULATORY AGENTS

14.8 Microbicides for sexually

transmitted diseases
Main article:
diseases

microbicides for sexually transmitted

123
donors.[17][19]

14.10 Immunomodulatory agents

Complementing eorts to control viral replication,

immunotherapies that may assist in the recovery of the
A microbicide for sexually transmitted diseases is a gel immune system have been explored in past and ongoing
which would be applied to the skin - perhaps a rectal mi- trials, including IL-2 and IL-7.[20]
crobicide for persons who engage in anal sex or a vaginal
microbicide for persons who engage in vaginal sex - and if The failure of vaccine candidates to protect against HIV
infected body uid such as blood or semen were to touch infection and progression to AIDS has led to a renewed
the gel, then HIV in that uid would be destroyed and the focus on the biological mechanisms responsible for HIV
people having sex would be less likely to spread infection latency. A limited period of therapy combining antiretrovirals with drugs targeting the latent reservoir may
between themselves.
one day allow for total eradication of HIV infection.[21]
On March 7, 2013, the Washington University in St. Researchers have discovered an abzyme that can destroy
Louis website published a report by Julia Evangelou the protein gp120 CD4 binding site. This protein is comStrait, in which it was reported that ongoing nanoparticle mon to all HIV variants as it is the attachment point for
research showed that nanoparticles loaded with various B lymphocytes and subsequent compromising of the imcompounds could be used to target infectious agents mune system.[22]
whilst leaving healthy cells unaected. In the study
detailed by this report, it was found that nanoparticles
loaded with Mellitin, a compound found in Bee venom, 14.11 New developments
could deliver the agent to the HIV, causing the breakdown
of the outer protein envelope of the virus. This, they
say, could lead to the production of a vaginal gel which A turning point for HIV research occurred in 2007, folcould help prevent infection by disabling the virus.[12] lowing the bone marrow transplant of HIV suerer TimoDr Joshua Hood goes on to explain that beyond pre- thy Ray Brown. Brown underwent the procedure after he
ventative measures in the form of a topical gel, he sees developed leukaemia and the donor of the bone marrow
potential for using nanoparticles with melittin as ther- possessed a rare genetic mutation that caused Browns
apy for existing HIV infections, especially those that cells to become resistant to HIV. Brown attained the tiare drug-resistant. The nanoparticles could be injected tle of the Berlin Patient in the HIV research eld and
intravenously and, in theory, would be able to clear HIV is the rst man to have been cured of the virus. As of
April 2013, two primary approaches are being pursued
from the blood stream.[12]
in the search for a HIV cure: The rst is gene therapy
that aims to develop a HIV-resistant immune system for
patients, and the second is being led by Danish scientists,
14.9 Stem cell transplantation
who are conducting clinical trials to strip the HIV from
human DNA and have it destroyed permanently by the
[23]
[13]
In 2007, Timothy Ray Brown,
a 40-year-old HIV- immune system.
positive man, also known as the Berlin Patient, was
given a stem cell transplant as part of his treatment for
acute myeloid leukemia (AML).[14] A second transplant
was made a year later after a relapse. The donor was chosen not only for genetic compatibility but also for being
homozygous for a CCR5-32 mutation that confers resistance to HIV infection.[15][16] After 20 months without
antiretroviral drug treatment, it was reported that HIV
levels in Browns blood, bone marrow, and bowel were
below the limit of detection.[16] The virus remained undetectable over three years after the rst transplant.[14]
Although the researchers and some commentators have
characterized this result as a cure, others suggest that
the virus may remain hidden in tissues[17] such as the
brain (which acts as a viral reservoir).[18] Stem cell treatment remains investigational because of its anecdotal
nature, the disease and mortality risk associated with
stem cell transplants, and the diculty of nding suitable

Two more cases with similarities to the Brown case have

occurred since the 2007 discovery; however, they dier
because the transplanted marrow has not been conrmed
as mutated. The cases were publicized in a July 2013
CNN story that relayed the experience of two patients
who had taken antiretroviral therapy for years before they
developed lymphoma, a cancer of the lymph nodes. They
then underwent lymphoma chemotherapy and bone marrow transplantation, while remaining on an antiretroviral
regimen; while they retained traces of HIV four months
afterwards, six to nine months after the transplant, the
two patients had no detectable trace of HIV in their blood.
However, the managing clinician Dr. Timothy Heinrich
stated at the Malaysian International AIDS Society Conference where the ndings were presented:
Its possible, again, that the virus could return in a week, it could return in a month --

124

CHAPTER 14. HIV/AIDS RESEARCH

in fact, some mathematical modeling predicts
that virus could even return one to two years after we stop antiretroviral therapy, so we really
don't know what the long-term or full eects of
stem cell transplantation and viral persistence
is.[24]

14.12 See also

[9] Ferrantelli F, Cafaro A, Ensoli B (December 2004).

Nonstructural HIV proteins as targets for prophylactic
or therapeutic vaccine. Curr. Opin. Biotechnol. 15
(6): 54356. doi:10.1016/j.copbio.2004.10.008. PMID
15560981.
[10] Karlsson Hedestam GB, Fouchier RA, Phogat S, Burton
DR, Sodroski J, Wyatt RT (February 2008). The challenges of eliciting neutralizing antibodies to HIV-1 and to
inuenza virus. Nat. Rev. Microbiol. 6 (2): 14355.
doi:10.1038/nrmicro1819. PMID 18197170.

Discovery and development of CCR5 receptor antagonists

[11] N Engl J Med 2014; 370:901-910March 6, 2014DOI:

10.1056/NEJMoa1300662

Discovery and development of HIV protease inhibitors

[12] http://news.wustl.edu/news/Pages/25061.aspx

Discovery and development of non-nucleoside reverse transcriptase inhibitors

Health interventions
HIV superinfection
The Origin of HIV and AIDS
Sex education

14.13 References
[1] Vijay Nema (2015-07-29). Current Trends in AIDS Research.
[2] CDC. Male Circumcision.
[3] Diana Goode, Meropi Aravantinou, Sebastian Jarl, Rosaline Truong, Nina Derby, Natalia Guerra-Perez, Jessica Kenney, James Blanchard, Agegnehu Gettie, Melissa
Robbiani, Elena Martinelli (May 15, 2014). Sex Hormones Selectively Impact the Endocervical Mucosal Microenvironment: Implications for HIV Transmission.
PLOS. doi:10.1371/journal.pone.0097767.
[4] Zhang C, Zhou S, Groppelli E, Pellegrino P, Williams I,
Borrow P, Chain BM, Jolly C (2015). Hybrid Spreading Mechanisms and T Cell Activation Shape the Dynamics of HIV-1 Infection. PLOS Computational Biology
11 (4): e1004179. doi:10.1371/journal.pcbi.1004179.
PMID 25837979.
[5] Perelson AS, Ribeiro RM (2013). Modeling the withinhost dynamics of HIV infection. BMC Biology 11 (1):
96. doi:10.1186/1741-7007-11-96.
[6] ScienceDaily (August 29, 2014). Surprising discovery:
HIV hides in gut, evading eradication.
[7] Strikingly early seeding of HIV viral reservoir shown in
study. ScienceDaily. July 20, 2014.
[8] Horvath S, Levine AJ. (2015). HIV-1 infection accelerates age according to the epigenetic clock.. J Infect Dis:
jiv277. PMID 25969563.

[13] German HIV patient cured after stem cell transplant.

Belfast Telegraph. December 15, 2010. Retrieved December 15, 2010.
[14] Allers, K; Htter, G; Hofmann, J; Loddenkemper, C;
Rieger, K; Thiel, E; Schneider, T (2011-03-10). Evidence for the cure of HIV infection by CCR532/32
stem cell transplantation. Blood 117 (10): 27919.
doi:10.1182/blood-2010-09-309591. PMID 21148083.
[15] Mark Schoofs (November 7, 2008). A Doctor, a Mutation and a Potential Cure for AIDS. The Wall Street
Journal. Retrieved 2008-11-09.
[16] Htter G, Nowak D, Mossner M, Ganepola S, Ganepola
A, Allers K, Schneider T, Hofmann J, Kcherer C, Blau
O, Blau IW, Hofmann WK, Thiel E (2009). LongTerm Control of HIV by CCR5 Delta32/Delta32 StemCell Transplantation. N Engl J Med 360 (7): 692698.
doi:10.1056/NEJMoa0802905. PMID 19213682. Retrieved 2009-03-31.
[17] Levy JA (2009). Not an HIV Cure, but Encouraging New Directions. N Engl J Med 360 (7): 724725.
doi:10.1056/NEJMe0810248. PMID 19213687. Retrieved 2009-03-31.
[18] Nath, A; Clements, JE (2011-03-13). Eradication
of HIV from the brain:
reasons for pause.
AIDS (London, England) 25 (5):
57780.
doi:10.1097/QAD.0b013e3283437d2f. PMC 3681810.
PMID 21160414.(subscription required)
[19] Lunzen, J.; Fehse, B.; Hauber, J. (2011). Gene Therapy
Strategies: Can We Eradicate HIV?". Current HIV/AIDS
Reports 8 (2): 7884. doi:10.1007/s11904-011-0073-9.
PMID 21331536.(subscription required)
[20] Tincati, C; d'Arminio Monforte, A; Marchetti, G
(January 2009).
Immunological mechanisms of
interleukin-2 (IL-2) treatment in HIV/AIDS disease. Current molecular pharmacology 2 (1): 405.
doi:10.2174/1874467210902010040. PMID 20021444.
[21] Bowman MC, Archin NM, Margolis DM. (2009). Pharmaceutical approaches to eradication of persistent HIV
infection. Expert Reviews in Molecular Medicine 11
(e6): e6. doi:10.1017/S1462399409000970. PMID
19208267.

14.14. EXTERNAL LINKS

[22] Planque S, Nishiyama Y, Taguchi H, Salas M, Hanson C,

Paul S (June 2008). Catalytic antibodies to HIV: Physiological role and potential clinical utility. Autoimmun Rev
7 (6): 4739. doi:10.1016/j.autrev.2008.04.002. PMC
2527403. PMID 18558365.
[23] Jake Wallis Simons (27 April 2013). Scientists on brink
of HIV cure. The Telegraph. Retrieved 2 May 2013.
[24] Saundra Young (3 July 2013). Patients HIV-free for now
after transplant. CNN. Retrieved 4 July 2013.

14.14 External links

HIV and AIDS News (ScienceDaily)

125

126

CHAPTER 14. HIV/AIDS RESEARCH

14.15 Text and image sources, contributors, and licenses

14.15.1

Text

Retrovirus Source: https://en.wikipedia.org/wiki/Retrovirus?oldid=692201615 Contributors: Bryan Derksen, Ed Poor, Andre Engels, Josh
Grosse, Youssefsan, William Avery, Azhyd, David spector, Someone else, Edward, Lexor, Shyamal, Nina, Gbleem, Muriel Gottrop~enwiki,
Cyan, Andres, AhmadH, Ec5618, Fuzheado, Steinsky, Furrykef, Lumos3, Robbot, Wikibot, Xanzzibar, Giftlite, Nunh-huh, Marcika,
Unconcerned, Gubbubu, PDH, DragonySixtyseven, Trevor MacInnis, Rich Farmbrough, Drano, Vsmith, Spundun, Bender235, AyJay,
RoyBoy, Bobo192, BrokenSegue, Arcadian, Joe Jarvis, La goutte de pluie, Dillee1, Allstarzero, Monado, Malo, Arag0rn, Ickle~enwiki,
RyanGerbil10, JarlaxleArtemis, Oliphaunt, Vineet KewalRamani, EnSamulili, Schzmo, Eras-mus, SDC, Sci guy, Ketiltrout, Rjwilmsi,
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Anonymous: 58
Simian immunodeciency virus Source: https://en.wikipedia.org/wiki/Simian_immunodeficiency_virus?oldid=685129251 Contributors: AxelBoldt, Josh Grosse, Azhyd, Nina, Karada, Ahoerstemeier, Bueller 007, Morwen, Vardion, Saforrest, DocWatson42, Perl, CyborgTosser, Niteowlneils, Duncharris, Hob, Rainier Schmidt, Mr d logan, Icairns, Nina Gerlach, Bender235, Arcadian, Tiresias BC, RJFJR,
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Anonymous: 67
HIV Source: https://en.wikipedia.org/wiki/HIV?oldid=693063229 Contributors: AxelBoldt, Magnus Manske, Marj Tiefert, Sodium, The
Anome, Alex.tan, Andre Engels, Josh Grosse, Anthere, Azhyd, Valhalla, Montrealais, Modemac, AntonioMartin, Dominus, Gabbe, Ixfd64,
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ankan~enwiki, JWSchmidt, Darkwind, Aarchiba, Julesd, Bruckner, Evercat, Samuel~enwiki, Mxn, Robertkeller, Conti, Hp~enwiki, Sjoerd
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14.15. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

127

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128

CHAPTER 14. HIV/AIDS RESEARCH

KathrynMess, Amlui89, Jdsousa1, DPG1993, Aqua112233, Hindustanilanguage, Signssaids, Hazhk, MuzeMarc, Aparagraph, Thematrixmantor, Guptan99, Helpful Pixie Bot, , Bibcode Bot, Samuelredick, BZTMPS, BG19bot, Mleoking, Kndimov, Stevetihi,
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130

CHAPTER 14. HIV/AIDS RESEARCH

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honesty, Khazar2, TylerDurden8823, Soulparadox, SuperHero2111, Matt.haraszkiewicz, JYBot, Dexbot, Rezonansowy, Yash!, Mogism,
Magicturnips, Tessmac9708, Mahan, AndreaLange, Hobawido, ComfyKem, Misomucho, Reatlas, FairHousing, SimplesC, Epicgenius,
Alan, WikiU2013, Newthoughts34, AmericanLemming, Austinpk, Cgayhea, TheRobot Vegetable, Everymorning, Naruto9181, CensoredScribe, Clr324, HoboMcJoe, Pgcudahy, Jackmcbarn, Chemistry74, Rishabh2211, Aarongaming100, Coreyemotela, Anrnusna, 22merlin,
Savvyjack23, Monkbot, ShawntheGod, Suzi at NAT, Vittunaama, Qwertyxp2000, GoldenGuy23, AndyRatchick, Jack Matelot, Soupvector, Lise-lyse, MoreTomorrow, Emily Temple-Wood (NIOSH), Gamingforfun365, KasparBot, Park Lexington, ShartedOnU, Matterington
and Anonymous: 1463
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Bearcat, Malcolma, Doc James, Yobot, FrescoBot, Brandmeister, Sermadison, Monkbot and Anonymous: 3
Diagnosis of HIV/AIDS Source: https://en.wikipedia.org/wiki/Diagnosis_of_HIV/AIDS?oldid=685994960 Contributors: AxelBoldt, The
Anome, ChangChienFu, Modemac, Karada, Gbleem, Minesweeper, Kosebamse, Ronz, Nikai, Cratbro, Zoicon5, Wilke, Frazzydee, SD6Agent, Josh Cherry, Donreed, Nunh-huh, Jfdwol, Chowbok, Beland, Adashiel, Ta bu shi da yu, Random contributor, Rich Farmbrough, FT2, Wk muriithi, Bender235, JoeSmack, Ttguy, MBisanz, Nonpareility, EurekaLott, Bobo192, Wood Thrush, Davidruben, Arcadian, Docvalium, Orangemarlin, Pion, Ombudsman, TenOfAllTrades, Uncle G, Tabletop, Clemmy, Sci guy, Rjwilmsi, Koavf, Ligulem,
Keimzelle, Pfctdayelise, Alphachimp, Vidkun, YurikBot, Peter G Werner, Epolk, Donwarnersaklad, Rodasmith, Gaius Cornelius, Eleassar, Geo NoNick, Tribune, Gadget850, Bilz0r, Bsheppard, 2over0, Patiwat, SaulPerdomo, TechBear, SmackBot, Ingenium, Nickst,
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132

CHAPTER 14. HIV/AIDS RESEARCH

Coreyemotela, Monkbot, SkateTier and Anonymous: 178

Prevention of HIV/AIDS Source: https://en.wikipedia.org/wiki/Prevention_of_HIV/AIDS?oldid=692807706 Contributors: Miya, Beland, Klemen Kocjancic, Bender235, Bobrayner, Rjwilmsi, Turidoth, SmackBot, KVDP, Chris the speller, TimBentley, Terbayang, Cydebot, Theroadislong, Hamiltonstone, R'n'B, Neodymium-142, Doc James, WereSpielChequers, Mild Bill Hiccup, Legobot II, Bluerasberry,
Materialscientist, Amaury, FrescoBot, Edderso, Jonesey95, Serols, Trappist the monk, RjwilmsiBot, John of Reading, Dewritech, ClueBot
NG, Souzaj, BG19bot, 220 of Borg, BattyBot, Soulparadox, Dexbot, Jamesx12345, Sateirti, Gransford, Anrnusna, Robevans123, Monkbot,
Remembertowright, EuroHealthNet, Phinespedia, RH8738, Barbara (WVS) and Anonymous: 26
Management of HIV/AIDS Source: https://en.wikipedia.org/wiki/Management_of_HIV/AIDS?oldid=693157791 Contributors: Bryan
Derksen, Taw, Alex.tan, Ewlloyd, Someone else, Ahoerstemeier, Prometheus~enwiki, Angela, JWSchmidt, Julesd, Samw, Teresag, Maximus Rex, Finlay McWalter, Kstailey, Gak, Naddy, Chris Roy, Stewartadcock, Rholton, Acegikmo1, ElBenevolente, Lupo, Andries, Nunhhuh, Tom harrison, Zigger, Mzanon, Everyking, Gzornenplatz, Edcolins, Hob, Chowbok, Beland, OwenBlacker, Bodnotbod, Sam Hocevar,
Anodyne, Daevatgl, Davidstrauss, Rich Farmbrough, FT2, Roo72, Samboy, Bender235, ESkog, JoeSmack, Thickslab, John Vandenberg,
R. S. Shaw, Arcadian, Giraedata, Rje, Cherlin, Canek, GJeery, Smartneddy, Kelly Martin, Alvis, Barrylb, Wikiklrsc, Joerg Kurt Wegner, Graham87, V8rik, Sci guy, Rjwilmsi, Tizio, Nneonneo, Unfocused, Ian Pitchford, Lmatt, Terrace4, Joonasl, EvilStorm, Roboto de
Ajvol, Splette, Rodasmith, Truetone, Yegorka, Moe Epsilon, Grcampbell, Bdell555, 2over0, Esprit15d, Modify, Vicarious, Caballero1967,
Junglecat, Paul Erik, TechBear, SmackBot, Ratarsed, Espresso Addict, Royalguard11, Trezatium, Edgar181, Gilliam, Chris the speller,
Bartimaeus, RDBrown, AtmanDave, Uthbrian, Muboshgu, Scray, Ender3057, CarbonNYC, Flubbit, Letmeinnow, Wen D House, G716,
Drphilharmonic, DMacks, Ligulembot, Turpin, ArglebargleIV, CharlesDexterWard, Jaganath, Punkrawkhighrllr, TastyPoutine, Mkasp73,
Ragingbullfrog, Mystylplx, Dgw, Cydebot, Procrastinator supreme, Michaelas10, Hopping, Thijs!bot, Yboord028, Escarbot, AntiVandalBot, TimVickers, Arch dude, Godcast, Magioladitis, MastCell, JNW, Rivertorch, RAShippy, DerHexer, WLU, Yobol, CliC, KBlott,
Mccajor, Mikael Hggstrm, Veganaxos, Jnp2109, Ajfweb, Wikimandia, Red Fox 2007, DSRH, Zkbt, Fourthwit, Sciencewatcher, Optigan13, Madhero88, Stepheng4, Doc James, Ronsword, Martha p, SieBot, Nubiatech, VVVBot, Tm1947, Loveless2, Mimihitam, Lightmouse, PsyberS, Kinkyturnip, ClueBot, Radiofreejohn, Auntof6, Kitsunegami, Noca2plus, Arjayay, SchreiberBike, Anishviz, Princetonstevens, NJGW, SoxBot III, Vanished user uih38riiw4hjlsd, Abhishek727, DumZiBoT, Falcor7, XLinkBot, Alexius08, Addbot, C6541,
DOI bot, Kongr43gpen, LaaknorBot, Wildcursive, Keepcalmandcarryon, Zorrobot, Luckas-bot, Yobot, Aoso0ck, AnomieBOT, Rubinbot,
Killiondude, Eteklema-GMU, Bluerasberry, Materialscientist, Swithrow2546, Citation bot, Naj-GMU, LilHelpa, The sock that should not
be, Plwha, Ched, Rocker162, Meet poonam, Dmjacobsen, Frankie0607, Prunesqualer, RibotBOT, , Jatlas, FrankMJohnson,
Citation bot 1, Citation bot 4, Nirmos, Imtoogodly184, Trappist the monk, January, Hopur32009, Aslimarati, Wordhabit3, Dewritech,
JacoNiel, John Mackenzie Burke, Netha Hussain, Martin Waldhausen, Therexbanner, Amildixon, ClueBot NG, Hagi90210, Smtchahal, Gauteisntme, Thisbites, Zainmemon, Rezabot, CaroleHenson, Harmdu, Helpful Pixie Bot, BG19bot, Wit1115, John Cummings,
MusikAnimal, MuanN (usurped), MrBill3, Italicus84, BattyBot, Aliwal2012, JesseAlanGordon, PICAWN, Thanoslygdas, Bszl, Misomucho, Tara.jackson, Joelxsfu, Vaccinationist, Clr324, BrillLyle, Didi.hristova, Pgcudahy, AbunaiHateem, Annie1616, Monkbot, Renamed
user 51g7z61hz5af2azs6k6, Ethylfox, Chiu.161, Richard070, Victorialul and Anonymous: 210
Epidemiology of HIV/AIDS Source: https://en.wikipedia.org/wiki/Epidemiology_of_HIV/AIDS?oldid=681529104 Contributors: The
Anome, Ed Poor, Rmhermen, Gabbe, Ppe42, Philwelch, Everyking, Mboverload, Golbez, Beland, PDH, Carl Henderson, David Schaich,
Bender235, Dalf, Cmdrjameson, Alansohn, Wouterstomp, Avenue, Uucp, Birdmessenger, Ultramarine, Kjetor, GregorB, Sci guy, Vanderdecken, Rjwilmsi, Tim!, Nightscream, Koavf, StephanieM, Fred2005, Vsion, Elmer Clark, Zotel, Valentinian, DVdm, Antiuser, Wjfox2005, EamonnPKeane, Taejo, Hatethedj, Muntuwandi, Furious Stormrage, Hakeem.gadi, Gnusbiz, Grcampbell, Joe747, Zello, American2, 2over0, Zzuuzz, ASmartKid, Wsiegmund, Garion96, Aliza250, Roke, Cmglee, The Minister of War, TechBear, SmackBot, Macgreco, Urania3, FloNight, Gigs, Jagged 85, Rtmullins, Trezatium, Kintetsubualo, Flamarande, Apers0n, Uxejn, Chris the speller, Bluebot, DroEsperanto, MaxSem, Dethme0w, Ultra-Loser, Hairouna, DenisDiderot, Cybercobra, DMacks, Soap, Writtenonsand, Green Giant, Reddragon300, Dl2000, Makeemlighter, Zeus1234, Argon233, Karenjc, Johnlogic, A876, Jkokavec, Rracecarr, Chrislk02, JCO312,
Death motor, Jsteph, Epbr123, Ufwuct, Kungfujoe, The Hybrid, AntiVandalBot, AtikuX, Davewho2, Globalhealth, Wasell, Magioladitis,
Cambio~enwiki, Bigdan201, Chessdude111, WhatamIdoing, Adrian J. Hunter, Hamiltonstone, Yobol, MartinBot, Manwiththemasterplan,
Threedots dead, AlphaEta, MistyMorn, ArjunTheOne, Natty4bumpo, Gallador, Ahuskay, RicegoneWILD, Dirie, BigHairRef, Yellowver,
Bonadea, Funandtrvl, Je G., Ryan032, Marekzp, Malandro, Mcognato, RadiantRay, Eubulides, Doc James, BobVega, Fibo1123581321,
Anchor Link Bot, Martarius, Sfan00 IMG, ClueBot, SummerWithMorons, Leviel, Dwrcan, Bald Zebra, NJGW, SilvonenBot, Thatguyint,
HexaChord, Addbot, Krawndawg, Keepcalmandcarryon, Tachophil, Tide rolls, Lightbot, Yobot, Gingkid, AnomieBOT, Eteklema-GMU,
Citation bot, Naj-GMU, Xqbot, Bianca2010, Hoping To Help, 78UnicornBrina, AndersonH.K., Torne, Baron.atreid, LucienBOT, HannibalLecter5, Citation bot 1, Fuzbaby, Loyalist Cannons, Abc518, Antemister, Begilm, Diannaa, RjwilmsiBot, DASHBot, Dewritech,
ZroBot, Aaa1, QEDK, Highvale, Alice.odin, L Kensington, Operative67, Bofolo, Eg-T2g, Dshylee, ClueBot NG, Dwc89, Cardnl12, Frietjes, Runehelmet, Guptan99, Helpful Pixie Bot, Bstbll, Pluo, BattyBot, Ectomy5874, ChrisGualtieri, Agarrd, LightandDark2000, AldezD,
Antonio2105, Alexander9595, Fopollito, Purnendu Karmakar, Shiningroad, Coreyemotela, OutstandingPinoy, Monkbot, Filedelinkerbot,
TWil2014, Pigi5, ColossalPvP, Mohamed banjeey and Anonymous: 183
HIV/AIDS research Source: https://en.wikipedia.org/wiki/HIV/AIDS_research?oldid=689290617 Contributors: PFHLai, Rjwilmsi,
Splette, Scray, Valoem, CommonsDelinker, Meters, 21stcenturypolitix, Yobot, Bluerasberry, Trappist the monk, Everyone Dies In the
End, Widr, Mohamed CJ, Mleoking, Stevetihi, Cold Season, BattyBot, Biosthmors, Soulparadox, Dexbot, LightandDark2000, Mogism,
Prokaryotes, Coreyemotela, Monkbot, Kookymiyuki, Joy654321, Umahmood15, Welcome-v and Anonymous: 10

14.15.2

Images

File:AIDS_Clinic,_McLeod_Ganj,_2010.jpg Source:
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McLeod_Ganj%2C_2010.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: John Hill
File:AIDS_Poster_If_You're_Dabbling_in_Drugs_1989.jpg Source: https://upload.wikimedia.org/wikipedia/commons/b/bd/AIDS_
Poster_If_You%27re_Dabbling_in_Drugs_1989.jpg License: Public domain Contributors:
Source site: http://www.nlm.nih.gov/exhibition/visualculture/hivaids14.html Original artist: The original uploader was Grcampbell at
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File:AIDS_and_HIV_prevalence.svg Source: https://upload.wikimedia.org/wikipedia/commons/e/ee/AIDS_and_HIV_prevalence.svg
License: Public domain Contributors: UNAIDS, Image:HIV Epidem.png, Image:BlankMap-World6.svg Original artist: Escondites Permission= PD-self

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File:AIDS_and_HIV_prevalence_2009.svg Source:
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prevalence_2009.svg License: Public domain Contributors: This le was derived from AIDS and HIV prevalence.svg: <a
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src='https://upload.wikimedia.org/wikipedia/commons/thumb/e/ee/AIDS_and_HIV_prevalence.svg/50px-AIDS_and_HIV_prevalence.
svg.png' width='50' height='25' srcset='https://upload.wikimedia.org/wikipedia/commons/thumb/e/ee/AIDS_and_HIV_prevalence.
svg/75px-AIDS_and_HIV_prevalence.svg.png 1.5x, https://upload.wikimedia.org/wikipedia/commons/thumb/e/ee/AIDS_and_HIV_
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File:HIV-1_Transmission_electron_micrograph_AIDS02bbb_lores.jpg Source: https://upload.wikimedia.org/wikipedia/commons/
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File:HIV-1_subtype_prevalence_in_2002.png Source:
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prevalence_in_2002.png License: CC-BY-SA-3.0 Contributors: Based on Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza
J; WHO-UNAIDS Network for HIV Isolation and Characterization. (2002) Estimated global distribution and regional spread of HIV-1
genetic subtypes in the year 2000. J Acquir Immune Dec Syndr. 29(2):184-90. Original artist: The original uploader was Grcampbell at
English Wikipedia
File:HIV-AIDS_world_map_-_DALY_-_WHO2002.svg Source: https://upload.wikimedia.org/wikipedia/commons/f/fe/HIV-AIDS_
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File:HIV-SIV-phylogenetic-tree_straight.svg
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domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with
identication number #10000. Original artist:
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Contributors: Own work Original artist: Thomas Splettstoesser (www.scistyle.com)
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File:HIV-replication-cycle.svg Source: https://upload.wikimedia.org/wikipedia/commons/5/51/HIV-replication-cycle.svg License: CC
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File:HIV.png Source: https://upload.wikimedia.org/wikipedia/commons/e/ea/HIV.png License: CC BY-SA 4.0 Contributors: Own work
Original artist: BruceBlaus
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PNG License: Public domain Contributors:
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File:HIV_Membrane_fusion_panel.svg Source:
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panel.svg License: CC BY-SA 3.0 Contributors: Own work Original artist: Mike Jones
File:HIV_Rapid_Test_being_administered.jpg Source: https://upload.wikimedia.org/wikipedia/commons/7/76/HIV_Rapid_Test_
being_administered.jpg License: CC BY-SA 3.0 Contributors: File made available by Equality Michigan through the LGBT Free Media
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AIDS_explained_in_a_simple_way.webm License: CC BY-SA 3.0 Contributors: https://www.youtube.com/channel/UCDfdXzYssMFD_
lQOrN5WXUg Original artist: Jake Schneider

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File:HIV_on_macrophage.png Source: https://upload.wikimedia.org/wikipedia/commons/a/a7/HIV_on_macrophage.png License: CC

BY 2.5 Contributors: Reconrming the Traditional Model of HIV Particle Assembly. Gross L, PLoS Biology Vol. 4/12/2006, e445. doi:
10.1371/journal.pbio.0040445 Original artist: see Source
File:Hiv-timecourse.png Source: https://upload.wikimedia.org/wikipedia/commons/a/a4/Hiv-timecourse.png License: CC-BY-SA-3.0
Contributors: Based on Figure 1 in Pantaleo, G et al. (February 1993). New concepts in the immunopathogenesis of human immunodeciency virus infection. New England Journal of Medicine 328 (5): 327-335. PMID 8093551. Original artist: Jurema Oliveira
File:Hiv-timecourse_copy.svg Source: https://upload.wikimedia.org/wikipedia/commons/0/0e/Hiv-timecourse_copy.svg License: CC0
Contributors: Own work Original artist: Sigve
File:Itrafig2.jpg Source: https://upload.wikimedia.org/wikipedia/commons/4/47/Itrafig2.jpg License: CC BY 2.5 Contributors: http://
www.wormbook.org/chapters/www_intracellulartrafficking/intracellulartrafficking.html (Transferred from en.wikipedia to Commons by
Vojtech.dostal.) Original artist: Grant, B. D. and Sato, M
File:Know_Aids_-_No_Aids.jpg Source: https://upload.wikimedia.org/wikipedia/commons/3/34/Know_Aids_-_No_Aids.jpg License:
CC BY-SA 3.0 Contributors: Own work Original artist: John Hill
File:Life_Cycle_of_a_Retrovirus.svg Source: https://upload.wikimedia.org/wikipedia/commons/2/2b/Life_Cycle_of_a_Retrovirus.
svg License: CC BY-SA 3.0 Contributors: Own work Original artist: Mrdavis21
File:Life_expectancy_in_select_Southern_African_countries_1960-2012.svg Source:
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commons/d/d4/Life_expectancy_in_select_Southern_African_countries_1960-2012.svg License: CC BY-SA 4.0 Contributors: Own
work Original artist: Thomas Splettstoesser (www.scistyle.com)
File:Map-of-HIV-Prevalance-in-Africa.png
Source:
Map-of-HIV-Prevalance-in-Africa.png License: Public domain Contributors:

https://upload.wikimedia.org/wikipedia/commons/5/56/

HIV_Epidem.png Original artist: HIV_Epidem.png: User:Grcampbell

File:Mmwr-aids-July1981-report-101.png
Mmwr-aids-July1981-report-101.png License:
for Disease Control Original artist: US gov't

Source:
https://upload.wikimedia.org/wikipedia/commons/e/ed/
Public domain Contributors: MMWR Morbidity and Mortality Weekly, Centers

File:Oraquick.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/cc/Oraquick.jpg License: CC BY 3.0 br Contributors:

http://www.agenciabrasil.gov.br/media/imagens/2007/12/05/1200MC0038.jpg/view Original artist: Marcello Casal JR/ABr
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Contributors: http://www.ebi.ac.uk/pdbe-srv/view/images/entry/1k6c600.png, displayed on http://www.ebi.ac.uk/pdbe-srv/view/entry/
1k6c/summary Original artist: Jawahar Swaminathan and MSD sta at the European Bioinformatics Institute
File:Phylogeny_of_Retroviruses.svg Source: https://upload.wikimedia.org/wikipedia/commons/9/97/Phylogeny_of_Retroviruses.svg
License: CC BY 3.0 Contributors: Phylogeny_of_Retroviruses.png, Published in Weiss, Robin A. (2006). "The discovery of endogenous
retroviruses". Retrovirology 3 (67). Original artist: Phylogeny_of_Retroviruses.png: *Phylogeny_of_Retroviruses.jpg: Robin A Weiss
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File:SIV_primates.jpg Source: https://upload.wikimedia.org/wikipedia/commons/9/93/SIV_primates.jpg License: CC BY-SA 3.0 Contributors:
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org/wiki/Discussion_User:Dancojocari' class='extiw' title='en:Discussion User:Dancojocari'></a>
File:Sida-aids.png Source: https://upload.wikimedia.org/wikipedia/commons/2/2f/Sida-aids.png License: CC-BY-SA-3.0 Contributors:
User:FoeNyx 2004 (artistic illustration) Original artist: User:FoeNyx 2004 (artistic illustration)
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labeling.jpg License: CC BY-SA 4.0 Contributors: Own work Original artist: JrgenMoorlag
File:Symptoms_of_AIDS.svg Source: https://upload.wikimedia.org/wikipedia/commons/6/6b/Symptoms_of_AIDS.svg License: CC0
Contributors: All used images are in public domain. Original artist: Mikael Hggstrm.
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File:Tobias-AIDS-test.jpg Source: https://upload.wikimedia.org/wikipedia/commons/f/f5/Tobias-AIDS-test.jpg License: Public domain Contributors: ? Original artist: ?

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