Académique Documents
Professionnel Documents
Culture Documents
1
HIV and AIDS
History of an infectious agent
In Los Angeles 1967-1978: only two cases of
Pneumocystis carinii pneumonia
• 1979 - 5 cases of All Homosexual
Pneumocystis carinii
pneumonia
Dot-like intracystic
bodies of
Pneumocystis
carinii in lung
Cytologic preparation
from a bronchoalveolar
lavage – Giemsa stain
Pneumocystis
jiroveci 2
HIV and AIDS
History of an infectious agent
Pneumocystis pneumonia
3
HIV and AIDS
6
HIV and AIDS
Two rare diseases in the gay community linked to
IMMUNOSUPPRESSION
OPPORTUNISTIC INFECTIONS
Also
Lymphadenopathy (diffuse, undifferentiated non-Hodgkins
lymphoma)
1977- 1980: No cases in the young male (20 - 39 years old) population
of the San Francisco area
March 1981 - January 1982: four cases within 10 months
Suggests an infectious
agent
9
HIV and AIDS
More evidence for an infectious agent
Different ways of getting a similar syndrome
• Blood transfusions
• Intravenous drug use
• Hemophilia (clotting factor)
11
HIV and AIDS
Obvious agent:
A virus……that is now in the
blood supply
Primary route of
transmission: Sex
AIDS is a sexually-transmitted viral disease
12
HIV and AIDS
The Cellular Picture
ss of one cell type throughout the course of the dise
CD4+ T4 helper cells
A fall in the CD4+ cells always precedes disease
In advanced disease: the loss of another cell
type
CD8+ cytotoxic killer cells
Suggests an infectious agent
A virus
But initially difficult to grow
13
Rapidly kills cells on which it grows
AIDS
Definition
• AIDS is currently defined as the presence of
one of 25 conditions indicative of severe
immunosuppression
OR
• HIV infection in an individual with a CD4+ cell
count of <200 cells per cubic mm of blood
17
HIV and AIDS
Prevalaence
AIDS
Deaths
18
HIV and AIDS
Black
White
Hispanic
19
AIDS Statistics
Sub-Saharan Africa
• About 1 million new cases of AIDS per year
20
Impact of AIDS on life expectancy in five African countries, 1970–2010
70
65
60 Botswana
55
Life South Africa
50
expectancy
45 Swaziland
at birth
(years) 40
35 Zambia
30
Zimbabwe
25
20
1970–1975 1980–1985 1990–1995 2000–2005
1975–1980 1985–1990 1995–2000 2005–2010
Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database. 21
4.1
HIV prevalence (%) in adults in Africa, 2005
Zimbabwe
Botswana
Lesotho
Swaziland 22
2.5
•Several countries in sub-Saharan Africa
report infection rates of over 25%,
especially urban areas
24
HIV and AIDS
The Virus
The virus only grows on T4 cells that are proliferating
in response to an immune stimulus -- Therefore
difficult to grow in culture
Reverse transcriptase in
activated T4 cells in blood of patients
with AIDS
• Robert Gallo : HTLV-3
virus
antibody
CD4 cells
26
HIV and AIDS
The cellular and immunological picture - The course of
the disease
CD8 cells
27
HIV and AIDS
The cellular and immunological
picture
The course of the disease
1. titer
• High virus Acute Infection
• Mild symptoms
• Fall in CD4+ cells but recovers
• Rise in CD8+ cells but recovers
• A high virus titer (up to 10 million viruses
per ml blood)
• Macrophages infected
Macrophages bring HIV into the body if sexually transmitted 28
HIV and AIDS
2. A strong immune response
•
HIV and AIDS
3. A latent state
31
HIV and AIDS
4. The beginning of disease
Massive loss of CD4+ cells
• CD4+ cells are the targets of the virus
• Cells that proliferate to respond to the
virus are killed by it
• Dendritic cells present antigen and virus
to CD4 cells
• Epitope variation allows more and more HIV
to
escape from immune response just as response
wanes
• Apoptosis of CD4+ cells 32
HIV and AIDS
5. Advanced disease - AIDS
CD8+ cells destroy more CD4+
cells
• CD4 cell loss means virus and
infected
cells no longer controlled
• As CD4+ cells fall below 200 per
cu mm
virus titer rises rapidly and
remaining immune response
collapses
• CD8+ cell number collapses
33
• Opportunistic infections
HIV and AIDS
34
HIV and AIDS
35
HIV and AIDS
36
HIV and AIDS
Cofactors
Not all cases of Kaposi’s are associated
with HIV
Not all HIV infected persons suffer from
Kaposi’s
20% of homosexual HIV+ males get
Kaposi’s sarcomaKaposi’s
associated herpes virus
Few IVHuman
drug users or hemophiliacs
herpes virus-8 get
37
HIV and AIDS
Three Views of AIDS
Group-Specific Antigens
p24: nucleocapsid
9: nucleocapsid associated with RNA
GAG gene
Polyprotein 41
HIV - The Virus
Enzymes Retrovirus
• Polymerase (reverse
transcriptase – RNA
dependent DNA polymerase)
• Integrase
• Protease (cuts
polyproteins)
• POL gene
Polyprotein 42
The Genome of HIV
44
HIV - The Virus
Life History
A retrovirus
• Latency
• Specific destruction of
CD4+ cells
Human cells must possess a co-factor for infection that mouse cells do not
Co-Receptors
CD8+ Cells
48
Block HIV infection of macrophages
HIV - Life History
HIV
chemokin
e Mutant
CD4 CCR CCR5
CCR5 5 CD4
CD4
macrophage
Chemokine receptors are necessary co-receptors along with CD4 antigen
49
HIV and AIDS
Some people do not get AIDS
50
HIV and AIDS
Co-receptors and HIV infection
• CCR5 is a chemokine receptor
• Cells with homozygous mutant CCR5
molecules are not infected by HIV
1 in 100 Caucasians
No Africans
• Persons with heterozygous mutant CCR5
molecules progress to AIDS more slowly
51
HIV and AIDS
Co-receptors
• 25% of long term survivors are
CCR5 or CCR2 mutants (deletions)
• The same CCR5 mutation (called
“delta 32”) is thought to be the
mutation that rendered some people
immune to the plague in the middle
• Many other chemokine
ages receptors
52
HIV and AIDS
Long term non-progressers
• People who have been infected with HIV for
more than seven years that have stable CD4+
cell counts above 600 per cu mm with no
symptoms and no chemotherapy
53
HIV and AIDS
• Nairobi prostitutes
Client infection rate more than 25%
vaccine problem 55
HIV - Life History
Latency – Cellular – The problem of memory T4 cell
cel
Clinical Latency
HIV infection is not manifested as disease for years
56
During apparent clinical latency, virus is being replicated
Dynamics of CD4 T cells in an
Cell death
HIV infection Chronically-
apoptosis etc infected
memory T
cells with
Return provirus
Uninfecte
Infectio to
resting
d n state
activat
ed Long
T cell lived! Reactivati
on
Immune response
T4 resting T4 activated
memory cell
Why do all
T4 cells
1. PUNCTURED
MEMBRANE disappear?
60
Why do all T4 cells disappear? -
2
But syncytia
not common
Infected CD4 cell Most T4 cells
Cells Fuse are not HIV+
Gp120 positive
Could “sweep
up”
uninfected
cells
Uninfected CD4
Killing of CD4 cells cell
2. Syncytium Formation Gp120 negative
61
Why do all
T4 cells
disappear?
Cytotoxic
T cell
G protein
CXCR4
signal
? chemokine
receptor
?
Binding to CXCR4
Binding to CXCR4
results in
results in expression of
expression of TNF- TNF-alpha on the 64
alpha receptor II cell surface
Why do all T4 cells disappear?
Induction of apoptosis
CD8 cell
CXCR4
Macrophage
Death
CD8 T cell
apoptotic
bodies 65
Macrophages may be infected
by two routes
HIV gp12
0 CD
4 HIV gp120 binds to
macrophage CD4
antigen
Virus is opsonized by
anti gp120
antibodies which
bind to macrophage
Fc Fc receptors - an
receptor enhancing antibody
Anti-
gp120
vaccine problem
66
HIV
Macrophages - The Trojan
Horse
Early HIV isolated during infection are macrophage
tropic (have a macrophage chemokine co-receptor
(CCR5))
Virus probably infects patient via macrophages in
semen etc
Infection by HIV leads to altered cytokine production
“slim disease”
Macrophages
Slim form
disease very a reservoir
like outside
Visna in sheep the infects
- also blood
macrophages
Carry virus into different organs (brain)
Non-proliferating mature macrophages sustain HIV
67
production for a long time without being killed by
Population Polymorphism
HIV is a retrovirus
Retroviruses use host cell RNA polymerase II
to replicate their genome
Pol II has a high error rate 1:2,000-10,000
HIV genome 9749 nucleotides
Therefore EVERY new virus has at least one mutation!
Every possible single mutation arises daily
1% of all possible double mutations arise daily
vaccine problem
vaccine problem 71
Population Polymorphism
• Variation in reverse transcriptase leads to
resistance to nucleoside analogs
drug problem
Galactocerebroside
73
Anti-HIV Strategies
• Education
Sexually transmitted
Not highly infectious
• Chemotherapy
Mutation selection Resistance
but
Suppress replication No capacity for mutation74
Anti-HIV Strategies
Highly
Active
Anti-
Retroviral
Therapy
HAART: Two nucleoside analog RT inhibitors and 1
protease inhibitor
Or: Two nucleoside analog RT inhibitors and 1 non
75
nucleoside
Does HIV Cause AIDS?
Single common factor between:
• Gay San Franciscans
• New York I.V. drug users
• African heterosexuals
• Hemophiliacs
• Spouses of hemophiliacs and drug users
• Children of hemophiliacs and drug users
76
Does HIV Cause AIDS?