HIV infection

HIV produces a pandemic

infection whose impact on societies is
without precedent.

N. Negrut, MD,
Infectious Disease Specialist, Teaching Assistant
Faculty of Medicine and Pharmacy, University of Oradea
 Human immunodeficiency virus (HIV)
 Fam. Retroviridae
 Genus Lentivirus
 Types:
 HIV-1
 4 groups
 M (major): clades

- A, B, C, D, F, G, H, J, K, CRFs.
 O (outlier),

 N (non-M and non-O),

 P (2009).

 HIV-2
 5 groups: A, B, C, D, E

CRFs -"circulating recombinant forms“

new hybrid virus  two viruses of different subtypes meted in the cell of an infected person
(genetic materials are mix together)
Global distribution of HIV-1
 Possible origin of HIV:
HIV-1  SIVcpz (chimpanzees)
HIV-2  SIVsmm (sooty mangabeys)
- monkey from West Africa.
- the monkey version of the immunodeficiency virus (called simian
immunodeficiency virus or SIV) was transmitted to humans and mutated into HIV
when humans hunted them for meat and came into contact with their infected blood.

- the new virus slowly spread later into other parts of the world.

 HIV-1
-responsible for the worlwide pandemy
-more aggressive than HIV-2

 HIV-2
-predominantly found in west Africa but rarely elsewhere
-viral genome is more like SIV
-immunodeficiency develops more slowly than HIV-1
-less infectious early in the course of
infection than HIV-1
DISTRIBUTION
33.3 million
people were living
with HIV worldwide
in 2009.
Regional statistics for HIV and AIDS-2009
Global trends:1990 - 2009
HIV STRUCTURE
A single HIV virus particle is called a virion. It is spherical and one 10,000th of a millimeter in diameter.

1.Viral envelope:
•Two layers of fatty molecules
•2 glycoproteins: SUgp120 and TMgp41

2.Matrix:
•between the viral core and the viral envelope
•protein p17

3.Viral core (nucleocapsid):

•Viral genome (two single strands of HIV RNA)

•Protein p7 (the HIV nucleocapsid protein)
•Protein CA p24
•Enzymes:
•RT(Reverse transcriptase)
•Interase
•Protease
HIV genomic structure
 Major genes:
 env - codes gp160, the precursor to gp120 and gp41
 gag - codes p17, p24, p7, and p6 proteins
 pol - codes viral enzymes RT, integrase, and protease.
 Regulatory genes:
 tat – trans-activator of transcription
 rev – regulator of expression of virion protein
 Accessory genes:
 nef – negative regulatory factor
 vif – virion infectivity protein
 vpu - viral protein U (HIV 1)
 vpx – virion protein X (HIV 2)
 vpr – viral protein R
 HIV REPLICATION CYCLE

1. Fusion of the HIV cell to the host cell surface.

2. HIV RNA, reverse transcriptase, integrase,

and other viral proteins enter the host cell.

3. Viral DNA is formed by reverse transcription.

4. Viral DNA is transported across the nucleus

and integrates into the host DNA.

5. New viral RNA is used as genomic RNA and

to make viral proteins.

6. New viral RNA and proteins move to cell

surface and a new, immature, HIV virus forms.

7. The virus matures by protease releasing individual

HIV proteins.
HIV’s source of infection
 blood, blood products,
 sexual fluids,
 breast milk,
 amniotic fluid.
Route of transmission

 Sexual transmission:
 heterosexual transmission
 homosexual transmission.

 Vertical transmission (mother to child)

 Prepartum (fetomaternal blood shunts within the placenta)
 Intrapartum (infant's oral mucosa is contaminated with infected
vaginal secretions)
 Post partum (breast feeding)

 Blood transmission
 sharing infected injection equipment
 infected blood products
 needle-stick injuries.

 Unidentified
 HIV is not transmitted

 routine casual contact,

 air,
 insect bites.
Risk factors
1. Unprotected sexual intercourse, anal intercourse
(8-fold)
 A large number of sexual partners
 Prior or current STDs:
 gonorrhea and chlamydia infections (3-fold),
 syphilis (7-fold),
 herpes genitalis (25-fold).
 Sharing of intravenous drug paraphernalia
 Receipt of blood products
 Mucosal contact with infected blood or needle-
stick injuries
 Maternal HIV infection (for newborns, infants, and
children)
HIV infection - stages
 STAGE 1 : Primary HIV infection
 STAGE 2 : Clinically asymptomatic stage
 STAGE 3 : Symptomatic HIV infection
 STAGE 1 :

Primary HIV infection - Acute Retroviral Syndrome - Mononucleosis-

Like Syndrome

Symptoms typically appear a few

days to a few weeks after
exposure to HIV, persist for 2-4
weeks and include:
 Fever
 Anorexia
 Fatigue
 Night sweats
 Headache, retroorbital pain
 Myalgia/arthralgia
 Pharyngitis
 Generalized lymphadenopathy,
may last longer than 2-3 weeks
 Rash, (erythematous
maculopapular, urticaria)
 Mucocutaneous ulceration
 Weight loss
 Neurologic symptoms (eg,
aseptic meningitis, radiculitis, •Seroconversion: 3-12 weeks after exposure
myelitis)
•Viral load ↑↑↑↓6 months”set point”
•CD4+ ↓↓for 2-3 weeks ↑(<n.v.)
STAGE 2 : Clinically asymptomatic stage

 - can persist for ten years 

 - clinical manifestations: generalized lymphadenopathy or free from major symptoms

•Viral replication↑ CD4+ ↓

 STAGE 3 : Symptomatic HIV infection
Early-Stage

 Generalized lymphadenopathy (Ø>1cm, >2 inguinal

areas, >3-6 months, without etiology)
 Oral hairy leukoplakia (filamentous white lesions,
generally along the lateral borders of the tongue)
 Aphthous ulcers
 Rash (maculopapular).

Oral hairy leukoplakia Aphthous ulcers Rash (maculopapular)

Medium-Stage

 Asymptomatic or with minimum of

symptomatology
 Non specific symptomatology:
 Fever, weight loss, night sweats, fatigue
 Persistent and drug resistant candidiasis
 Persistent and recurrent diarrhea
 Recurrent herpes simplex virus infection
 Recurrent bacterial infection with common
agents

•CD4+:200-500 cell/mm3 or 14-28% of all lymphocytes

Late-Stage (AIDS - Acquired immune deficiency syndrome)

 opportunistic infections (Pneumocystis carinii pneumonia,

Coccidioidomycosis, disseminated or extra-pulmonary, Cryptococcosis, extra-pulmonary,
CMV retinitis, Herpes simplex-chronic ulcers, Histoplasmosis, disseminated extra-pulmonary,
Isosporiasis, chronic intestinal, Candidiasis of bronchi, trachea, or lungs, etc.)
 malignant diseases (Kaposi's Sarcoma, invasive cervical cancer, Burkitt's
lymphoma, immunoblastic lymphoma, etc.)

CD4+<200 / µL or 14% of all lymphocytes

The relationship between HIV copies (viral load) and
CD4 counts over the average course of untreated HIV
infection
CD4+ (cells/mm³)                 
HIV RNA copies/mL of plasma
Chest radiograph: diffuse bilateral infiltrates
(Pneumocystis carinii pneumonia)
Kaposi's Sarcoma
a tumor caused by Human herpesvirus 8 (HHV8)

Papular cutaneous Kaposi's Sarcoma

 Profiles of disease progression
 Rapid progressors:
 a small proportion of patients
 1-2 years AIDS
 high levels of viral replication
 precipitous decline in CD4+.
 Intermediate progressors:
 the majority of the patients
  many years  AIDS
 steady decline of CD4+
 Long-term non-progressors:
 a small proportion of the patients
 control HIV viral load without antiretroviral therapy.
 low-to-undetectable viral loads and well-preserved
CD4 counts for many years.
 Lab tests:

 CD4 T-cell count - indicator of the risk of acquiring opportunistic infections.

CD4= 500-2000 cells/μL(>30%)
CD4 < 200/μL=AIDS

 HIV antibodies (ELISA, Western Blot)

The ELISA test is repeated if positive.It requires Western Blot , to confirm the results because false positives can occur.
Are negative in immune window period (period between the moment of exposure and seroconversion )

For immune window period:

 HIV p 24 antigen (ELISA)
 Viral culture
 Viral load (NASBA, RT-PCR)
 Treatment: HAART "Highly active
antiretroviral treatment"

The goals:
 to improve quality of life,
 reduce HIV-related mortality and morbidity,
 maximally suppress the viral load for as long
as possible,
 restore and preserve immune function.
 The classes of antiretrovirals and
their mechanisms of action:

1. a. Nucleoside reverse transcriptase inhibitors (NRTIs) inhibit RT

b. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

2. Protease inhibitors (PIs) inhibit fully infectious viral offspring from

assembling and maturing

3. Entry inhibitors
 fusion inhibitor bind to the gp41
 chemokine receptor antagonist" or a "CCR5 inhibitor “ bind chemokine receptors CCR5

and inhibit entry of the virus into immune cells

4. Integrase inhibitors Inhibit integrase, preventing HIV DNA

integrating into the nucleus
1. a. Nucleoside reverse transcriptase
inhibitors (NRTIs)

 Abacavir (Ziagen, ABC)

 Didanosine (Videx, Videx EC, ddI)
 Emtricitabine (Emtriva, FTC)
 Lamivudine (Epivir, 3TC)
 Stavudine (Zerit, Zerit XR, d4T)
 Tenofovir DF (Viread, TDF)
 Zalcitabine (Hivid, ddC)*
 Zidovudine (Retrovir, ZDV, AZT)

*No longer available on market

1. b.Non-nucleoside reverse
transcriptase inhibitors (NNRTIs)

 Delavirdine (Rescriptor, DLV)

 Efavirenz (Sustiva, EFV)
 Etravirine (Intelence, ETR)
 Nevirapine (Viramune, NVP)
2. Protease inhibitors (PIs)
 Amprenavir (Agenerase, AVP)*
 Atazanavir (Reyataz , ATV)
 Darunavir (Prezista, DRV)
 Fosamprenavir (Lexiva, f-APV)
 Indinavir (Crixivan, IDV)
 Lopinavir and ritonavir (Kaletra, LPV/r)
 Nelfinavir (Viracept, NFV)
 Ritonavir (Norvir, RTV)
 Saquinavir (Invirase [hard gel] capsule, SQV)
 Tipranavir (Aptivus, TPV)

*No longer available on market

3. Entry inhibitors
 Fusion inhibitors
 Enfuvirtide (Fuzeon, T-20)
 Cellular chemokine receptor (CCR5)
antagonists
 Maraviroc (Selzentry, MVC)
4. Integrase inhibitors
 Raltegravir (Isentress, RAL)
Prevention
 avoidance of sexual contact outside
a monogamous relationship,
 the use of safer sex practices for all
other sexual encounters,
 abstinence from nonmedical
parenteral drug use
 chemoprophylaxis
Bibliography
1. http://www.who.int
2. http://bestpractice.bmj.com
3. http://www.nwabr.org/education/hiv.htm
4. http://www.tibotec-hiv.com
5. http://www.niaid.nih.gov
6. Burke DS: “Recombination in HIV: an important viral evolutionary
strategy”, Emerg Infect Dis. 1997 Jul-Sep;3(3):253-9.
7. Plantier JC, and all: “A new human immunodeficiency virus derived
from gorillas”, Nat Med. 2009 Aug;15(8):871-2. Epub 2009 Aug 2.
8. http://www.nature.com
9. http://visualsonline.cancer.gov/details.cfm?imageid=2168