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U2P8G2 1

Scribe: Salsabeel M

Case No. 8: Infection by HIV

Human Immunodeficiency Virus (HIV)

1. Structure

Belongs to the Lentivirus subfamily of

Retrovirus.( Lentivirus cause slow
degenerative disease)
Two copies of the ss(+)RNA
Long incubation period
Spherical in shape
Enveloped with 3 layers namely;
Innermost genome layer
Middle nucleocapsid consisting of
3 enzymes; reverse transcriptase,
integrase and protease
Outer membrane of glycoprotein surrounded by lipoprotein envelope
Contains 3 major genes namely gag,pol and env encoding for the structural proteins.



Group-specific antigens
Reverse transcriptase

Structural proteins
Capsid protein
Core nucleocapsid protein
Matrix protein
Produces dsDNA provirus
Viral DNA integration into host cell DNA
Cleaves viral protein
Surface protein that binds to CD4 and coreceptors
Transmembrane protein for viral fusion to host cell


DNA, long terminal repeats

Regulatory protein
Regulatory proteins


Regulatory proteins

Integration and viral gene expression

Facilitate viral gene transcription
Transport of mRNA from nucleus into the
Suppresses MHC class I proteins

2. Mode of transmission

Sexual transmission
Perinatal transmission
Intravenous drug use
Blood transfusion
Occupational exposure

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Scribe: Salsabeel M

3. Pathogenesis (Life Cycle)

1) Transmission of HIV can occur across intact mucosal surface but abrasions increase
the risk of infection.
In stratified epithelium for e.g. vagina, exocervix, tonsils, anus and prepuce,
infection is mediated by dentritic cells.
In simple epithelium for e.g. rectum, endocervix, infection is mediated by
dendritic cells or M cells.

Primary cell target of HIV-1:

CD4 for T cells and DC
Lectin and proteoglycans for
Lipid receptor for genital and
intestinal epithelial cells

CXCR4 on T cells
CCR5 on epithelial cells,
macrophage, DC and T cells

2) Attachment, Binding and Entry

Attachment: Env interact with DC-SIGN
Gp120 binds to CD4 conformational change bind to CCR5 on macrophage
or DC and CXCR4 on T cells activates gp41 fusion of viral and host
membrane forms bundle span
3) Reverse transcription
Nucleocapsid uncoats in cytoplasm reverse transcription of viral RNA
yields a dsDNA out of 2 RNA molecules contain in the virion.
4) Nuclear transport
dsDNA in PIC actively transported to the nucleus along microtubules PIC
cross nuclear envelop through nuclear pore complex which comprises of
multiple nucleoporins).
5) Proviral DNA integration
After entry into the nucleus, PIC gains access to chromatin viral DNA is
integrated into host chromosome with the help of viral integrase.
6) Transcription
Transcription of viral DNA into messenger RNA (mRNA)
7) Translation
mRNA translated into viral proteins (rev,tat,nef, envelope proteins,vpr,RT)
The new viral RNA forms the genetic material of the next generation of
8) Viral Assembly and Budding
The viral proteins are assembled at the cell surface the virus buds from the
cell surface released to infect another cell.

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Scribe: Salsabeel M

4. Course of HIV-1 infection

Acquisition of infection

Eclipse phase (approx. 10days following infection) : T cells and DC affected at the
site of infection


End of eclipse phase: virus to draining lymph nodes meet activated CD4+ and
CCR5+ T cells (targets for further infection) virus replicate rapidly spread to
GALT where activated T cells are present in high numbers recruitment of
additional T cells to site.
In GALT, 20% T cells infected and 60% uninfected T cells are activated and die
by apoptosis release of microparticles suppress immune system

Primary HIV infection

Dissemination of virus burst of HIV viremia Primary infection in peripheral

blood decrease CD4+ level in blood due to HIV mediated cell killing or to cell
retrafficking to lymphoid tissues.

Asymptomatic HIV infection

Time between infection and onset of clinically apparent disease= approx. 10yrs

However HIV is not uniformly expressed in all individuals.

Few HIV infected develop AIDS and die within month of primary infection (rapid
About 5% of HIV infected individuals remain assymptomatic even after 12years
or more.

Early symptomatic infection

Skin rash, fatigue, slight weight loss, mouth ulcers, fungal skin and nail infection

Hairy leukoplakia

Late symptomatic infection

Chronic oral and vaginal thrush, recurrent herpes blisters on mouth or genitals,
ongoing fever, persistent diarrhoea, significant weight loss

Advanced HIV disease

Opportunistic infection; some of the common opportunistic infections include

pneumocystis carinii pneumonia, mycobacterium avium complex disease,
cytomegalovirus, toxoplasmosis, candidiasis

An AIDS diagnosis can be given to an HIV positive person who has a CD4 count
of less than 200/mm3 or a history of an AIDS defining illness( such as one of the
opportunistic infection mentioned above).

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Scribe: Salsabeel M

5. Mechanism of CD4+ T cell depletion

1) Killing of infected CD4+ T cells
2) Killing of bystander CD4+ T cells- when bystander CD4+ T cells come in contact
with HIV infected CD4+ T cells, they get killed by FasL-Fas-induced apoptosis.
3) The Gut hypothesis- HIV replicates massively in CD4+ T cells from GIT mucosa
suggesting that the gut is the site where all CD4+ T cells are killed.

6. HIV latency

At the level of individual T cells

Rare but appear to arise when activated CD4+ T cells become infected and survive
long enough to revert back to a resting memory state which is non permissive for
viral gene expression( cannot replicate).
As it resides in memory T cells, it persists indefinitely even in patients on potent
antiretroviral therapy.
Molecular mechanisms for HIV latency:
Absence of host transcription factor(NFkB or NFAT) in nucleus of resting
CD4+ T cells
Absence of tat and associated host factors that promote efficient
transcriptional elongation
Transcriptional interference (displace transcription factor or decrease in
expression of transcription factor)
Epigenetic changes inhibiting HIV gene expression ( chromatin
configuration or methylation)

7. Immune Response
A. Innate Immunity
1. TLR : PAMPS generated by HIV infection are recognised by TLR leading to
expression of antiviral and inflammatory gene products
2. DCs: HIV does not induce maturation of DCs leading to bystander DCs.
3. NK cells: decreased intracellular stores of perforin and granzyme A and
incomplete activation of NK cells due to chronic stimulation.
4. Macrophages : escape killing and act as reservoir for viral replication
B. Adaptive Immunity
1. B cells responses
HIV induced B cell hyperactivity leading to hypergammaglobulinemia,
increased polyclonal B cell activation, increased differentiation into
plasmablasts, increase production of autoantibodies, increase frequency
of B cell malignancies (e.g Non-Hodgins lymphoma)
B cell exhaustion leading to increased level of inhibitory receptors such
as programmed cell death
2. Cytotoxic CD8+ T cell- control HIV replication
3. Inactivation of Helper CD4+ T cells

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8. Diagnostic Test- cannot detect HIV in eclipse phase.

Initial screening

Rapid test


Western blot

Detection of virus in blood (evaluate

viral load)
Detect HIV infection in newborns of
HIV+ mother (provirus)
Early marker of infection


Evaluate progression of disease

CD4;CD8 T cell ratio

p24 antigen

NOTE: RT-PCR tests for circulating viral RNA and is used to monitor the efficacy of treatment while
PCR detects integrated virus (provirus). Viral load has been demonstrated to be the best prognostic
indicator during infection.

9. Treatment
Antiretroviral drugs against HIV-(start at CD4 < 500)
1. Reverse transcriptase inhibitor

Interact with catalytic

Nucleoside reverse transcriptase inhibitors (NRTIs)
site of the enzyme RT
Nucleotide reverse transcriptase inhibitors (NtRTIS)
Non-Nucleoside reverse transcriptase inhibitors (NNRTIS)- interact with an
allosteric site located at a short distance from catalytic site

2. Protease inhibitor (e.g Ritonavir)

Inhibit maturation of viral proteins
3. Fusion inhibitor (e.g. enfuvirtide)
Block fusion of viral particle with outer cell membrane
4. Co receptor inhibitor (e.g. moraviroc)
Interact with the co-receptor CCR5 or CXCR4
5. Integrase strand transfer inhibitor (e.g.Raltegravir)
Inhibit the final step in integration of strand transfer of the viral DNA into
host DNA.


+ a protease inhibitor or a non-nucleoside RTI or an integrase


Obtain synergism between different compounds

To lower individual drug dosage to reduce their toxic side effects
To diminish the likelihood of development of drug resistance

Higher efficacy
and low side
effects profile