CCS 010

THE BIOLOGY OF THE HIV VIRUS.

A Brief History of AIDS

1981
CDC reports unusual incidences of pneumonia caused by Pneumocystis carinii and of skin cancers, Kaposi's sarcoma. Patient's immune system were impaired.

1982
CDC recognized a new disease: Acquired Immune Deficiency Syndrome (AIDS). Don Francis suggests screening blood for hepatitis C as a surrogate test for the AIDS infectious agent.

1983
The infectious agent was isolated by L. Montagnier (Paris) and R. C. Gallo (NIH). First called it HTLV for human T-cell leukemia virus. Now called Human Immunodeficiency Virus, or HIV.

2001
500,000 - 1,000,000 people infected in the US. More than 30 million people infected world-wide; ~70% in Sub-Saharan Africa.

Some of the evidence that HIV causes AIDS

1. Virus can be isolated from almost all with the disease. 2. Advanced disease correlates with higher virus titer. 3. Asymptomatic individuals that have antibodies to coat proteins later develop the disease. 4. Recipients of contaminated blood frequently develop AIDS. 5. About 30% of children born to infected mothers are infected with the virus; those that are, go on to develop AIDS, but uninfected siblings do not. 6. AIDS does not appear in a new locality without the prior presence of HIV. 7. Treatments that target the virus alleviate the disease.

Topic Two

Biology of HIV
2008 Nobel Prize in
physiology or medicine: French researchers Francoise BarreSinoussi and Luc Montagnier for their discovery of human immunodeficiency
Dr. Pattle Pun, Biology, Wheaton College, IL 60187

 HIV is a retrovirus.
A more specific name is Lentivirus. Retroviruses have an RNA genome that is
replicated via a DNA intermediate in infected cells. DNA also integrates in the host genome to form provirus.

HIV is more complex than RNA tumor

viruses, such as MLV, murine leukemia virus.
HIV encodes a number of extra regulatory and accessory proteins.

Structure of HIV
Sarcophagus-shaped capsid contains 2 copies of RNA genome (SS (+) strand), a reverse transcriptase, integrase, and protease. P7 coats the RNA, and P24 forms the nucleocapsid structure, which is enclosed by a lipid bilayer. Lipid bilayer comes from the host cell, but contains two viralencoded glycoproteins, gp41 (41 kDa) and gp120 (120 kDa). gp120 binds the CD4 receptor on helper T cells.

HIVs genome is ~ 9.8 KB, and encodes 2 other classes of proteins besides the usual GAG-POL-ENV proteins.

HIV gene expression is mainly from integrated provirus and is separated temporally into early genes and late genes. Late gene expression requires Rev (which
moves un- and partially spliced RNA to cytoplasm).

RRE is the binding site for Rev. Unspliced RNA is incorporated into virions (genome).

Infection Cycle
Tat, nef and rev genes expressed early.

Gag, Pol and Env genes expressed late.

Co-receptors for HIV Chemokine receptor

family: CCR5, CXC, CXCR4, CCR2b CD4 is necessary but not sufficient for HIV entry into CD4+ Tlymphocytes. The chemokine receptors act as coreceptors.

Why is the disease less aggressive in some people? Mutations in chemokine co-receptors that confer resistance. CCR5 polymorphism - About 1% of Caucasians are resistant to the virions - 32 bp deletion in this gene (second extracellular loop) - these people can still get HIV from variants that can use the CXCR4 co-receptor.

CXCR4 3' UTR mutation - ~ 1% Caucasians - delays the disease onset and time of death - point mutation in the 3' UTR. Mechanism unknown.
As disease progresses, get variants that use CCR3 or CCR2b; these virions are more aggressive. Late stages, the CXC co-receptor is used; these virions are cytopathic and syncytium-inducing.

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How does HIV kill cells? Virus budding from cell membrane is not lethal. Cells die by autofusion, syncytial formation, and apoptosis. Other mechanisms?

1. Autofusion CD4 and gp120/41 proteins mediate fusion and intracellular vesicle formation.

2. Syncytium formation gp120/41 proteins on infected cells bind to CD4 receptors on normal cells, causing cell fusion. The giant multi-nucleated syncytium dies before long.

Infected cell
Normal cell

3.Apoptosis
An infected helper T cell can direct an uninfected T helper cell to undergo apoptosis (programmed cell death). Apoptosis can be normal, for example, to eliminate auto-reactive T lymphocytes to establish selftolerance.

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Topic Three

Epidemiology of AIDS

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HIV infections 2007

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HIV prevalence, 2005

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According to the United Nations Development Fund for Women,

" Close to half of 37.2 million adults living
with HIV are women, according to new UNAIDS/WHO report released November 23 in Geneva. The AIDS Epidemic Update 2004 shows that the number of women living with HIV has risen in each region of the world over the past two years, with the steepest increases in East Asia, followed by Eastern Europe and Central Asia. In East Asia, there was a 56% increase over the 23 Dr. Pattle past two years,Pun, Biology, Wheaton by Eastern Europe followed College, IL 60187

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If present AIDS infection rate continues:

By 2020, 30 millions new

AIDS related deaths and 9 million orphans will be added just in sub-Sahara Africa alone.
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A Major Challenge in Maintaining Control of HIV

HIV evolves rapidly The RT is error-prone (no proof- reading) ~ 1-2 mutations in each cDNA copy of the
9.8 kb RNA genome

Conclusions
Prevention is always better than cure Remember the ABC of Aids prevention A- ABSTINENCE B- BE FAITHFUL TO ONE SEXUAL
PARTNER C- USE A CONDOM Finally get tested!!!!