CCS 010 Biology of Hiv

8/4/2019 CCS 010 Biology of Hiv

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CCS 010

THE BIOLOGY OF THE HIV

VIRUS.


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1981CDC reports unusual incidences of pneumonia caused by Pneumocystiscariniiand of skin cancers, Kaposi's sarcoma. Patient's immune systemwere impaired.

1982CDC recognized a new disease: Acquired Immune Deficiency Syndrome

(AIDS). Don Francis suggests screening blood for hepatitis C as asurrogate test for the AIDS infectious agent.

1983The infectious agent was isolated by L. Montagnier (Paris) and R. C.

Gallo (NIH). First called it HTLV for human T-cell leukemia virus. Nowcalled Human Immunodeficiency Virus, or HIV.

2001500,000 - 1,000,000 people infected in the US. More than 30 million

people infected world-wide; ~70% in Sub-Saharan Africa.

A Brief History of AIDS


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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 todevelop AIDS, but uninfected siblings do not.

6. AIDS does not appear in a new locality without the priorpresence of HIV.7. Treatments that target the virus alleviate the disease.


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Topic Two

Biology ofHIV

2008 Nobel Prize inphysiology or medicine:French researchersFrancoise Barre-Sinoussi and LucMontagnier for theirdiscovery of human

immunodeficiency 4Dr. Pattle Pun, Biology, Wheaton College, IL 60187


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HIV is a retrovirus.

A more specific name is Lentivirus.

Retroviruses have an RNA genome that isreplicated via a DNA intermediate in infectedcells. DNA also integrates in the host genometo form provirus.

HIV is more complex than RNA tumorviruses, such as MLV, murine leukemia virus. HIV encodes a number of extra regulatory and

accessory proteins.


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Structure of HIV

Sarcophagus-shaped capsid

contains 2 copies of RNA genome(SS (+) strand), a reversetranscriptase, integrase, andprotease.

P7 coats the RNA, and P24 forms

the nucleocapsid structure, whichis enclosed by a lipid bilayer.

Lipid bilayer comes from the hostcell, but contains two viral-encoded glycoproteins, gp41 (41

kDa) and gp120 (120 kDa).

gp120 binds the CD4 receptor onhelper T cells.


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HIVs genome is ~ 9.8 KB, and encodes 2 other classes of

proteins besides the usual GAG-POL-ENV proteins.


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HIV gene expressionis mainly fromintegrated provirusand is separatedtemporally into earlygenes and lategenes.

Late gene expression

requiresRev

(whichmoves un- and partiallyspliced RNA tocytoplasm).

RRE is the binding

site for Rev.

Unspliced RNA isincorporated intovirions (genome).


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Infection Cycle

Tat, nefand

revgenesexpressedearly.

Gag, PolandEnvgenesexpressed late.


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Chemokine receptor

family: CCR5, CXC,CXCR4, CCR2b

CD4 is necessary butnot sufficient for HIVentry into CD4+ T-lymphocytes.

The chemokine

receptors act as co-receptors.

Co-receptors for HIV


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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.

Why is the disease less aggressive in some people?Mutations in chemokine co-receptors that confer resistance.

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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Dr. Pattle Pun, Biology, WheatonCollege, IL 60187 13


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

mechanisms?

1. Autofusion

CD4 and gp120/41proteins mediate fusionand intracellular vesicleformation.


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2. Syncytium formationgp120/41 proteins oninfected cells bind to CD4receptors on normal cells,

causing cell fusion. Thegiant multi-nucleatedsyncytium dies beforelong.

3.ApoptosisAn infected helper T cell can direct an uninfected T helper cell to undergoapoptosis (programmed cell death). Apoptosis can be normal, forexample, to eliminate auto-reactive T lymphocytes to establish self-tolerance.

Normal cellInfected cell


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Topic Three

Epidemiology of AIDS

19Dr. Pattle Pun, Biology, Wheaton College, IL 60187


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Dr. Pattle Pun, Biology, Wheaton College, IL 6018720

HIV

infections

2007


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HIV prevalence 2005


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HIV prevalence, 2005



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According to the United NationsDevelopment Fund for Women,

" Close to half of 37.2 million adults livingwith HIV are women, according to new

UNAIDS/WHO report released November 23in Geneva. The AIDS Epidemic Update 2004shows that the number of women livingwith HIV has risen in each region of the

world over the past two years, with thesteepest increases in East Asia, followed byEastern Europe and Central Asia. In East

Asia, there was a 56% increase over theast two ears followed b Eastern Euro e23

Dr. Pattle Pun, Biology, Wheaton College, IL 60187


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If present AIDS infection ratecontinues:

By 2020, 30 millions new

AIDS related deaths and 9million orphans will be

added just in sub-SaharaAfrica alone.



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A Major Challenge in MaintainingControl of HIV

HIV evolves rapidly

The RT is error-prone (no proof- reading)

~ 1-2 mutations in each cDNA copy of the9.8 kb RNA genome


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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!!!!

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CCS 010 Biology of Hiv