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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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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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21Dr. Pattle Pun, Biology, Wheaton College, IL 60187
HIV prevalence 2005
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HIV prevalence, 2005
22Dr. Pattle Pun, Biology, Wheaton College, IL 60187
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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
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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.
30Dr. Pattle Pun, Biology, Wheaton College, IL 60187
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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!!!!