HIV and AIDS

According to the Joint United Nations Programme on HIV/AIDS, as of the end of 2000, the following trends of the worldwide epidemic

(or pandemic) of HIV are evident:

Today, 36.1 million people are estimated to be living with HIV/AIDS. Of these, 34.7 million are adults. 16.4 million are women, and 1.4 million are children under 15.

* An estimated 21.8 million people have died from AIDS since the epidemic began. 17.5 million were adults, including 9 million women. 4.3 million were children under 15.

* During 2000, AIDS caused the deaths of an estimated 3 million people, including 1.3 million women and 500,000 children under 15.

* Women are becoming increasingly affected by HIV. Approximately 47%, or 16.4 million, of the 34.7 million adults living with HIV or AIDS worldwide are women.

* The overwhelming majority of people with HIV - approximately 95% of the global total - now live in the developing world.

HIV vs. AIDS

• HIV is the virus that causes AIDS

• “HIV +” -----> person has antibodies to HIV in their bloodstream

• TH cell count greater than 200 cell/mm3

• Acquired Immunodeficiency Syndrome is a collection of symptoms associated with immune system failure

• TH cell count of 200 cell/mm3 or less

HIV TestsELISA Test

• Uses GP-120 from lab grown HIV to probe for antibodies to HIV in patient’s serum

• Prone to false negatives

PCR Test• Uses primers unique to

HIV to amplify viral DNA sequences

• False negatives are rare• Can be used to quantify

viral load (down to 50 virions/ml)

Stages of infection• Stage 1 (few weeks post infection): transient flu-like symptoms• Stage 2 (6 months): antibodies to HIV, rising T cell counts,

disappearance of allergies in some cases• Stage 3: subclinical immunosuppression• Stage 4: clinical immunosuppression• Stage 5: fungal and viral opportunistic infections

• Stage 6: severe immunosuppression (< 200 TH cells/mm3) AIDS, Pneumocystis carinii pneumonia, Kaposi’s sarcoma, dementia, death

Clinical Progress of HIV infection

Evolution

• Based on genetic homology between strains• Simian Immunodeficiency virus (SIV)• HIV II: slow replicator, predominant in Asia and

parts of Africa• HIV I: faster replicator, predominant in Europe and

America

HIV structure•Phospholipid bilayer envelope studded with

•GP120 a glycoprotein the viruses used to connect to Macrophages and TH cells

•GP41(aka Fusin) transmembrane portion of GP120/GP41 complex. a glycoprotein that enables HIV to fuse with target cells

•Capsid- viral core contains reverse transcriptase and integrase

http://www.virology.net/Big_Virology/BVretro.html

The Enemy

http://www.virology.net/Big_Virology/BVretro.html

Variations on a themeM-Tropic Viruses

• Predominate in early stages of infection

• Use CD-4 and CCR5 to gain entry to macrophages

• Replicate slowly• Less likely to form syncytia

T-tropic Viruses• Appear later• Use CD-4 and CXCR4 to

gain entry to TH cells

• Replicate more quickly• Form syncytia- groups of

fused cells

CD-4, CCR5 and CXCR4

http://www.brown.edu/Courses/Bio_160/Projects1999/hiv/infect.html

Lifecycle of HIVlytic vs. lysogenic

http://www.accessexcellence.org

Important Enzymes

• Reverse transcriptase: vRNA--->vDNAmutation rate: 1/2000

nucleotides

• Integrase: incorporates viral DNA into host cell chromosomes (provirus)

• Protease: cleaves GP160 into GP 120 and GP 41 so new viruses can be assembled

How does HIV spread from cell to cell?

• New viruses bud from infected cells and invade uninfected cells

• Replication of infected cells

• Fusion of infected cells with adjacent uninfected cells (syncytia)

The Mystery of Immunosuppression

• TH cell decline cannot be accounted for by viral budding rate, which varies from 1/10,000 TH cells in early infection to 1/40 TH cells later

• ? Cytotoxic (CD-8) T cells attack virally infected TH and macrophages?

• ?GP-120 binding triggers apoptosis in immature TH cells?

• ?Antibodies to GP-120 cross-react with MHC & trigger complement system?

A few clues….

• Circulating TH cells are NOT primary site of viral replication…lymph nodes are

• Viral surge late in infection Lymph node ‘burn out’• Infected cells produce a soluble immunosuppressive factor

Current Therapies

• Reverse Transcriptase inhibitors(Non-nucleoside analogs and

Nucleoside analogs, AZT, 3TC, ddI)

• Protease Inhibitors(crixivan, indinavir, retonavir,

etc.)

• Highly Active Anti-retroviral Therapy (HAART) = 2 RTIs + 1 PI

Vaccine Candidates

• What’s the biggest problem in making a vaccine for HIV?

• Attenuated SIV (Desrosiers et al)

• Recombinant GP-120 “cocktail” (Francis et al, VaxGen)– Phase III trials of AIDSVAX are currently

underway in North America, the Netherlands and Thailand. Results are due in 2003

– VaxGen.com

AIDSVAX

Vaxgen.com

Good News Bad News• In many people, HAART

successfully reduces viral load to undetectable levels (<50virions/mm3)

• Use of AZT/Neverapine during pregnancy reduces vertical transmission from 25-30% to 5-10%

• Public education can successfully raise awareness and increase the practice of safe sex

• Viral Load rebounds quickly if HAART is stopped

• High cost of drugs make them unattainable for many, particularly in the developing world

• Safe sex practices run counter to cultural practices in many countries