HIV and AIDS

1. HIV and AIDS

2. 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.

3. 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 vs. AIDS

4. ELISA 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) HIV Tests

5. 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

6. Clinical Progress of HIV infection

7. 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 Evolution

8. 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

9. The Enemy http://www.virology.net/Big_Virology/BVretro.html

10. M-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 Variations on a theme

11. CD-4, CCR5 and CXCR4 http://www.brown.edu/Courses/Bio_160/Projects1999/hiv/infect.html

12. Lifecycle of HIVlytic vs. lysogenic http://www.accessexcellence.org

13. Important Enzymes • Reverse transcriptase: vRNA--->vDNA mutation 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

14. 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)

15. 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?

16. A few clues…. • CirculatingTH 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

17. 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

18. 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

19. AIDSVAX Vaxgen.com

20. 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 Good News Bad News