The AIDS Epidemic: Immune selection pressure, viral evolution and prospects for a vaccine

1. The AIDS Epidemic:Immune selection pressure, viral evolution and prospects for a vaccine Bruce D Walker, MD Howard Hughes Medical Institute Massachusetts General Hospital Harvard Medical School Nelson Mandela School of Medicine University of KwaZulu-Natal Durban, South Africa

2. HIV RNA virus Error prone reverse transcriptase Average time to AIDS: 8-10 years Average time to death: 10-12 years

3. The Global AIDS Crisis • 60 million infections • 20 million deaths

5. One year The level of virus in the blood predicts outcome 10 Million RNA particles/ml plasma

6. One year The level of virus in the blood predicts outcome 10 Million Interquartile ranges Rapid Progression 60,000 RNA particles/ml plasma 30,000 12,000 Slow Progression

8. Factors influencing viral load and HIV evolution • Drug therapy

9. AIDS Deaths in the United States have declined since HAART was introduced 6,000 5,000 4,000 Number of Deaths 3,000 2,000 1,000 0 1985 1990 1995 1999

10. Challenges for HIV Treatment • Adherence • Toxicity • Cost • Drug resistance • Lifelong therapy: • Viral integration into the host chromosome

11. Factors influencing viral load and HIV evolution • Drug therapy • Immune responses

12. B cell

17. CTLs Infected cells T helper cells

18. Infantry (CTL) Infected cell Generals (T Helper cells)

19. CD8 T cell responses (CTL) CTL New virus assembly

20. What would a successful vaccine do? • Prevent infection OR • Allow for infection but keep the virus in check • Decrease the chance of transmission to others • Decrease the chance of disease progression

21. CD8 T cell responses (CTL) CTL T cell receptor Viral peptide HLA allele

22. T cell vaccination? RNA particles/ml plasma Placebo Vaccine Time

23. STEP Trial Design Months 0 1 2 12 3 6 9 3 Adeno vectors: clade B Gag clade B Pol clade B Nef

24. STEP Trial ResultsImpact on set-point viral load ? RNA particles/ml plasma Vaccine: 40,000 Placebo: 26,000 Time

25. Does the rationale for a T cell based vaccine make sense?

26. CTL IFN gamma Synthetic HIV peptides

27. Overlapping peptides pol gag etc…

28. There is no difference in breadth or magnitude of CD8 T cell responses in progressors vs. controllers (n=57) Breadth Magnitude Progressors Controllers Progressors Controllers Mann Whitney Addo/Draenert 2004

29. Observations • Huge differences in outcome • The epidemic is expanding in Africa • Can we do large scale studies at the heart of the epidemic to understand these differences?

31. HIV Prevalence trends in South Africa 1990 - 2002 30 26.5 24.8 24.5 22.8 25 22.4 20 17 14.2 Prevalence (%) 15 10.4 7.6 10 4 5 2.2 1.7 0.7 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year

32. Nelson Mandela School of Medicine University of KwaZulu Natal South Africa

33. 50% of pregnant women presenting for prenatal care are HIV infected

34. Initial Plans • Establish cohorts of infected persons • Initiate research projects to define immune responses to HIV in children and adults • $50,000 grant from EGPAF

38. Considerations • Major advances in biomedical research have been facilitated by having research adjacent to clinical care • Why not build the world’s best biomedical research institute in the heart of the HIV epidemic, and conduct basic science studies on site?

42. HIV/AIDS in South Africa: 2002 • At least 500,000 in need of treatment based on WHO guidelines (CD4 < 200 or symptomatic infection) • No treatment available in the public sector • Sparse access to treatment through NGOs

45. Additional Statistics • At least 8 teachers die each year in South Africa for each that can be trained • Some companies have mandated that employees can not miss more than one day of work per week for funerals

46. Considerations • How can we possibly conduct pathogenesis studies if we do not provide treatment for those in need? • Why not use our research infrastructure to initiate a proof of principle pilot study of HAART treatment in this resource constrained setting?