“The sovereign Lord has filled me with his spirit. He has chosen me and sent me

1. “The sovereign Lord has filled me with his spirit. He has chosen me and sent me to bring good news to the poor, To heal the broken-hearted, to announce release to the captives, And freedom to those in prison. He has sent me to proclaim that the time will come When the Lord will save his people and defeat their enemies” Excerpt from the passage from Isaiah 61 read at the inauguration of Jean Bertrand Aristide

2. HIV provides a chance to continue to explore how we can use basic science to guide the design of new treatments for disease

3. A series of basic science discoveries have given us substantial insight into the cause of AIDS Retroviruses reverse the central dogma A retrovirus causes AIDS http://www.avert.org/his81_86.htm

4. We have also learned a lot about the lifecycle of the virus and how it exploits host cells Viral fusion with host cells

5. We have also learned a lot about the lifecycle of the virus and how it exploits host cells Viral fusion with host cells Reverse transcription

6. We have also learned a lot about the lifecycle of the virus and how it exploits host cells Viral fusion with host cells Reverse transcription Proteolytic processing of viral protein

7. This knowledge provides us with opportunities To thwart the virus at each step Viral fusion with host cells Reverse transcription Proteolytic processing of viral protein

8. Let’s start where the field started: with reverse transcriptase Reverse transcription

9. Here’s the enzyme synthesizing a DNA complement To the HIV RNA genome

10. Let’s zoom in on this step

11. RT adds a DNA nucleotide complementary to Each RNA nucleotide in the HIV genome

12. Here’s the chemistry (don’t panic!!; I will not expect you to know any of the details): http://www.avert.org/his81_86.htm

13. If we get rid of this hydroxyl group, the enzyme can’t add another nucleotide http://www.avert.org/his81_86.htm

14. AZT (azidothymidine)is an exact match to the T nucleotide but without the hydroxyl group! http://www.avert.org/his81_86.htm

15. The result… http://www.avert.org/his81_86.htm

16. How did we get here? http://www.avert.org/his81_86.htm

17. The success of sulfa drugs in inhibiting bacterial metabolism inspired two scientists at Wellcome Research Labs to investigate other metabolic pathways George Hitchings Gertrude Elion Nobelprize.org , www.chemheritage.org, and www.achievement.org

18. The success of sulfa drugs in inhibiting bacterial metabolism inspired two scientists at Wellcome Research Labs to investigate other metabolic pathways They started just as people figured out That DNA is the genetic material! George Hitchings Gertrude Elion Nobelprize.org and www.chemheritage.org

19. They looked for derivatives of nucleotides That inhibited synthesis of DNA and RNA George Hitchings Gertrude Elion Nobelprize.org and www.chemheritage.org

20. They looked for derivatives of nucleotides That inhibited synthesis of DNA and RNA First drugs against leukemia George Hitchings Gertrude Elion Suppresses immune system (first kidney transplants) Nobelprize.org and www.chemheritage.org

21. When Hitchings became Vice President for Research Elion was promoted to Head of the Department of Experimental Therapy (without a Ph.D!) and her group continued to explore these pathways George Hitchings Gertrude Elion Nobelprize.org and www.chemheritage.org

22. When Hitchings became Vice President for Research Elion was promoted to Head of the Department of Experimental Therapy (without a Ph.D!) and her group continued to explore these pathways Treats gout and being tested against the Leishmania parasite George Hitchings Gertrude Elion They also explored mechanism of action Of acyclovir and its affect on Herpes virus Nobelprize.org and www.chemheritage.org

23. For all this hard work …. George Hitchings Gertrude Elion Nobelprize.org and www.chemheritage.org

24. Others followed their lead http://www.avert.org/his81_86.htm

25. Jerome Horwitz--first synthesized AZT in 1964 as a possible anticancer drug http://www.avert.org/his81_86.htm

26. But it failed! http://www.avert.org/his81_86.htm

27. The first treatment option: a time line Februrary 1985 Scientists at National Cancer Institute and at Burroughs Wellcome Collaborate to study effect of AZT on HIV in cell culture http://www.avert.org/his81_86.htm

28. The first treatment option: a time line Februrary 1985 Scientists at National Cancer Institute and at Burroughs Wellcome Collaborate to study effect of AZT on HIV in cell culture September 1986 Early clinical trials showed that AZT slowed down the attack of HIV. http://www.avert.org/his81_86.htm

29. The first treatment option: a time line Februrary 1985 Scientists at National Cancer Institute and at Burroughs Wellcome Collaborate to study effect of AZT on HIV in cell culture September 1986 Early clinical trials showed that AZT slowed down the attack of HIV. The AZT clinical trial: one group of patients received AZT and the other received placebo. At the end of six months, only one patient in the AZT group was dead, whilst there were 19 deaths among the placebo group. The clinical trial was stopped early, because it was thought to be unethical to deny the patients of the placebo groups a better chance of survival. Fischl M. A., et al. (1987)''The Efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex, a double-blind, placebo-controlled trial', The New England Journal Of Medicine, Vol. 317: 185-191, Number 4 FDA approved March 20, 1987! http://www.avert.org/his81_86.htm

30. The first treatment option: a time line August 1989 First large clinical trial of AZT in asymptomatic patients showed that it slowed progression of disease The day after the press conference, Burroughs Wellcome stock rose 32%. http://www.avert.org/his81_86.htm

31. The first treatment option: a time line August 1989 First large clinical trial of AZT in asymptomatic patients showed that it slowed progression of disease The day after the press conference, Burroughs Wellcome stock rose 32%. The high price of AZT angered many people; a year's supply cost ~$7,000 In September, the cost of the drug was cut by 20%. http://www.avert.org/his81_86.htm

32. Thus the early response of HIV to AZT was superb Does this sound familiar? Does it make you worried?

33. The bad news came quickly and was not unexpected

34. The bad news came quickly and was not unexpected

35. Mutations altering amino acids In the AZT binding site of Reverse transcriptase Led to resistance

36. By the early 1990s resistance was a serious problem

37. How do we get around this???

38. Same concept, new drugs! Inosine ddI Used in patients by October 1989 http://www.avert.org/his81_86.htm

39. Same concept, new drugs! Cytodine ddC FDA approved Summer 1991 http://www.avert.org/his81_86.htm

40. If you treat patients with ddI or ddC ALONE What will happen? Cytodine ddC FDA approved Summer 1991 http://www.avert.org/his81_86.htm

41. So how do you get around this?? Cytodine ddC FDA approved Summer 1991 http://www.avert.org/his81_86.htm

42. If it worked for TB….. http://www.avert.org/his81_86.htm

43. If it worked for TB….. September 1995 Two clinical trials, the Delta trial and the ACTG175 trial, showed that combinations of AZT with ddI or ddC were more effective than AZT alone in delaying disease progression and prolonging life. http://www.avert.org/his81_86.htm

44. Chemists keep Tinkering with nucleotides To make new drugs Retroviruses. CSHL Press Fig. 13-10

45. www.web-books.com/.../ Infectious/AIDS_Treat.htm

46. www.web-books.com/.../ Infectious/AIDS_Treat.htm