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. Throughout the class we will explore how
we can use basic science to guide the design
of new treatments for disease

3. Retroviruses reverse the central dogma A retrovirus causes AIDS
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

4. Potential Therapies- Life Cycle of HIV-1
Let’s start where the field started: with reverse transcriptase
Picture courtesy of Frank Church

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

6. Let’s zoom in on this step

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

8. Here’s the chemistry:

9. If we get rid of this hydroxyl group,
the enzyme can’t add another nucleotide

10. AZT (azidothymidine) is an exact match to the T nucleotide but
without the hydroxyl group!

11. The result…

12. How did we get here?

13. 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 and

14. 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

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

16. 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

17. 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

18. 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

19. For all this hard work …. George Hitchings Gertrude Elion
Nobelprize.org and

20. Others followed their lead

21. Jerome Horwitz--first synthesized AZT in 1964
as a possible anticancer drug

22. But it failed!

23. 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

24. 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.

25. 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: , Number 4
FDA approved March 20, 1987!

26. 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%.

27. 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%.

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

29. The bad news came quickly and was not unexpected

30. The bad news came quickly and was not unexpected

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

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

33. How do we get around this???

34. Used in patients by October 1989
Same concept, new drugs!
Inosine
ddI
Used in patients by October 1989

35. Same concept, new drugs! Cytodine ddC FDA approved Summer 1991

36. If you treat patients with ddI or ddC ALONE What will happen?
Cytodine
ddC
FDA approved Summer 1991

37. So how do you get around this??
Cytodine
ddC
FDA approved Summer 1991

38. If it worked for TB…..

39. 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.

40. Tinkering with nucleotides To make new drugs
Chemists keep
Tinkering with nucleotides
To make new drugs
Retroviruses. CSHL Press Fig

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

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