“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

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

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 http://www.avert.org/his81_86.htm

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

Viral fusion with host cells Reverse transcription 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

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

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

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

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

Let’s zoom in on this step

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The bad news came quickly and was not unexpected

The bad news came quickly and was not unexpected

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

By the early 1990s resistance was a serious problem

How do we get around this???

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

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

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

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

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

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

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

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

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