“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 comeWhen the Lord will save his people and defeat their enemies”

Excerpt from the passage from Isaiah 61read 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

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A retrovirus causes AIDS

A series of basic science discoveries havegiven us substantial insight into the cause of AIDS

Retroviruses reverse the central dogma

We have also learned a lot about the lifecycle of the virusand how it exploits host cells

Viral fusion with host cells

We have also learned a lot about the lifecycle of the virusand how it exploits host cells

Viral fusion with host cells

Reverse transcription

We have also learned a lot about the lifecycle of the virusand how it exploits host cells

Viral fusion with host cells

Reverse transcription

Proteolytic processing of viral protein

This knowledge provides us with opportunitiesTo thwart the virus at each step

Viral fusion with host cells

Reverse transcription

Proteolytic processing of viral protein

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

Reverse transcription

Here’s the enzyme synthesizing a DNA complementTo the HIV RNA genome

Let’s zoom in on this step

RT adds a DNA nucleotide complementary toEach RNA nucleotide in the HIV genome

Here’s the chemistry (don’t panic!!; I will notexpect you to know any of the details):

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

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AZT (azidothymidine) is an exact matchto the T nucleotide butwithout the hydroxyl group!

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The result…

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How did we get here?

The success of sulfa drugs in inhibiting bacterial metabolisminspired two scientists at Wellcome Research Labs

to investigate other metabolic pathways

Gertrude Elion

George Hitchings

Nobelprize.org , www.chemheritage.org, and www.achievement.org

The success of sulfa drugs in inhibiting bacterial metabolisminspired two scientists at Wellcome Research Labs

to investigate other metabolic pathways

Nobelprize.org and www.chemheritage.org

Gertrude Elion

George HitchingsThey started just as people figured outThat DNA is the genetic material!

They looked for derivatives of nucleotidesThat inhibited synthesis of DNA and RNA

Nobelprize.org and www.chemheritage.org

Gertrude Elion

George Hitchings

They looked for derivatives of nucleotidesThat inhibited synthesis of DNA and RNA

Nobelprize.org and www.chemheritage.org

Gertrude Elion

George Hitchings

Suppresses immune system(first kidney transplants)

First drugs against leukemia

When Hitchings became Vice President for ResearchElion was promoted to Head of the

Department of Experimental Therapy (without a Ph.D!)and her group continued to explore these pathways

Nobelprize.org and www.chemheritage.org

Gertrude Elion

George Hitchings

When Hitchings became Vice President for ResearchElion was promoted to Head of the

Department of Experimental Therapy (without a Ph.D!)and her group continued to explore these pathways

Nobelprize.org and www.chemheritage.org

Gertrude Elion

George Hitchings

Treats gout and being tested againstthe Leishmania parasite

They also explored mechanism of actionOf acyclovir and its affect on Herpes virus

For all this hard work ….

Nobelprize.org and www.chemheritage.org

Gertrude Elion

George Hitchings

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Others followed their lead

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

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But it failed!

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The first treatment option: a time line

Februrary 1985Scientists at National Cancer Institute and at Burroughs WellcomeCollaborate to study effect of AZT on HIV in cell culture

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The first treatment option: a time line

Februrary 1985Scientists at National Cancer Institute and at Burroughs WellcomeCollaborate to study effect of AZT on HIV in cell culture

September 1986Early clinical trials showed that AZT slowed down the attack of HIV.

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The first treatment option: a time line

Februrary 1985Scientists at National Cancer Institute and at Burroughs WellcomeCollaborate to study effect of AZT on HIV in cell culture

September 1986Early 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!

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The first treatment option: a time line

August 1989First 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%.

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The first treatment option: a time line

August 1989First 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%.

Thus the early response of HIV to AZT was superbDoes 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 acidsIn the AZT binding site ofReverse transcriptaseLed to resistance

By the early 1990s resistance was a serious problem

How do we get around this???

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Same concept, new drugs!

Inosine ddI

Used in patients by October 1989

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Same concept, new drugs!

Cytodine ddC

FDA approved Summer 1991

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If you treat patients with ddI or ddC ALONEWhat will happen?

Cytodine ddC

FDA approved Summer 1991

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So how do you get around this??

Cytodine ddC

FDA approved Summer 1991

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If it worked for TB…..

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September 1995Two 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.

If it worked for TB…..

Retroviruses. CSHL Press Fig. 13-10

Chemists keepTinkering with nucleotidesTo make new drugs

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