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“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
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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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http://www.avert.org/his81_86.htm
A retrovirus causes AIDS
A series of basic science discoveries havegiven us substantial insight into the cause of AIDS
Retroviruses reverse the central dogma
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We have also learned a lot about the lifecycle of the virusand how it exploits host cells
Viral fusion with host cells
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We have also learned a lot about the lifecycle of the virusand how it exploits host cells
Viral fusion with host cells
Reverse transcription
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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
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This knowledge provides us with opportunitiesTo thwart the virus at each step
Viral fusion with host cells
Reverse transcription
Proteolytic processing of viral protein
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Let’s start where the field started: with reverse transcriptase
Reverse transcription
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Here’s the enzyme synthesizing a DNA complementTo the HIV RNA genome
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Let’s zoom in on this step
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RT adds a DNA nucleotide complementary toEach RNA nucleotide in the HIV genome
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Here’s the chemistry (don’t panic!!; I will notexpect you to know any of the details):
http://www.avert.org/his81_86.htm
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If we get rid of this hydroxyl group, the enzyme can’t add another nucleotide
http://www.avert.org/his81_86.htm
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http://www.avert.org/his81_86.htm
AZT (azidothymidine) is an exact matchto the T nucleotide butwithout the hydroxyl group!
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http://www.avert.org/his81_86.htm
The result…
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http://www.avert.org/his81_86.htm
How did we get here?
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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
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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!
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They looked for derivatives of nucleotidesThat inhibited synthesis of DNA and RNA
Nobelprize.org and www.chemheritage.org
Gertrude Elion
George Hitchings
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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
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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
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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
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For all this hard work ….
Nobelprize.org and www.chemheritage.org
Gertrude Elion
George Hitchings
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http://www.avert.org/his81_86.htm
Others followed their lead
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http://www.avert.org/his81_86.htm
Jerome Horwitz--first synthesized AZT in 1964as a possible anticancer drug
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But it failed!
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http://www.avert.org/his81_86.htm
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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http://www.avert.org/his81_86.htm
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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http://www.avert.org/his81_86.htm
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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http://www.avert.org/his81_86.htm
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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http://www.avert.org/his81_86.htm
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%.
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Thus the early response of HIV to AZT was superbDoes this sound familiar?Does it make you worried?
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The bad news came quickly and was not unexpected
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The bad news came quickly and was not unexpected
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Mutations altering amino acidsIn the AZT binding site ofReverse transcriptaseLed to resistance
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By the early 1990s resistance was a serious problem
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How do we get around this???
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http://www.avert.org/his81_86.htm
Same concept, new drugs!
Inosine ddI
Used in patients by October 1989
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http://www.avert.org/his81_86.htm
Same concept, new drugs!
Cytodine ddC
FDA approved Summer 1991
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http://www.avert.org/his81_86.htm
If you treat patients with ddI or ddC ALONEWhat will happen?
Cytodine ddC
FDA approved Summer 1991
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http://www.avert.org/his81_86.htm
So how do you get around this??
Cytodine ddC
FDA approved Summer 1991
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http://www.avert.org/his81_86.htm
If it worked for TB…..
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http://www.avert.org/his81_86.htm
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…..
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Retroviruses. CSHL Press Fig. 13-10
Chemists keepTinkering with nucleotidesTo make new drugs
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www.web-books.com/.../ Infectious/AIDS_Treat.htm
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www.web-books.com/.../ Infectious/AIDS_Treat.htm