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