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Fighting the System

by Carole VanSickle

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Intro  |  Breaking the Chain  |  New Drug Alternatives

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Breaking the Chain

When HIV enters the body, it is not yet capable of causing AIDS. “The number of viral particles that you start out with in the system is relatively low — they’re not able to significantly impact the immune system,” said Nair. But by the time a person reaches even the early stages of AIDS, the number of viral particles produced each day may be in the many hundreds of millions to more than a billion, incapacitating the immune system and allowing infections to run rampant and eventually killing the host. This period of time from initial infection to full-blown AIDS may be as short as a few years or as long as a decade or more. Researchers refer to this period as the time between small and expanded HIV populations, and Nair said this time gives scientists and doctors “windows in which to act.”

Growing up in the Fiji Islands, Vasu Nair experimented with folk remedies alleged to stop bleeding by applying them to cuts on his hands. Years later he did his doctoral work on the chemistry of natural products, but many years ago shifted his research focus from natural remedies to drug discovery. He enjoys growing roses with his wife, Barbara (pictured above) and advising his daughter, Alison, who is now a second-year medical student at The University of Chicago School of Medicine.

“Until replication reaches the full-blown state,” Nair said, “many people show no ill effects at all.”

Several years ago, Nair identified a weak point in the reproduction process and zoned in on his target – an enzyme called HIV integrase that helps newly-minted viral DNA infiltrate the nucleus of the host cell and become part of the cell’s DNA [see picture on p. 17]. Once this is accomplished, the integrase falls off the DNA strand. When normal cellular DNA replication ensues, viral genetic information is reproduced as well. This results in the production of individual viral proteins that eventually assemble to form a new viral particle.

“If we can stop the virus from getting its DNA incorporated into the host’s DNA, then it can’t replicate,” explained Nair. “This enzyme presents a particularly attractive target because we humans don’t need to integrate our DNA with a foreign organism’s genetic material.” As a result, he said, any treatments that disable or even destroy HIV integrase are less likely to harm the patient in the process.

Early in their research, Nair and his team realized that HIV integrase recognized certain chemical components of DNA that made it “want” to incorporate into human DNA. “The strongest of these attractions was to a pyrimidine, a basic component of DNA. So we built our inhibitor around a pyrimidine scaffold. “The pyrimidine functions like a fishing lure for HIV integrase,” Nair explained. The enzyme recognizes the pyrimidine scaffold and latches onto the inhibitor, which in effect hooks HIV integrase so that it cannot escape and bind to the host DNA. Eventually the enzyme/inhibitor compound is eliminated by natural bodily processes.

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Intro  |  Breaking the Chain  |  New Drug Alternatives

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