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Closeups of HIV

AIDS researchers, for years blind to the atomic structure of HIV, were recently given a more detailed blueprint of their deadly foe.

In the June 18 issue of Nature, a team of researchers including Peter Kwong, AB’85, SM’85, reported the atomic structure of gp120, a protein studding the outer surface of HIV. This new picture shows the virus at a crucial moment of infection: the key-like gp120 locked into the immune system’s T-lymphocyte cells.

The image provides a wellspring of information for AIDS researchers who, like Kwong, are now racing to design vaccines and drugs that could stall, or even stop, the worldwide AIDS epidemic.

“Gp120 is an obvious therapeutic target in terms of drug design,” Kwong explains. “We can now see some of the defenses of the gp120 protein against the immune system, and we’re designing mutants that don’t have some of these defenses.” Without the defenses, he says, “you might have an appropriate vaccine.”

To get the new image, the researchers relied on X-ray crystallography, which allows them to infer the structure of a molecule from the behavior of X-rays reflecting off billions of closely-packed copies of that molecule. But because the technique only works on molecules that can be crystallized, the researchers faced a challenge with gp120: Certain proteins—called variable loops and carbohydrate groups—that the virus uses to evade the body’s immune system also keep gp120 from forming a crystal lattice. Kwong, working under Columbia University’s Wayne Hendrickson, had to remove the proteins.

Enter Joe Sodroski, a researcher at the Dana-Farber Cancer Institute in Boston who had produced some gp120 mutants without the variable loops. Kwong’s team was trying to snip off the carbohydrate groups, and the two teams forged a quick alliance. “I put my results together with his results,” says Kwong, “and that broke through the two lines of defense, allowing us to make crystals.”

Looking ahead, Kwong is optimistic about the search for a way to outsmart the virus’ defenses. “The pharmaceutical and biomedical community can overcome this scourge,” he predicts, “not by just allowing the body to do it, but by seeing what these defenses are and figuring out how to get around them intellectually.”—M.D.B.

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