Broken Weapon: Mutation disarms HIV-fighting gene

A gene that once produced a small protein able to prevent HIV from infecting cells now lies unusable in the human genome, scientists have found. In addition to suggesting a new weapon in the battle against AIDS, this so-called pseudogene reignites speculation about why infection with HIV kills people but not nonhuman primates.

Several years ago, researchers found that rhesus monkeys have a gene encoding a novel microbe-killing protein (SN: 10/30/99, p. 283). More recently, Robert I. Lehrer of the University of California, Los Angeles School of Medicine and his colleagues noticed that people have a closely related gene that’s active in their bone marrow cells. Yet the human gene contains a mutation that prevents cells from completing manufacture of the protein it encodes.

Intrigued, the researchers deduced what the amino acid sequence of the protein might be if the pseudogene didn’t have the flaw. They synthesized this protein, dubbed it retrocyclin, and tested it against various bacteria and fungi growing in test tubes. Retrocyclin turned out to have antimicrobial activity similar to that of the related monkey protein.

Recreating retrocyclin is “ingenious,” says Charles Bevins of the Lerner

Research Institute in Cleveland, who studies similar antimicrobial compounds.

In further test-tube experiments, Lehrer’s group found that retrocyclin protects cells from infection by several distinct HIV strains. In the Feb. 19 Proceedings of the National Academy of Sciences, the scientists report that the protein blocks the virus early in its infection cycle, perhaps preventing HIV from entering cells.

Both Lehrer and Bevins suggest that retrocyclin could serve as a prototype for a new class of anti-HIV agents. Bevins also raises a provocative question about the ancient mutation that deprived people of retrocyclin. “Could this be part of the reason we are so much more susceptible to HIV compared to monkeys?” he asks.

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