HIV protein counters immune-cell gene. (Disabled Defense).
Some investigators suggest that the new-found gene is part of the body's antiviral defense system. Not all biologists embrace that interpretation, but they nonetheless hail the gene's discovery as an important advance in HIV biology. Several investigators also suggest that the work will renew consideration of Vif as a target for AIDS drugs.
"It's a very exciting breakthrough," says Dana Gabuzda of the Dana-Farber Cancer Institute in Boston. "The specific mechanism of action of Vif has been poorly understood."
The AIDS virus naturally targets select immune cells, primarily ones called T cells. Vif, which stands for virion infectivity factor, seems to play a vital role when HIV infects such cells. If the virus lacks Vif, new viruses produced by an infected T cell can't infect other cells. Oddly, however, Vif-deficient HIV generates infectious viruses when it reproduces in some other types of cells.
In 1998, research groups led by Michael Malim, then at the University of Pennsylvania School of Medicine in Philadelphia, and by David Kabat of the Oregon Health Sciences University in Portland independently concluded that T cells and other natural cellular targets of HIV possess a factor that inhibits its replication but that Vif counteracts the then-unknown factor.
"That's a pretty remarkable finding, that the cellular defenses that could cure AIDS are in the body but neutralized by a viral protein," says Kabat.
The race was then on to identify the defense defused by Vif. In an upcoming Nature, Malim, who is now at King's College London, and his colleagues report success. The researchers compared the genes active in human cells in which Vif-deficient HIV can produce infectious virus with those in cells in which it can't. They ultimately homed in on a gene encoding a protein that they call CEM15. When the researchers added the CEM15 gene to cells in which Vif-deficient HIV produces infectious virus, the cells began generating noninfectious HIV, Malim's group found.
The CEM15 protein has no previously known function, although its amino acid sequence suggests that it modifies strands of ribonucleic acid, or RNA. That's provocative because HIV stores its genetic information as RNA. Indeed, Malim's group reports that CEM15 gets incorporated into newly built AIDS viruses.
"I think [Malim's] found something very important," says Kabat. He speculates that Vif binds to HIV's RNA and prevents CEM15 from attacking the virus' genes.
Landau, however, contends that CEM15's natural role probably has nothing to do with thwarting viruses. The protein may simply modify cellular RNA and only by accident interfere with HIV's RNA, he says.
"We need more information about what CEM15 normally does," says Gabuzda. For example, she wonders whether Vif-directly interacts with CEM15.
One of the most immediate outcomes of identifying CEM15'S modus operandi would be the creation of assays for rapidly identifying Vif-inhibiting compounds, which could become anti-AIDS drugs. Gabuzda notes that so far, only she and a few other investigators have been pursuing such potential medications.
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|Article Type:||Brief Article|
|Date:||Jul 20, 2002|
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