The best drugs against AIDS intervene after HIV infects a cell. But scientists have now found a molecule that prevents HIV from even getting into cells at all, at least in the test tube. The findings, published in today's issue of the Journal of Experimental Medicine, suggest that an entirely new kind of anti-AIDS drug may eventually join the physician's arsenal.
Last year scientists confirmed that it takes at least two steps for HIV to enter a human cell: First, the virus must attach to a receptor molecule on the cell's surface, then it has to change its shape to match one of two coreceptors. Soon after entering the body, HIV tends to attach to a coreceptor called CCR5; months or years later, the virus mutates into a nastier strain that attaches to a different coreceptor called CXCR4. "When the CXCR4 viruses emerge, that's bad news," says Robert Doms, an AIDS researcher at the University of Pennsylvania, Philadelphia. The number of T cells starts falling, and full-blown AIDS develops.
Doms' group, and two others working in Japan and Belgium, have now found that a peptide compound called ALX40-4C blocks the CXCR4 route of entry. When added to cultured cells, the molecule blocked infection. The work is a "proof of principle," says Doms, that virus-entry inhibitors can work. These experiments "are good starting points," he says. "Now you can change [the inhibitors] in subtle ways to try to make them work better." Doms notes that such molecules would only be effective if combined with others that can shut off the alternate CCR5 route of entry. No satisfactory candidates for that job have been reported yet.
"This is a potentially important study," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "This new small molecule has been shown to be very potent." But Fauci cautions that it's too early to say how long it might take to develop useful virus-entry inhibitors. "You have to go step by step," he says. "It usually takes years."