AIDSWEEKLY Plus; Monday, November 1, 2004
Staff Medical Writers

Their findings were reported in the October 15, 2004, issue of Science and at the American Medical Association's 23rd Annual Science Reporters Conference.

"Effective methods for blocking the transmission of HIV are urgently needed," said Michael Lederman, MD, Scott R. Inkley Professor of Medicine and director of the Case Western Reserve University/University Hospitals of Cleveland Center for AIDS Research, in Cleveland, Ohio, and lead author on the paper. "Our study focuses on a strategy for preventing transmission of HIV through the vagina. We have identified a potential target, a mechanism critical for the transmission at vaginal sites of infection, that may offer a simple strategy for preventing HIV transmission.

"The vast majority of HIV infections in the world are sexually transmitted, most commonly through heterosexual sex," Lederman said. "But there has been substantial debate as to how the virus actually gets into cells at these sites of transmission, called mucosal sites. HIV can use certain cell surface molecules such as CCR5 to gain entry into immune system cells called CD4. We knew that people with a mutation whose CD4 cells' surface lack CCR5 are almost completely protected from acquiring HIV infection.

"But HIV can also use other target molecules to get into other cells. Thus, there was some uncertainty as to how HIV was transmitted at mucosal sites and therefore which pathways needed to be blocked in order to prevent HIV transmission there," he continued.

"We decided to test the hypothesis that blocking CCR5 alone would be sufficient to protect rhesus macaques from vaginal challenge with a virus like HIV. A natural immune messenger [chemokine] called RANTES can bind to CCR5 and by binding, forces the cell to internalize the CCR5 receptor so HIV cannot bind to it. We developed an altered RANTES molecule, called PSC-RANTES, that is thousands of times more effective than RANTES at targeting CCR5, making it unavailable to the virus."

In their experiment, Lederman and his colleagues applied a highly concentrated solution containing the altered chemokine to the vaginal membranes of rhesus macaque monkeys and challenged them with high doses of a virus that combined the outer surface of HIV and the inner workings of SIV (simian immunodeficiency virus, or SHIV) .

The solution was successful in protecting the macaques without any detectable side effects, the team reported.

"There is still a lot of work to be done before we have an affordable, easy to use method of blocking transmission of HIV through the vaginal membranes," Lederman said. "But we have taken an important step. Now that we have shown that it is possible to block SHIV transmission through the vagina in macaques and have identified the target molecule for blocking that transmission, the door is open to the development of a topical agent that could prevent infection with HIV in humans."

This work was supported by grants from the U.S. National Institutes of Health and the Swiss National Science Foundation.

This article was prepared by AIDS Weekly editors from staff and other reports.

Reference

Lederman MM, Veazey RS, Offord R, et al., "Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5", Science. 2004 Oct 15;306(5695):485-7

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