Michael Lederman, MD, of Case Western Reserve University (Case) School of Medicine and University Hospitals of Cleveland (UH), and research colleagues have shown that it may be possible to block male to female HIV transmission in heterosexual intercourse and have identified the target for blocking that transmission, according to an article from the Oct. 14 issue of
Michael Lederman, MD, of Case Western Reserve University (Case) School of Medicine and University Hospitals of Cleveland (UH), and research colleagues have shown that it may be possible to block male to female HIV transmission in heterosexual intercourse and have identified the target for blocking that transmission, according to an article from the Oct. 14 issue of Science.
Effective methods for blocking the transmission of HIV are urgently needed, said Lederman, MD, the Scott R. Inkley professor of medicine and director of the Center for AIDS Research at Case and UH, 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 cells. 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. 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 that is even more effective than RANTES at targeting CCR5 and 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 -- so called SHIV. The solution was successful in protecting the macaques without any detectable side effects.
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.
Other authors on the paper who contributed equally with Lederman are Ronald S. Veazey of the Tulane National Primate Research Center and Robin Offord of the Department of Structural Biology and Bioinformatics Faculty of Medicine at the University of Geneva.
Source: Case Western Reserve University