HIV Transmission

In the absence of an effective vaccine, educational or interventional strategies that decrease sexual transmission of HIV hold the greatest promise for slowing infection rates. Although a safe and effective microbicide could greatly help in this regard, progress in this area has been disappointing with microbicide development often failing to take into account advances in our understanding of how HIV is transmitted and infects cells. In this issue, Hu et al. demonstrate that HIV infection of human cervical tissue ex vivo can be prevented not only by using antibodies that target the virus but by a cocktail of compounds that target the cell surface receptors to which the virus binds, thus providing a basis for the design of microbicides that prevent virus infection in a highly specific manner (1). Potential microbicides for HIV can be placed into one of three categories: compounds that inhibit virus infection nonspecifically, compounds that specifically target the virus, and compounds that target the cell surface receptors to which the virus binds. Most microbicide candidates tested to date fall squarely into the first category and illustrate the pitfalls of using agents that do not discriminate between pathogen and host. The first candidate microbicide for HIV to reach phase III clinical trials was the spermicidal detergent nonoxynol-9. Although the compound inactivates HIV in vitro by disrupting the outer viral membrane, it failed to prevent sexual transmission of the virus in vivo (2). In fact, women who used nonoxyl-9 containing gels had a higher rate of infection by HIV, most likely because the detergent disrupted the membranes of the epithelial cells in the genital tract which otherwise serve as an important barrier to virus infection. The failure of nonoxynol-9 has increased interest in agents that more specifically target HIV. That HIV transmission can be prevented has been shown most clearly through the use of neutralizing antibodies. Passive administration of neutralizing antibodies can confer sterilizing immunity to macaques who are vaginally challenged with virus, provided that the antibodies are present within several hours of virus application (3–5). Likewise, a vagi-nally applied neutralizing antibody prevented infection of macaques (6). Although promising, the greatest drawbacks to the use of monoclonal antibodies is their cost and the structural variability of the viral Env protein to which they bind (7). Only a handful of broadly cross-reactive, neutralizing antibodies have been developed over the past 20 yr, and none of these recognize all virus …