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 vaginally 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 strains. Even when used in combination, it is not difficult to identify virus strains that are neutralized only at very high concentrations of antibody or that escape neutralization altogether. Still, these results demonstrate that specific antiviral agents can prevent transmission of virus across the genital mucosa.
Recently, an impressive array of small molecule inhibitors that prevent HIV entry into cells have been developed, with many in clinical trials and one having been licensed in 2003 (8). Since viral attachment to and entry into host cells is the first step in establishing an infection, this process is a particularly attractive target for microbicides. Because attachment and entry involve interactions between the virus and host cells, it is important to use model systems that recapitulate the cellular environment in which infection is thought to occur as closely as possible. A major strength of the Hu et al. study is the use of human cervical tissue explants to elucidate the pathways by which HIV can establish an infection in genital mucosal tissue (1). Their work suggests two important principles that should guide the formulation of new microbicides. First, there are multiple ways by which HIV can infect target cells in the genital mucosa (Fig. 1). Thus, a successful host-targeted microbicide formulation will have to block all the potential pathways of HIV entry. Second, even if all host receptors for viral entry are blocked, HIV may be capable of evading these inhibitors by hitching a ride on dendritic cells (DCs). This may allow HIV to remain in an infectious state long enough to reach areas where microbicides do not penetrate (Fig. 1). As a result, targeting the molecules on the DC surface to which the virus binds may also be necessary for a microbicide to be as effective as possible.