Past, present, and future of entry inhibitors as HIV microbicides.

Preventing the transmission of human immunodeficiency virus (HIV) is the main goal of numerous studies trying to develop an effective vaccine and microbicide agents. Here we review the use of antiretroviral drugs to inhibit viral entry as potential HIV microbicides. After the failure of nonoxynol-9 microbicide strategies shifted towards the use of compounds creating a physical barrier to virus attachment (e.g., surfactants) or inhibit the virus in the vaginal milieu (e.g., polyanions). These early, non-specific inhibitors showed promise in both in vitro and in vivo(non-human primates) studies but provided only modest protection from HIV transmission in clinical efficacy trials. The next generation of HIV entry microbicides was based on specifically blocking virus from entering host cells by targeting CD4 attachment, gp120 binding, and virus-cell membrane fusion events. Although protection from an SIV-HIV hybrid was evident in non-human primates treated and challenged in the vaginal cavity, none of these compounds have advanced to clinical trials as a microbicide. Here we will discuss the reasons for these failures, including the selection of drug resistant HIV variants, which raises questions as to the future of broadly effective microbicides based on HIV entry inhibitors. The outcome of continued research and potential efficacy trials on the next generation of entry inhibitors might reveal whether or not an effective entry microbicide can be developed.