Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of
infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as
topical microbicides. Potential
microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside
reverse transcriptase inhibitor (NNRTI)
dapivirine as a vaginal
microbicide. In tissue compatibility studies,
dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants.
Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore,
dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures,
dapivirine was able not only to inhibit direct
infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore,
dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated
infection for as long
as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that
dapivirine has considerable promise as a potential
microbicide candidate.