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.