title: Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor.
abstract: 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.
authors.affiliation: St George's University of London, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Fletcher
authors.forename: S
authors.initials: S
authors.lastname: Harman
authors.forename: H
authors.initials: H
authors.lastname: Azijn
authors.forename: N
authors.initials: N
authors.lastname: Armanasco
authors.forename: P
authors.initials: P
authors.lastname: Manlow
authors.forename: D
authors.initials: D
authors.lastname: Perumal
authors.forename: M-P
authors.initials: MP
authors.lastname: de Bethune
authors.forename: J
authors.initials: J
authors.lastname: Nuttall
authors.forename: J
authors.initials: J
authors.lastname: Romano
authors.forename: R
authors.initials: R
authors.lastname: Shattock
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use* / Q000633:toxicity; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000821:virology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D009924:Organ Culture Techniques; D011743:Pyrimidines / Q000627:therapeutic use* / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology
chemical_list: D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D008156:Luciferases; C481671:Dapivirine