title: Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor.
abstract: An effective vaginal microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. Among microbicide candidates in clinical development is Maraviroc (MVC), a small-molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells. Delivered systemically, MVC reduces viral load in HIV-1-infected individuals, but its ability to prevent transmission is untested. We have now evaluated MVC as a vaginal microbicide with use of a stringent model that involves challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3. Gel-formulated, prescription-grade MVC provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/mL). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (half life of approximately 4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated postinfection viremia. These findings validate MVC development as a vaginal microbicide for women and should guide clinical programs.
authors.affiliation: Tulane National Primate Research Center, Covington, LA, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Veazey
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: Jason
authors.initials: J
authors.lastname: Dufour
authors.forename: Terri
authors.initials: T
authors.lastname: Moroney-Rasmussen
authors.forename: Linda C
authors.initials: LC
authors.lastname: Green
authors.forename: P J
authors.initials: PJ
authors.lastname: Klasse
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003510:Cyclohexanes / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D023581:HIV Fusion Inhibitors; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D000077592:Maraviroc; D019713:Receptors, CCR5 / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use; D014623:Vaginal Diseases / Q000517:prevention & control* / Q000821:virology; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc