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Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor.

TitleProtection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor.
Publication TypeJournal Article
Year of Publication2010
AuthorsVeazey RS, Ketas TJ, Dufour J, Moroney-Rasmussen T, Green LC, Klasse PJ, Moore JP
JournalJ Infect Dis
Volume202
Issue5
Pagination739-44
Date Published2010 Sep 1
ISSN1537-6613
KeywordsAdministration, Intravaginal, Animals, Anti-HIV Agents, Cyclohexanes, Female, HIV Fusion Inhibitors, HIV Infections, HIV-1, Humans, Macaca mulatta, Receptors, CCR5, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, Treatment Outcome, Triazoles, Vaginal Diseases, Virus Internalization, Virus Replication
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.

DOI10.1086/655661
Alternate JournalJ. Infect. Dis.
PubMed ID20629537
PubMed Central IDPMC2916941
Grant ListR01 AI041420-14 / AI / NIAID NIH HHS / United States
R01 AI041420-17 / AI / NIAID NIH HHS / United States
R01 AI41420 / AI / NIAID NIH HHS / United States
U19 AI076982 / AI / NIAID NIH HHS / United States
U19 AI076982-02 / AI / NIAID NIH HHS / United States

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