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Anti-HIV activity of the candidate microbicide maraviroc, a CCR5 receptor antagonist
Presented by Annalene Nel (South Africa), Katherine Young (South Africa).
P.S. Fletcher1, C. Herrera1, N. Armanasco1, A. Nel2, J. Nuttall3, J. Romano3, R.J. Shattock1
1St George's University of London, Centre for Infection, CMM, London, United Kingdom, 2International Partnership for Microbicides, Paarl, South Africa, 3International Partnership for Microbicides, Silver Spring, United States
Background: Topical blockade of CCR5 is one possible strategy by which microbicides could prevent HIV infection. Maraviroc, a CCR5 receptor antagonist recently approved as an anti-HIV therapeutic, has been licensed to the International Partnership for Microbicides for microbicide development. We present a preclinical evaluation of maraviroc, using ex vivo genital and colorectal tissue to determine its suitability as an anti-HIV microbicide.
Methods: Maraviroc was assessed for biocompatibility and efficacy (HIV-1BaL) in TZM-bl cells and human cervical, penile and colorectal tissue explants. Maraviroc toxicity was determined following overnight exposure. Maraviroc efficacy in TZM-bl cells was determined in the presence of compound, and absence/presence of biological fluids (12.5% seminal plasma (SP) or synthetic cervical mucus (CM)). Efficacy in genital/colorectal tissue was determined following pulsed (3 hours), overnight or continuous exposure to maraviroc. Cultures were maintained in the absence or presence of maraviroc accordingly for the duration of the assay.
Results: Maraviroc was biocompatible in ex vivo tissue explants at concentrations up to 100uM, with a CC50 in TZM-bl cells of 114uM. Using TZM-bl cells, maraviroc demonstrated an IC50 of 33±9nM, and retained activity in the presence of CM and SP. In experiments to evaluate the potential for preventing HIV-1 infection of ex vivo tissue explants, maraviroc was most active against infection of colorectal tissue (IC50 values of 109.9±84.5nM, 22.1±13.8nM and 2.2±1.1nM for a 3-hour pulse, overnight or continuous exposure respectively). In genital tissue explants, maraviroc was also more active with increased exposure times, with 50% protection observed at 100-1000nM following a 3 hour pulse, and 10-100nM following overnight exposure.
Conclusions: The results demonstrate that maraviroc is able to inhibit HIV-1 infection of genital and colorectal tissue cultured ex vivo, and its potency can be increased through sustained delivery. This suggests that maraviroc is a good candidate for development as a microbicide.
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