Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor - PubMed (original) (raw)

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

Ronald S Veazey et al. J Infect Dis. 2010.

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.

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Conflict of interest statement

None of the authors has any commercial or other association that might pose a conflict of interest.

Figures

Figure 1

Figure 1. Dose-dependent protection of rhesus macaques by MVC

HMC gel-formulated MVC at the indicated concentrations was applied in a 4 ml volume to the vaginas of rhesus macaques 30 min prior to vaginal challenge with SHIV-162P3. The outcome of challenge was determined by measuring plasma viremia at weekly intervals. The percentage of test animals infected at each MVC dose is recorded, with the number of animals used listed in brackets next to the symbol. Note that the 7 animals receiving 6 mM MVC 30 min before challenge are the same 7 animals recorded at this time point in Fig.2.

Figure 2

Figure 2. Protection of rhesus macaques by MVC is time-dependent

HMC gel-formulated MVC at 6 mM (3 mg/ml) was applied in a 4 ml volume to the vaginas of rhesus macaques at the indicated times before vaginal challenge with SHIV-162P3. The outcome of challenge was determined by measuring plasma viremia at weekly intervals. The percentage of test animals infected at each time point is recorded, with the number of animals used listed in brackets next to the symbol. Note that the 7 animals receiving 6 mM MVC 30 min before challenge are the same 7 animals recorded at MVC concentration in Fig.1.

Figure 3

Figure 3. Viral loads in macaques infected with SHIV-162P3 after receiving MVC

Viral loads are plotted as a function of time after challenge for all breakthrough infections in the experiment shown in Figure 1. The MVC concentration given to the animals is indicated by the color of the curves: grey solid (0 mM, n=1); black solid (2 mM, n=1); dotted (0.6 mM, n=1); long dashes (0.2 mM, n=2); short dashes (0.06 mM, n=4). NB, the VL profile in the control animal (0 mM MVC) is typical of what we have observed in other studies using and this and other stocks of SHIV-162P3 for vaginal challenge.

Figure 4

Figure 4. Viral loads in macaques infected with SHIV-KU1

Viral loads are plotted as a function of time after challenge for all the infected animals. The macaques received 2 mM MVC in HMC gel (black solid curves, n=3) or a control gel (dotted curves, n=3) before challenge with the X4 virus, SHIV-KU1 (10 TCID50).

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