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 people, but its ability to prevent transmission is untested. We have now evaluated MVC as a vaginal microbicide, using a stringent model involving 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 (T1/2 ~ 4 h). As expected, MVC neither protected against challenge with a CXCR4-using virus, SHIV-KU1, nor exacerbated post-infection viremia. These findings validate MVC development as a vaginal microbicide for women, and should guide clinical programs.

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

“…Thus, the frequency of incoming (i.e., transmitted/founder) viruses with reduced inhibitor susceptibility is lower than that seen with chronic viruses, and infections of resting T cells, which may express a large proportion of inhibitor-sensitive, G-protein-uncoupled CCR5 forms, predominate at such sites. Note that CCR5 inhibitors can indeed inhibit the vaginal transmission of test viruses to macaques when applied topically or orally (58)(59)(60)(61).…”

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

“…Cyanovirin, a cyanobacterial protein that binds non-competitively to gp120, was also effective in protecting pig-tailed macaques against vaginal infection [203]. CCR5 antagonists CMPD167 and maraviroc, and modified chemokines such as PSC-Rantes have shown protection in rhesus macaques against RLD vaginal challenge with SHIV [201,204,205].…”

Use of Animal Models for Anti-HIV Drug Development

“…Compounds tested in macaque models have aimed to interfere with nonspecific viral attachment (Ambrose et al, 2008;Boadi et al, 2005;Kenney et al, 2011;Kim et al, 2006;Lagenaur et al, 2011;Li et al, 2009;Manson et al, 2000;Tevi-Benissan et al, 2000;Tsai et al, 2004;Wyand et al, 1999), specific interactions of envelope with receptor/co-receptors (KishCatalone et al, 2007;Lederman et al, 2004;Mascola et al, 2000;Parren et al, 2001;Veazey et al, 2008;Veazey et al, 2010;Veazey et al, 2003a;Veazey et al, 2005a;Veazey et al, 2009;Veazey et al, 2003b;Veazey et al, 2005b), and reverse transcription Parikh et al, 2009;Stolte-Leeb et al, 2011;Turville et al, 2008). Another study investigated hormone treatment, which leads to thickening of the vaginal epithelium, to prevent vaginal transmission of SIV in macaques (Smith et al, 2000b).…”