Background:  Current research on ameliorating the HIV epidemic is focusing on strategies to prevent HIV infection through the use of topical microbicides that could be applied to the vagina. Since many microbicides that can damage or destroy the lipid envelope of HIV may also increase mucosal tissue damage and the rate of HIV transmission, we are testing the potential for small-molecule fusion inhibitors that can prevent vaginal transmission by binding to receptors on susceptible cells and interfering with HIV attachment and/or fusion on mucosal surfaces. CMPD 167 is a small-molecule CCR5 inhibitor developed by Merck that we have previously shown can effectively reduce viral loads in simian immunodeficiency virus (SIV)-infected macaques. Here we demonstrate the efficacy of CMPD 167 in preventing transmission following a topical intravaginal application.

Methods:  Five Depo-Provera pre-treated macaques were intravaginally dosed with 4 mL of CMPD 167 (3 mg/mL) formulated in hydroxymethyl cellulose (HMC), and 6 control macaques were treated with HMC alone. Thirty minutes after dosing, animals were intravaginally exposed to 300 TCID50 of the CCR5-using simian immunodeficiency virus/HIV162P3 (SHIV). Viral loads in plasma were monitored weekly by bDNA assays.

Results:  Four out of 5 macaques pre-treated with CMPD 167 were completely protected from transmission, as evidenced by consistently undetectable virus in plasma. In contrast, all 5 placebo-treated control macaques were infected. These results were highly significant (p = 0.015) by Fisher’s exact test.

Conclusions:  These results demonstrate that topical application of a small-molecule inhibitor of CCR5 can completely protect macaques against vaginal SHIV 162P transmission. Since CCR5- utilizing strains predominate in early mucosal transmission, these findings suggest that targeting CCR5 is sufficient to block vaginal SHIV transmission, and that small-molecule inhibitors may be an effective and economical strategy for preventing mucosal HIV-1 transmission.

Keywords: Microbicides; CCR5; fusion inhibitor