Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus–cell fusion

Abstract

Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse. Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian-human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus-cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.

One Percent Tenofovir Applied Topically to Humanized BLT Mice and Used According to the CAPRISA 004 Experimental Design Demonstrates Partial Protection from Vaginal HIV Infection, Validating the BLT Model for Evaluation of New Microbicide Candidates

“…4). Prior to selection for in vivo efficacy evaluation here, each inhibitor was shown to efficiently inhibit HIV in vitro (3,5,39,43,50,52,54,56). Our experimental approach for testing these six inhibitors was a single dose of the product administered prior to exposure rather than the two doses of drug administered within 24 h as used in CAPRISA 004 (1).…”

“…each sexual encounter" protocol has been the most common microbicide application protocol applied in clinical trials and animal model studies (19,23,29,35,38,44,47,50,52). The six additional candidate microbicides that we tested using this experimental design represent a broad spectrum of inhibitors with distinct mechanisms capable of blocking HIV infection at several different steps of the viral replication cycle from preentry to postbudding (Table 1).…”

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

“…Moreover, they are also significantly less susceptible to chimeric SHIV (SIV with HIV-1 envelope); therefore, infection of high percentage of macaques through mucosal exposure with SHIV remains to be a challenge. To circumvent this low susceptibility issue, two macaque models; single-dose DMPA and repeated low-dose (non-DMPA) infection models, have been investigated [11,12,42]. DMPA causes non-physiological thinning of vaginal epithelia to enhance virus penetration through mucosa.…”

“…The pandemic spread of HIV/AIDS through sexual contact and the slow progress towards an effective vaccine have prompted the search for effective vaginal and rectal microbicides to help mitigate HIV mucosal transmission [2-10]. Various agents have been investigated as topical anti-HIV microbicides including nonnucleoside reverse transcriptase inhibitors (NNRTIs) [2,3,5,11-23]. For an effective preclinical evaluation of these agents, validated animal models are urgently needed.…”

The Future of HIV Prevention: Prospects for an Effective Anti-HIV Microbicide

“…These are the chemokine receptors CCR5 and CXCR4 [51], and blockade of these receptors has been shown to be effective in clinical trials in HIV-AIDS patients [52]. Because most sexual transmission of HIV is believed to occur by CCR5-tropic strains [51], it is CCR5-blockers that have greater potential as microbicides, and a number of these compounds are under investigation for this purpose [53].…”