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

Anti-HIV microbicide A trial of three inhibitors of HIV-1 entry into target cells, administered vaginally in macaque monkeys prior to intercourse, shows that they can protect against infection by a simian-human immunodeficiency virus. One molecule, the antiviral CMPD 167, is particularly potent, providing protection when applied 6 hours before challenge. The macaque model is a proven test of AIDS prevention strategies, so these findings bode well for the prospects of similar compounds in humans. Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available 1 . 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 2 . 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 3 , 4 , CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association 5 , and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion 6 . 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.