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

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.