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

• Published in: Nature Vol. 438; no. 7064; pp. 99 - 102
• Main Authors: Moore, John P, Klasse, Per Johan, Schader, Susan M, Marx, Preston A, Dufour, Jason, Colonno, Richard J, Ketas, Thomas J, Hu, Qinxue, Lu, Min, Shattock, Robin J, Springer, Martin S, Veazey, Ronald S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 03.11.2005; Nature Publishing Group
• Subjects: Administration, Intravaginal; Animals; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - pharmacology; Behavior modification; Biological and medical sciences; CCR5 Receptor Antagonists; CD4 Antigens - metabolism; Cell Fusion; Drug Therapy, Combination; Female; General aspects; HIV; HIV - drug effects; HIV - metabolism; HIV Envelope Protein gp120 - metabolism; HIV Infections - prevention & control; HIV Infections - transmission; HIV Infections - virology; Human immunodeficiency virus; Infections; Macaca; Macaca mulatta - virology; Medical sciences; Membrane Fusion - drug effects; Monkeys & apes; Piperazines - administration & dosage; Piperazines - pharmacology; Prevention; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Receptors, CCR5 - metabolism; Receptors, Virus - antagonists & inhibitors; Receptors, Virus - metabolism; Sexually transmitted diseases; Simian Acquired Immunodeficiency Syndrome - prevention & control; Simian Acquired Immunodeficiency Syndrome - transmission; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - drug effects; Simian Immunodeficiency Virus - metabolism; Simian/human immunodeficiency virus; STD; Time Factors; Vagina - drug effects; Vagina - virology; Valine - administration & dosage; Valine - analogs & derivatives; Valine - pharmacology; Viruses; Monkey; Retroviridae; Vagina; Lentivirus; Biological activity; Fusion inhibitor; Virus; Vertebrata; Experimental disease; Mammalia; Animal; Primates; Simian immunodeficiency virus; Protection
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature04055

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.