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.

• Authors: Ronald S Veazey, Per Johan Klasse, Susan M Schader, Qinxue Hu, Thomas J Ketas, Min Lu, Preston A Marx, Jason Dufour, Richard J Colonno, Robin J Shattock, Martin S Springer, John P Moore
• Journal: Nature (Nature) Vol. 438 Issue 7064 Pg. 99-102 (Nov 03 2005) ISSN: 1476-4687 [Electronic] England
• PMID: 16258536 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-HIV Agents
• BMS-378806
• CCR5 Receptor Antagonists
• CD4 Antigens
• CMPD 167
• HIV Envelope Protein gp120
• Piperazines
• Pyrazoles
• Receptors, CCR5
• Receptors, Virus
• Valine

Topics

• Administration, Intravaginal
• Animals
• Anti-HIV Agents (administration & dosage, pharmacology)
• CCR5 Receptor Antagonists
• CD4 Antigens (metabolism)
• Cell Fusion
• Drug Therapy, Combination
• Female
• HIV (drug effects, metabolism)
• HIV Envelope Protein gp120 (metabolism)
• HIV Infections (prevention & control, transmission, virology)
• Macaca mulatta (virology)
• Membrane Fusion (drug effects)
• Piperazines (administration & dosage, pharmacology)
• Pyrazoles (administration & dosage, pharmacology)
• Receptors, CCR5 (metabolism)
• Receptors, Virus (antagonists & inhibitors, metabolism)
• Simian Acquired Immunodeficiency Syndrome (prevention & control, transmission, virology)
• Simian Immunodeficiency Virus (drug effects, metabolism)
• Time Factors
• Vagina (drug effects, virology)
• Valine (administration & dosage, analogs & derivatives, pharmacology)