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

TitleProtection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion.
Publication TypeJournal Article
Year of Publication2005
AuthorsVeazey RS, Klasse PJohan, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, Springer MS, Moore JP
JournalNature
Volume438
Issue7064
Pagination99-102
Date Published2005 Nov 3
ISSN1476-4687
KeywordsAdministration, Intravaginal, Animals, Anti-HIV Agents, Antigens, CD4, Cell Fusion, Drug Therapy, Combination, Female, HIV, HIV Envelope Protein gp120, HIV Infections, Macaca mulatta, Membrane Fusion, Piperazines, Pyrazoles, Receptors, CCR5, Receptors, Virus, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, Time Factors, Vagina, Valine
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.

DOI10.1038/nature04055
Alternate JournalNature
PubMed ID16258536

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