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J. Virol. doi:10.1128/JVI.00335-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Candidate Microbicide PPCM Blocks HIV-1 Infection in Cell and Tissue Cultures and Prevents Genital Herpes in a Murine Model

Department of Cellular and Molecular Medicine, St. George's University of London, London, United Kingdom and Departments of Pediatrics, Microbiology & Immunology, and Medicine, Albert Einstein College of Medicine, Bronx, NY

	Abstract

A structurally novel candidate microbicide, PPCM, which is formed from the reaction of D,L-mandelic acid with sulfuric acid, provides activity against HIV and HSV and is not cytotoxic. The objectives of the current studies were to comprehensively evaluate its activity in cell and explant cultures, explore the possibility of combining PPCM with HIV-specific reverse transcriptase inhibitors and evaluate the efficacy of a formulated gel against genital herpes in a murine model. PPCM inhibited infection by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical and endocervical tissue explants exposed to HIV-1_BaL in the presence of PPCM were protected (IC₅₀ 3.9µg/ml for ectocervix; 3.1µg/ml for endocervix), and transfer of virus to target T-cells via migratory cells was significantly impaired (IC₅₀ 35.7µg/ml from ectocervix, IC₅₀ 54.6µg/ml from endocervix). The drug also blocked infection by cell-associated virus. Combinations of PPCM with UC-781 or PMPA in vitro exhibited additive anti-HIV activity. PPCM was incorporated into a stable, low pH gel formulation at concentrations of 0.4% and 4%. Both gels prevented genital herpes infection in mice, even when virus was introduced in human seminal plasma. The ability of PPCM to inhibit primary HIV isolates, reduce infection by cell-associated virus and transfer of HIV from migratory to T cells, combined with the complete protection provided by formulated gel against genital herpes indicates that this drug is an excellent candidate for inclusion in a combination microbicide and would provide protection against both HIV and HSV.