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Antimicrob. Agents Chemother. doi:10.1128/AAC.00588-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

BIOCOMPATIBILITY OF SOLID DOSAGE FORMS OF ANTI-HIV-1 MICROBICIDES WITH THE HUMAN CERVICO-VAGINAL MUCOSA MODELED EX VIVO

Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

^* To whom correspondence should be addressed. Email: rfichorova{at}rics.bwh.harvard.edu.

	Abstract

Topical anti-HIV microbicides are being sought to reduce the spread of HIV-1 during sexual intercourse. The success of this strategy depends upon the selection of formulations compatible with the natural vaginal mucosal barrier. This study applied ex vivo modeled human cervicovaginal epithelium to evaluate experimental solid-dosage forms of the anti-HIV-1 microbicide cellulose acetate 1,2-benzenedicarboxylate (CAP) and OTC vaginal products for their impact on inflammatory mediators regarded as potential HIV-1 enhancing risk factors. We assessed product-induced imbalances between IL-1 ( and ) and the natural IL-1 receptor antagonist (RA) and changes in levels of IL-6, TNF, IL-8, interferon- inducible protein (IP)-10 and macrophage inflammatory protein (MIP)-3, known to recruit and activate monocytes, dendritic and T cells to the inflamed mucosa. CAP film and gel formulation, similarly to the hydroxyethylcellulose universal vaginal placebo gel and the OTC K-Y® moisturizing gel, were nontoxic and caused no significant changes in any inflammatory biomarker. In contrast, vaginal OTC cleansing and contraceptive films (VCF) containing Octoxynol-9 or Nonoxynol-9 (N-9) demonstrated similar levels of toxicity but distinct immunoinflammatory profiles. IL-1, IL-1, IL-8 and IP-10 were increased after treatment with both VCF films; however, MIP-3 was significantly elevated by the N-9-based film only (p<0.01). Although both films increased extracellular IL-1RA, the cleansing film only significantly elevated the IL-1RA/IL1 ratio (p<0.001). The N-9-based film decreased intracellular IL-1RA (p<0.05), which has anti-inflammatory intracrine functions. This study identifies immunoinflammatory biomarkers that can discriminate between formulations better than toxicity assays and should be clinically validated in relevance to the risk of HIV-1 acquisition.