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02611_2 PRECLINICAL EVALUATION OF CANDIDATE VAGINAL MICROBICIDE -2 RANTES Kish-Catalone, Tina* The development of topically-applied, female-controlled, vaginal microbicides for the prevention of HIV-1 sexual transmission has gained support as an alternative strategy for women to protect themselves against viral infection. The ideal microbicide would have substantial activity against HIV-1, while possessing no or minimal toxicity. Inhibiting HIV-1 entry can be achieved with CCR5-targeted ligands. In this study, we examine the synthetic -2 isoform of RANTES, a natural and selective CCR5 ligand, as a candidate microbicide for the prevention of HIV-1 sexual transmission. MTS cytotoxicity assays demonstrated that levels up to 1 mg/mL of 2 RANTES were non-toxic to HeLa cell cultures following short-term (30 minutes) and long-term (24 hours) exposures. Preclinical toxicity profiles were examined in vivo utilizing the murine Swiss Webster vaginal model and the New Zealand white rabbit vaginal irritation model. These studies measured cervicovaginal tissue integrity and inflammation following exposure to 2 RANTES formulations. The formulation vehicles, Novasomes&Mac226; 7474, a non-phospholipid liposome, K-Y Jelly, a commonly used vaginal lubricant, and hydroxymethyl cellulose, have been demonstrated as safe for vaginal application. Formulations with 1 mg/mL of 2 RANTES have exhibited minimal toxicity to the mucosal epithelium following short-term (10 minutes) and long-term (24 hours) exposure with single and multiple applications. Overall, these preclinical studies suggest that 2 RANTES has an excellent safety profile for use as an anti-HIV-1 microbicide. Tina Kish-Catalone, Ph.D. |
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