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02639_1 PRECLINICAL EVALUATION OF LEAD CANDIDATE POLYANIONIC MICROBICIDES Watts, Patricia Background: With 5 million new cases of HIV-1 in 2002, there is an urgent need for strategies to reduce its transmission. The potential of microbicides to reduce transmission across mucosal surfaces has been clearly identified, and some agents are currently under evaluation in clinical trials. Many of these first generation microbicides consist of polyanionic compounds. We have evaluated a panel of polyanions, including PRO 2000 and dextrin sulphate, to determine their mechanism of action and efficacy in different model systems. Methods: In vitro activity of compounds was determined using both cell-based assays and an established ex-vivo, human cervical explant model. Results: Pretreatment of viral strains prior to culture with permissive cells demonstrated differential activity, with compounds being more active against an X4 (HIV-1 RF) than an R5 (HIV-1 BaL) strain. While compounds showed little or no prevention of viral binding to THP-1 DC-SIGN+ cells, the transfer of bound virus to permissive cells was inhibited, with a higher concentration of compound necessary to block transfer of the R5 strain compared to the X4 strain. The presence of test compound during viral exposure demonstrated highly potent activity directed towards both viral phenotypes, with some differential activity also observed. Additionally, the infection of cervical explants with HIV-1 BaL was significantly inhibited when exposure occurred in the presence of compound. Discussion: Polyanion compounds such as PRO 2000 and dextrin sulphate demonstrate highly potent activity against HIV-1 when present during viral exposure and thus show promise as candidate microbicides about to enter Phase III clinical trials. Miss Patricia Watts |
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