In order to be effective in the prevention of the sexual transmission of HIV-1, topical microbicides have to inactivate the virus or block virus infection while preserving or enhancing the natural mucosal barrier in the human genital tract. The epithelial lining of the human cervix and vagina maintains a healthy mucosal environment through a tight physical barrier and a dynamic balance between pro-inflammatory and anti-inflammatory mediators which shifted upon confrontation with microbial pathogens or chemical irritants. Inflammatory events are generally beneficial for clearance of bacterial vaginal infection; however, in the case of HIV-1, they may increase the risk of HIV infection/transmission through mucosal influx of HIV-1 susceptible leukocytes and/or cytokine-mediated increase of HIV-1 expression in latently infected cells. Previous investigations indicate that these inflammatory events may underlie the failure of Nonoxynol-9 [N 9] containing products to protect against HIV in recent clinical trials. While Nonoxynol-9 can disrupt the epithelial cell barrier due to its detergent nature, other classes of microbicides such as the cellulose derivative CAP (cellulose acetate phthalate) possess low cytotoxicity, but may still harm the mucosal barrier by inducing/amplifying proinflammatory signals. The applicant hypothesizes that activation of proinflammatory pathways in epithelial cells by irritating anti-microbial compounds can perpetuate influx of HIV-1 susceptible leukocytes and/or cytokine-mediated increase of HIV-1 expression in latently infected cells in the genital tract mucosa beyond the time when these compounds will be physically present to kill/suppress the virus. In this study, well characterized immortalized human cervical and vaginal epithelial cell lines and HIV reporter lines will be used to examine effects of CAP on: 1) mucosal barrier functions (epithelial permeability and epithelial cell production of cytokines, chemokines and anti-inflammatory/anti-HIV-1 molecules); 2) HIV-1 expression and defined inflammatory correlates of HIV-1 replication (NF-kB activation and cytokines) in latently infected cells; 3) leukocyte-epithelial interactions that mediate a downstream effect on HIV-1 infection, such as cytokine upregulation under coculture conditions and leukocyte trafficking. The data obtained through this study will characterize the proinflammatory potential of CAP in vitro and its capacity to reactivate HIV replication. The experimental approach will establish an algorithm of comparisons, which may guide future investigations of microbicide action in vivo.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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New York Blood Center
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