The potential role of microbicides in preventing the mucosal transmission of HIV-i has been clearlyidentified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection ofthe best compounds for clinical trials, since this will, in the end, provide savings in costs and time, given theexpense and length of formal efficacy trials. Concerns with performing efficacy trials with incompletelyoptimized microbicide candidates have been highlighted by recent failed or halted Phase III trials (COL-1492, SAVVY and Cellulose Sulphate); these trials have suggested that development and formulation ofeffective microbicides may not be as easy as first thought. While mononuclear cell cultures and animalmodels may provide important information for the evaluation of microbicides, anatomical, physiological andimmunological issues suggest they may not adequately model events that occur in human mucosal tissue.Therefore a comprehensive program for pre-clinical development of microbicide candidates requires thatinformation be accrued from several different model systems. Hence Dr. Shattock's and Robbiani's groupshave developed in vitro models of the earliest events in HIV-i infection of human mucosal tissue anddendritic cell driven HIV-i spread. These models are ideally suited to test the efficacy of agents designed toblock HIV-i sexual transmission and have been widely used to evaluate potential microbicide candidates.Furthermore, experiments described here and cross validation with experiments described in project III,may identify potential biomarkers of efficacy, safety and compliance that could inform future clinical trials.In this project, we will use these established models to evaluate the efficacy and compatibility of HIV-i entryinhibitors (alone and in combination) and their formulations. This research will be influenced and guided bywork carried out within Core A, and will involve extensive interactions and collaborations with the scientistsleading Research Projects II and III. The interactions between the different groups will result in the fasttrackingof the most promising inhibitor combinations and formulations for evaluation in the macaquemodel (Research Project III).
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