The long-term goal of this program grant is to develop in vitro, tissue and animal based models for evaluation of the efficacy and safety of topical microbicides. In addition, new combination microbicides and novel compounds will be developed. The longer-term goals of this work are to develop topical agents which could be used intravaginally or rectally to prevent acquisition of sexually transmitted infections including HIV. This continuing program project grant includes an administrative core, two scientific cores (Microbiology and Chlamydia trachomatis) and four projects. The first Project will further develop the pigtailed macaque model for evaluation of topical microbicides vaginally and rectally. The second Project ill test the hypothesis that combining antimicrobial lipids with antimicrobial peptides such as magainins, lytic peptides, and defensins, will produce a more effective topical microbicide compared to peptides or lipids alone. Further, the mechanism of retinoic acid inhibition on herpes simplex virus will be assessed with the objective of designing a novel antiviral compound based on inhibitors of N-glycosylation. The third Project will evaluate effects of topical microbicides on self cell associated HIV in PBMC, T-cell lines and epithelial cell lines, while evaluating the effect of pH, semen, and vaginal fluid. Vaginal and cervical tissues in an organ culture model will be used to evaluate cytotoxicity of microbicides and transmission of HIV across cervical tissue. The fourth Project will describe the basic transport kinetics of hydrophilic and lipophilic substances across vaginal and cervical tissue, describe the effects of formulation excipients on normal flora organisms, genital pathogens and HIV, and employ basic pharmaceutical techniques to develop a formulation for the antimicrobial lipids. The scientific cores and projects included in this application will evaluate the effects of topical microbicides on vaginal, cervical and rectal tissues using organ culture and the monkey model, and will focus on HIV, HSV, C. trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis and members of the normal microflora. This program project proposal integrates microbiologists, retrovirologists, experts in biologic structures and pharmaceutics, as well as biochemists in a collaborative and integrated approach towards development of topical microbicides.
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