This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The overall goal of this program project is to develop safe and effective topical antimicrobial agents for vaginal or rectal use that will block sexual transmission of human immunodeficiency virus (HIV) and other sexually transmitted pathogens including herpes simplex virus (HSV). The overall program project focuses on the development of a novel class of candidate compounds based on the parent compound, sodium dimandelic acid ether (SAMMA). SAMMA has excellent anti-HIV and HSV activity, while exhibiting no cytotoxicity in tissue culture. Project 3 of the Program focuses on determining the efficacy of SAMMA and its derivatives in biologically relevant culture systems. While mononuclear cell cultures may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately simulate events that occur in human genital tract fluids and mucosal tissues. In preliminary studies, we have demonstrated that cervicovaginal lavage fluid (CVL) has intrinsic antiviral activity against HSV, and to a lesser extent, HIV. The goal of this ancillary study is to further characterize the anti-viral activity of CVL. It is important to control for factors such as age, menstrual cycle and intercurrent infections. Therefore, we propose to obtain CVL from a cohort of 20 subjects who will be assessed twice (2-weeks apart). The anti-viral (HSV and HIV) activity in the CVL will be assayed and correlated with age, phase of menstrual cycle, and presence of intercurrent infections. In addition, studies to define the mechanism of anti-HSV activity will be conducted. The stability of SAMMA, leading derivatives and other candidate topical compounds in the presence of CVL will also be assessed. Defining the antiviral activity present in genital tract fluids and their impact on microbicide activity is critical in the development of candidate microbicides.
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