Vaccines do not exist for most STDs, and because vaccine development and implementation is costly and time-consuming, officials of the World Health Organization and the National Institutes of Health have recognized that on practical approach to control and prevention of STDs is development of topical microbicides which would be affordable, stable at ambient temperature and could be used discreetly by women. Vaginal microbicides are products for vaginal administration that can be used to prevent human immunodeficiency virus (HIV) infection and/or infections by other STDs. During the three years since this Program Project was initiated, great success has been achieved in establishing tubular, vaginal, human epithelial xenografts and susceptibility of these grafts to representative STDs [HPV and herpes simplex virus type 2 (HSV-2)] has been demonstrated. Uninfected grafts recapitulate the histological and cytochemical features of normal human vagina while infected grafts produce a profile of pathologic features and virus macromolecular synthesis identical to those in patient lesions. Xenografts have also been successfully used to demonstrate microbicidal prevention of HPV infection (by microbicides from the alkyl sulfate chemical family and by the microbicide C31G) as well as HSV-2 infection (by C1G). In the next phase of the grant, we will expand use of this model.
Our Specific Aims will be to: (1) Continue characterization of human xenografts at the tissue and cellular level by: (a) Optimizing growth parameters for the grafts, including comparison of growth in nude mice, severe combined immunodeficient (SCID) mice, and SCID mice reconstituted with human lymphoreticular cells; (b) Characterizing the profile of xenografts in a progesterone-dominant (as opposed to an estrogen-dominant) state; (b) Determining the repertoire of non-epithelial cells, specifically lymphoreticular cells, in the xenografts: (2) Complete the characterizing of the toxicity and efficacy of alkyl sulfate microbicides in the human vaginal xenograft system: (3) Determine the minimal inhibitory concentrations of non-formulated and formulated alkyl sulfates in inactivating or interdicting establishing grafts from human, fetal anal epithelium, in which efficacy of microbicides and infections of this target tissue might be studied.
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