MICROBICIDAL AGENTS FOR HSV AND HIV-1--IN VITRO STUDIES

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In this project, investigators from three sites in Chicago (Northwestern University Medical School, University of Chicago Medical Center, and Rush- Presbyterian-St. Luke's Medical Center) propose collaborative studies on herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and human immunodeficiency virus type 1 (HIV-1). One of the principal objectives of this project is to identify antimicrobial agents that are effective in preventing the infection of cultured cells by HSV-1, HSV-2 and HIV-1. The cultured cell types will include those used routinely for in vitro infectivity studies (HeLa cells for HSV and peripheral blood mononuclear cells [PMNC] for HIV) as well as primary human cells cultured from the female preproductive tract (principally cells obtained from the epithelium of the cervix and adjacent vagina). The candidate antimicrobial agents include sulfated polysaccharides selected for their potential to block the binding of HSV and HIV-1 to cells and surface-active agents that are expected to damage the envelopes of these viruses. A second important objective of project 1 is to explore the cellular and viral determinants for HSV and HIV-1 infection of primary human cells cultured from the female reproductive tract, in order to assess whether the requirements are similar to or different from those already established for permanent cell lines. The specific aims are to (i) evaluate the efficacy and cytotoxicity of potential topical microbicides in prevention of HSV-1, HSV-2 and HIV-1 infection of cultured cell types as outlined above; (ii) generate mutants of pathogenic strains of HSV-1 and HSV-2 to obtain strains that are impaired in ability to affect HeLa cells and other permanent cell lines; and (iii) evaluate HSV parental strains and mutants and selected strains of HIV-1 for their ability to infect primary human cells cultured from the female reproductive tract, before and after treatments of athe cells that are predicted to alter or mask cell receptors for the viruses. The HSV mutants generated in this project will also be used in project 3 for studies designed to define determinants of pathogenicity in the guinea pig model of genital infection. From the information obtained in all three projects, we will identify the microbicide that are most effective in protecting cells and tissues of the female reproductive tract against infection by HIV-1, HSV and chlamydia and will define some of the key cellular and viral determinants for establishment of infection in these cells and tissues.