TOPICAL MICROBICIDES AND BIOLOGY OF VENEREAL PATHOGENS

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Sexually transmitted diseases (STD) are a major public health problem worldwide. Control of this epidemic will require multiple approaches including vaccine development, increased use of barrier methods, improved patient education and development of new antimicrobial drugs. An important strategy that warrants exploration is the development of topical microbicides designed for intravaginal use and intended to prevent infection at the portal of entry. In this application we propose three projects designed to evaluate the in vitro and in vivo efficacy and toxicity of candidate microbicidal compounds and to further explore the pathogenesis of sexually transmitted viral (HSV and HIV) and bacterial (chlamydia) pathogens. We have selected a series of polysulfated carbohydrates and surface-active agents expected to have in vitro microbicidal activity. In Project 1 (Microbicidal agents for HSV and HIV-1: In vitro studies), Dr. Patricia Spear and her colleagues will determine the in vitro antiviral and cytotoxic activities of these candidate microbicides. Additionally they will construct HIV mutants and explore the role of envelope glycoproteins in initiating viral infection. They will also investigate HSV mutants and explore the role of envelope glycoproteins in initiating viral infection. They will also investigate HSV and HIV infection of primary human cells derived from the female reproductive tract and determine the ability of lead compounds to protect these cells. In Project 2 (Effects of microbicides on chlamydial infections) Dr. Morris Cooper will evaluate the antichlamydial activity and cellular cytotoxicity of the compounds in cell and human fallopian tube organ cultures. As a possible target for microbicidal action he will also examine the role of chlamydial glycosaminoglycan ligands in initiating infection of human genital epithelial cells. Microbicides found to have potent antimicrobial activity and low cellular toxicity in Projects 1 and 2 will be evaluated in Project 3 (Studies with animal models of STD) by Dr. Lawrence Stranberry to determine whether they can prevent genital HSV-2 or chlamydial infection in guinea pigs. Additional studies in project 3 are intended to increase our understanding of the pathogenesis of genital herpes and facilitate the development of chemoprophylactic approaches to the control of HSV infections. Compounds with in vivo activity (and in vitro activity against HIV) will be referred to the Toxicology Core, directed by Dr. Shirley Reising, for evaluation of their spermicidal activity, genital tract irritant effects, mucosal immunotoxicological properties and effects on fertility and vaginal flora. We expect this cooperative effort will identify broad spectrum intravaginal microbicides that will be safe and effective in women. In addition, these projects will yield new information regarding the pathobiology of HSV, HIV and chlamydia that will be useful in designing strategies to prevent sexually transmitted diseases.