TOPICAL MICROBICIDES AND BIOLOGY OF VENEREAL PATHOGENS

性传播疾病(STD)是一大公共卫生问题 全世界。控制这一流行病需要采取多种方法 包括疫苗开发，增加屏障方法的使用，改进 患者教育和新型抗菌药物的开发。一个重要的 值得探讨的策略是主题的发展 专为阴道内使用的杀微生物剂，旨在防止 入口处的感染。在本申请中，我们提出了三个 旨在评估体外和体内疗效的项目和 候选杀微生物剂的毒性，并进一步探讨 性传播病毒(HSV和HIV)和细菌的发病机制 (衣原体)病原体。 我们已经选择了一系列多硫酸盐碳水化合物和表面活性 预期具有体外杀菌活性的试剂。在项目1中 (HSV和HIV-1的杀微生物剂：体外研究)，Patricia博士 斯皮尔和她的同事们将确定体外抗病毒和 这些候选杀微生物剂的细胞毒活性。此外，他们还 将构建HIV突变体并探索包膜糖蛋白的作用 在引发病毒感染方面。他们还将研究单纯疱疹病毒的变种和 探索包膜糖蛋白在启动病毒感染中的作用。 他们还将研究人类原代细胞的单纯疱疹病毒和艾滋病毒感染 来自女性生殖道，并决定了 铅化合物可以保护这些细胞。在项目2中(影响 杀微生物剂治疗衣原体感染)莫里斯·库珀博士将评估 化合物的细胞内抗衣原体活性和细胞毒作用 和人类输卵管器官培养。作为一个可能的目标 他还将研究衣原体的作用 糖胺多糖配体在启动人类生殖器感染中的作用 上皮细胞。杀微生物剂被发现具有很强的抗菌活性 项目1和2中的低细胞毒性将在项目中进行评估 3(STD动物模型研究)，劳伦斯·斯特兰贝里博士 确定它们是否可以预防生殖器HSV-2或衣原体感染 豚鼠。项目3中的其他研究旨在增加我们的 了解生殖器疱疹的发病机制，促进 控制单纯疱疹病毒感染的化学预防方法研究进展 感染。具有体内活性(和体外抗肿瘤活性)的化合物 HIV)将被转介到由雪莉博士指导的毒理学核心 Reise，用于评估其杀精活性，生殖道 刺激性作用、粘膜免疫毒理学特性及对 生育力和阴道菌群。 我们希望这次合作能在阴道内鉴定出广谱的 对妇女安全有效的杀微生物剂。此外，这些 项目将产生关于单纯疱疹病毒、艾滋病毒的病理生物学的新信息。 和衣原体感染，这将有助于制定预防策略 性传播疾病。

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.