TOPICAL MICROBICIDES AND BIOLOGY OF VENEREAL PATHOGENS

性传播疾病是一个主要的公共卫生问题 国际吧 控制这一流行病需要采取多种办法 包括疫苗开发，增加屏障方法的使用， 患者教育和开发新的抗微生物药物。 一个重要 一个值得探索的战略是发展专题 设计用于阴道内使用的杀微生物剂， 入口处感染 在本申请中，我们提出三个 旨在评价体外和体内疗效的项目， 候选杀微生物化合物的毒性，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。 我们选择了一系列多硫酸化碳水化合物和表面活性剂， 预期具有体外杀微生物活性的试剂。 项目1 （HSV和HIV-1的杀微生物剂：体外研究），Patricia博士 斯皮尔和她的同事将确定体外抗病毒药物， 这些候选杀微生物剂的细胞毒活性。 他们还 将构建HIV突变体并探索包膜糖蛋白的作用 引发病毒感染 他们还将研究HSV突变体， 探索包膜糖蛋白在启动病毒感染中的作用。 他们还将研究HSV和HIV对原代人类细胞的感染 来自女性生殖道，并决定能力， 铅化合物来保护这些细胞。 项目2（影响） 莫里斯库珀博士将评估 化合物的抗衣原体活性和细胞毒性 和人类输卵管器官培养物。 作为一个可能的目标 他还将研究衣原体的作用， 糖胺聚糖配体在引发人类生殖道感染中的作用 上皮细胞 发现具有强效抗菌活性的杀微生物剂 项目1和项目2中的低细胞毒性将在项目1中进行评估。 3（STD动物模型研究），Lawrence Stranberry博士， 确定他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，并促进 开发控制HSV的化学预防方法 感染. 具有体内活性（和体外活性， HIV）将提交给毒理学核心，由Shirley博士指导 Reising，用于评价其杀精子活性，生殖道 刺激作用、粘膜免疫毒理学特性和对 生育力和阴道植物群。 我们希望这种合作努力将确定广谱阴道内 对妇女安全有效的杀微生物剂。 另外这些 这些项目将产生关于HSV、HIV 和衣原体，这将有助于设计策略，以防止 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.