INHIBITORS OF HIV-DENDRITIC CELL INTERACTIONS AS MICROBICIDES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 90%以上的新艾滋病毒1型感染是由于无保护措施的性行为造成的，妇女在生理上更容易感染艾滋病毒1型。 由于性别不平等，特别是在发展中国家，避孕套（如果坚持正确使用，可以有效预防HIV-1感染）对许多妇女来说根本不是一个可行的选择。 发展一种妇女自己可以控制的预防方法可以挽救数百万人的生命。 该项目将测试新化合物的可行性和有效性，这些化合物已被证明可以在细胞培养实验中阻断HIV-1感染，但我们的重点将是与组织结合的化学物质，从而产生一种涂层，防止HIV病毒附着到阴道等易感组织。 在3年的时间里，我们将这些新化合物单独和重复地应用于猕猴的阴道，以观察它们是否能阻止SIV和SHIV经阴道传播给猕猴。 将进行重复暴露，以确保这些化合物在继续使用时是安全的。据推测，生殖器粘膜中的树突状细胞（DC）以及朗格汉斯细胞（LC）是第一个遇到HIV-1的细胞。在恒河猴中，LC和位于生殖器粘膜中的常驻DC已被证明是非创伤性阴道内暴露于SIV后感染的主要细胞类型。由于我们和其他人已经表明，无细胞病毒颗粒不能有效地穿过生殖器上皮细胞，很可能是HIV-1劫持宿主细胞作为“特洛伊木马”，在没有病变的情况下穿过正常不渗透的生殖器上皮。我们在这个项目中的目标是开发化合物，防止HIV-1劫持LC和DC，并测试它们作为杀微生物剂在体内阴道传播试验。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Over 90% of new HIV-1 infections occur as the result of unprotected sex, and women are biologically more vulnerable to HIV-1 infection. Because of gender inequality, particularly in developing countries, condoms (while effective at preventing HIV-1 infection when used consistently and correctly) are simply not a feasible option for many women. The development of a prevention method that women themselves could control could save millions of lives. This project will test the feasibility and efficacy of new compounds that have been demonstrated to block HIV-1 infection in cell culture experiments, but our focus will be on chemicals that bind to tissues and thus create a coating that prevents attachment of the HIV virus to susceptible tissues such as the vagina. Over the course of 3 years, we will apply these new compounds to the vagina of macaques singly and repeatedly to see if they prevent vaginal transmission of SIV and SHIV to macaques. Repeated exposures will be performed to ensure that these compounds are safe with continued use. It has been postulated that dendritic cells (DC) as well as Langerhans cells (LC) in the genital mucosa are the first cells to encounter HIV-1. In rhesus monkeys LC and resident DC located in the genital mucosa have been shown to be the dominant cell type infected following non-traumatic intravaginal exposure to SIV. Since we and others have shown that cell-free viral particles ineffectively cross genital epithelial cells, it is likely that HIV-1 hijacks host cells as "Trojan horses" to cross the normally impermeable genital epithelium in the absence of lesions. Our goal in this project is to develop compounds that prevent HIV-1 hijacking of LC and DC and to test them as microbicides in an in vivo vaginal transmission assay.