INHIBITORS OF HIV-DENDRITIC CELL INTERACTIONS AS MICROBICIDES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 超过90%的艾滋病毒-1新感染是由于无保护措施的性行为造成的，从生物学上讲，妇女更容易感染艾滋病毒-1。由于性别不平等，特别是在发展中国家，避孕套(如果持续和正确地使用，虽然在预防艾滋病毒-1感染方面有效)对许多妇女来说根本不是一个可行的选择。开发一种妇女自己可以控制的预防方法可以拯救数百万人的生命。该项目将测试在细胞培养实验中已被证明可以阻止艾滋病毒-1感染的新化合物的可行性和有效性，但我们的重点将是与组织结合的化学物质，从而创造一种防止艾滋病毒附着在阴道等敏感组织上的涂层。在3年的时间里，我们将把这些新化合物单独和重复地应用于猕猴的阴道，看看它们是否能阻止SIV和SIV向猕猴的阴道传播。将进行反复曝光，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)和朗格汉斯细胞(LC)是第一个遇到HIV-1的细胞。在恒河猴中，位于生殖器粘膜的LC和常驻DC已被证明是非创伤性阴道内SIV暴露后感染的主要细胞类型。由于我们和其他人已经证明了无细胞的病毒颗粒不能有效地穿过生殖器上皮细胞，所以HIV-1很可能劫持宿主细胞作为“特洛伊木马”，在没有病变的情况下穿过通常不透水的生殖器上皮。我们在这个项目中的目标是开发防止HIV-1劫持LC和DC的化合物，并在体内阴道传播试验中测试它们作为杀微生物剂的作用。

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.