EARLY MECHANISMS OF HIV TRANSMISSION USING THE SIV/MACAQUE MODEL FOR AIDS

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。次级项目的主要支助 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 表示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。 性传播人体免疫缺陷病毒（艾滋病毒）占全世界新感染的大多数。一种能够防止通过生殖器或直肠粘膜表面的性传播的疫苗可能提供一种阻止艾滋病流行的方法。预防艾滋病毒性传播战略的最终成功部分取决于更好地了解性传播的病毒学和免疫学机制。许多研究表明，使用胃肠外免疫接种难以实现对阴道或直肠获得的HIV/SIV的无菌保护。粘蛋白免疫被认为是在病毒进入的粘膜部位实现可持续免疫应答的最佳方法。确定阴道HIV传播的机制，特别是最初的免疫反应，是制定有效策略以开发成功的粘膜艾滋病疫苗的核心。我们对粘膜传递所涉及的初始靶细胞的认识仍在不断发展。越来越多的证据表明，生产性感染的初始部位发生在粘膜表面原位。阴道传播的研究表明，潜在的初始靶细胞可能是活化的CD 4 + T细胞或上皮内树突状细胞。精确剖析艾滋病毒性传播中涉及的病毒靶点和途径将被证明对于全球开发保护性疫苗的努力至关重要。初始靶细胞的鉴定以及在粘膜部位引发和增强细胞或体液免疫应答的能力可能是开发新型疫苗的关键步骤。这些问题在人类身上进行实验是非常困难的。在这项研究中，我们建议检查原位病毒感染的粘膜入口处的SIV/食蟹猴（食蟹猴）模型使用SIV标记的GFP。 具体目标将包括：1）鉴定最初感染的细胞类型（即，研究SIV感染后阴道粘膜细胞免疫应答的发生情况。

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. Sexual transmission of human immunodeficiency virus (HIV) accounts for the majority of new infections worldwide. A vaccine capable of preventing sexual transmission across genital or rectal mucosal surfaces could provide a method for stopping the AIDS epidemic. The ultimate success of strategies to prevent sexual transmission of HIV depends, in part, on a better understanding of the virological and immunological mechanisms that underlie sexual transmission. Numerous studies have demonstrated the difficulty to achieve sterile protection from vaginally or rectally acquired HIV/SIV using parenteral immunization. Mucosal immunization is seen as the best approach to achieve sustainable immune responses at mucosal sites of viral entry. Defining the mechanisms of vaginal HIV transmission, in particular the initial immune response is central to the development of effective strategies to develop a successful mucosal AIDS vaccine. Our knowledge of the initial target cells involved in mucosal transmission is still evolving. Increasing evidence suggests that the initial site of productive infection occurs in situ at the mucosal surface. Studies of vaginal transmission suggest that the potential initial target cell may be either activated CD4+ T cells or intraepithelial dendritic cells. Precise dissection of viral targets and pathways involved in sexual HIV transmission will prove essential to the global effort to develop a protective vaccine. The identification of initial target cells and the ability to elicit and to enhance cellular or humoral immune responses at mucosal sites is likely to be a crucial step in the development of novel vaccines. These questions are extremely difficult to pursue experimentally in humans. In this study we propose to examine in situ viral infection at mucosal portal of entry in the SIV/cynomolgus (Macaca fascicularis) macaque model using SIV tagged with GFP. Specific aims will include: 1) To identify the types of cells initially infected (i.e., lymphocytes, macrophages, and dendritic cells), their phenotype and function; 2) To investigate the mechanisms, time course, and pathways of viral spread from site of initial infection; and, 3) To explore generation of early mucosal cellular immune response at vaginal site of SIV infection.