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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 性传播人类免疫缺陷病毒(艾滋病毒)占全球新增感染的大部分。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以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在一定程度上取决于对作为性传播基础的病毒学和免疫学机制的更好理解。许多研究表明，使用非肠道免疫很难实现对通过阴道或直肠获得的艾滋病毒/SIV的无菌保护。黏膜免疫被认为是在病毒进入的粘膜部位实现可持续免疫反应的最好方法。确定艾滋病毒经阴道传播的机制，特别是初始免疫反应，是开发成功的粘膜艾滋病疫苗的有效策略的核心。我们对参与粘膜传播的最初靶细胞的了解仍在发展中。越来越多的证据表明，生殖性感染的初始部位发生在粘膜表面。对阴道传播的研究表明，潜在的初始靶细胞可能是活化的CD4T细胞或上皮内树突状细胞。对艾滋病毒经性传播所涉及的病毒目标和途径的精确剖析，将被证明对开发保护性疫苗的全球努力至关重要。识别最初的靶细胞以及在粘膜部位诱导和增强细胞或体液免疫反应的能力可能是开发新型疫苗的关键一步。这些问题在人体实验中是极其困难的。在这项研究中，我们建议使用GFP标记的SIV来检测SIV/食蟹猴模型中黏膜入口的原位病毒感染。具体目标包括：1)鉴定最初感染的细胞的类型(即淋巴细胞、巨噬细胞和树突状细胞)，它们的表型和功能；2)研究病毒从初始感染部位传播的机制、时间进程和途径；以及3)探索SIV感染后阴道部位早期粘膜细胞免疫反应的产生。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.