HIV-Specific T Cell Responses in Rectal Mucosa

描述(申请人提供)：这项建议的总体目标是阐明胃肠道粘膜中HIV特异性CD8 T细胞在控制病毒复制和传播中的作用。胃肠道(GI)粘膜是HIV传播的主要部位，也是病毒复制和CD4耗尽的关键早期部位，也是体内最大的淋巴器官。因此，宿主在该组织中的防御可能是决定临床结果的关键。胃肠道也是一种独特的粘膜组织，具有固有的和适应性的防御系统，这些防御系统受到仔细的调节，以保持对共生细菌和食物抗原的免疫耐受性与对病原体的快速免疫反应之间的微妙平衡。在急性HIV/SIV感染期间，由于固有层CD4T细胞耗尽，CD8T细胞扩张和/或流入；然而，这些细胞无法清除感染或阻止病毒的广泛传播。在接受HAART的患者中，肠道CD4T细胞的快速耗尽和它们缓慢的重建表明，大多数人的粘膜CD8T细胞反应不足或功能失调。在特定的目标1中，我们将检验这样的假设，即组织特有的机制，包括转录和/或表观遗传调节，限制了穿孔素介导的CD8T细胞效应 胃肠粘膜的功能。在具体目标2中，我们将重点研究被诊断为急性/早期艾滋病毒感染的个体的粘膜T细胞反应，通常在血清转换后30天内。我们将检验这样的假设：(A)早期感染期间黏膜CD8 T细胞的强烈反应预示着低病毒载量设定点；以及(B)在早期感染期间启动HAART将导致钝化的粘膜CD8 T细胞反应，但可能保持粘膜的完整性。在特定的目标3中，我们将研究临床图谱两端的慢性HIV感染患者的粘膜T细胞反应：HIV对照组，在没有HAART的情况下，VL&lt；2000拷贝/毫升，以及非对照组，在没有HAART的情况下，VL&GT；10000拷贝/毫升。我们将测试这一预测，即HIV控制者的粘膜CD8 T细胞强烈表达穿孔素和其他细胞毒性颗粒成分，而HIV非控制者的粘膜CD8 T细胞表现出一种可能被HAART部分逆转的“疲惫”表型。这些研究解决了有关黏膜免疫反应调节的重要未解答问题，这些问题对于旨在诱导粘膜CD8 T细胞反应的疫苗方法的设计具有特别重要的意义。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the role of HIV-specific CD8 T-cells in the gastrointestinal mucosa in controlling viral replication an dissemination. The gastrointestinal (GI) mucosa is a major site of HIV transmission, a critical early site of viral replication and CD4 depletion, as well as the largest lymphoid organ in the body. Accordingly, host defenses in this tissue may be critical in determining clinical outcome. The GI tract is also a unique mucosal tissue with innate and adaptive defenses that are carefully regulated to maintain a delicate balance between immune tolerance to commensal bacteria and food antigens versus the ability to mount rapid immune responses to pathogens. During acute HIV/SIV infection, as lamina propria CD4 T-cells are depleted, there is an expansion and/or influx of CD8 T-cells; however, these cells fail to clear infection or prevent widespread virus dissemination. This rapid depletion of gut CD4 T-cells, and their slow reconstitution in patients on HAART, suggests that mucosal CD8 T-cell responses are inadequate or dysfunctional in most individuals. In Specific Aim 1, we will test the hypothesis that tissue- specific mechanisms, including transcriptional and/or epigenetic regulation, limit perforin-mediated CD8 T-cell effector functions in the gastrointestinal mucosa. In Specific Aim 2, we will focus on mucosal T-cell responses in individuals diagnosed with acute/early HIV infection, generally less than 30 days post-seroconversion. We will test the hypotheses that (a) robust mucosal CD8 T-cell responses during early infection are predictive of low viral load set-point; and (b) HAART initiation during early infection will lead to blunted mucosal CD8 T-cell responses, but may preserve mucosal integrity. In Specific Aim 3, we will study mucosal T-cell responses in patients with chronic HIV infection at opposite ends of the clinical spectrum: HIV controllers, with VL <2,000 copies/mL in the absence of HAART, and non-controllers, with VL >10,000 copies/mL in the absence of HAART. We will test the prediction that mucosal CD8 T-cells in HIV Controllers strongly express perforin and other cytotoxic granule constituents, while mucosal CD8 T-cells in HIV non-controllers display an 'exhausted' phenotype that may be partially reversed by HAART. These studies address important unanswered questions regarding the regulation of mucosal immune responses, which are of particular significance for the design of vaccine approaches aimed at induction of mucosal CD8 T-cell responses.