HIV-Specific T Cell Responses in Rectal Mucosa

描述（由申请人提供）：本提案的总体目标是阐明胃肠道粘膜中HIV特异性CD 8 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，是病毒复制和CD 4耗竭的关键早期部位，也是体内最大的淋巴器官。因此，在这种组织中的宿主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，具有先天性和适应性防御，其被仔细调节以维持对肠道细菌和食物抗原的免疫耐受性与对病原体产生快速免疫应答的能力之间的微妙平衡。在急性HIV/SIV感染期间，由于固有层CD 4 T细胞耗尽，存在CD 8 T细胞的扩增和/或流入;然而，这些细胞不能清除感染或防止广泛的病毒传播。这种肠道CD 4 T细胞的快速消耗及其在HAART患者中的缓慢重建表明，大多数个体中粘膜CD 8 T细胞应答不足或功能失调。在具体目标1中，我们将检验组织特异性机制（包括转录和/或表观遗传调节）限制穿孔素介导的CD 8 T细胞效应子表达的假设。 在胃肠道粘膜中起作用。在具体目标2中，我们将重点关注被诊断为急性/早期HIV感染的个体的粘膜T细胞反应，通常在血清转换后不到30天。我们将检验以下假设：（a）早期感染期间强粘膜CD 8 T细胞应答预测低病毒载量设定点;（B）早期感染期间开始HAART治疗将导致粘膜CD 8 T细胞应答减弱，但可能保持粘膜完整性。在具体目标3中，我们将研究慢性HIV感染患者的粘膜T细胞反应，这些患者处于临床谱的两端：HIV控制者，在没有HAART的情况下VL <2，000拷贝/mL，以及非控制者，在没有HAART的情况下VL > 10，000拷贝/mL。我们将测试的预测，粘膜CD 8 T细胞在HIV控制器强烈表达穿孔素和其他细胞毒性颗粒成分，而粘膜CD 8 T细胞在HIV非控制器显示一个'耗尽'的表型，可以部分逆转HAART。这些研究解决了关于粘膜免疫应答的调节的重要的未回答的问题，这对于旨在诱导粘膜CD 8 T细胞应答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.