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，是病毒复制和CD4耗竭的关键早期部位，也是机体最大的淋巴器官。因此，该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，具有先天和适应性防御，在对共生细菌和食物抗原的免疫耐受与对病原体的快速免疫反应之间保持微妙的平衡。在急性HIV/SIV感染期间，由于固有层CD4 t细胞被耗尽，CD8 t细胞扩增和/或涌入；然而，这些细胞不能清除感染或阻止病毒的广泛传播。这种肠道CD4 t细胞的快速耗竭，以及HAART患者的缓慢重建，表明粘膜CD8 t细胞反应在大多数个体中是不充分或功能失调的。在特异性目标1中，我们将检验组织特异性机制，包括转录和/或表观遗传调控，限制穿孔蛋白介导的CD8 t细胞效应的假设

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.