HIV-Specific T Cell Responses in Rectal Mucosa

描述(申请人提供)：由于胃肠道粘膜是病毒复制和CD4T细胞耗尽的关键早期部位，也是体内最大的淋巴器官，评估该组织中发挥作用的适应性免疫机制可能为我们理解宿主与病原体的关系提供重要的新见解。我们在前一个资助周期中的研究表明，在慢性HIV感染期间，肠道粘膜中安装了一种强大的、通常是多功能的CD8T细胞反应。在下一个资金周期中，我们将在先前研究的基础上，测试关于粘膜免疫在HIV发病机制中的作用的三个互补假说。我们的研究将集中在(1)多功能粘膜T细胞作为非进行性免疫相关；(2)抗逆转录病毒疗法(ART)对肠道CD8 T细胞表型和功能的影响；以及(3)粘膜调节性T细胞在形成多功能适应性免疫反应中的作用。这些研究将对接受抗逆转录病毒治疗的HIV+受试者和非抗逆转录病毒治疗的HIV+受试者的血液和粘膜样本进行配对，其中包括一组具有良好特征的艾滋病毒控制者和健康对照组。在特定的目标1中，我们将测试假设，即粘膜组织中多功能的HIV特异性CD8 T细胞是非进展性的免疫相关。出于本研究的目的，我们将多功能T细胞定义为能够在体外刺激下分泌多种细胞因子/趋化因子并释放细胞溶解颗粒的细胞。我们的假设预测，被描述为精英控制者(EC，病毒载量75)和病毒控制者(VC，病毒载量75-2,000)的个体的粘膜T细胞反应比非控制者(NC，病毒载量10,000)更强，功能更复杂，范围更广。对于特定的目标2，我们将重点放在开始ART的非控制者身上。我们将测试假设：(A)肠道微环境驱动病毒特异性记忆CD8+T细胞免疫衰老，原因是抗原负荷高，CD4 T细胞耗尽，以及PD-1配体的局部表达；以及(B)ART将仅导致肠道内部分CD4恢复和免疫衰老逆转。最后，对于特定的目标3，我们将测试这一假设，即在HIV感染者的粘膜组织中存在调节性T细胞，并且这些细胞在粘膜组织中局部作用以抑制HIV特异性效应器功能。综上所述，这些研究应该会极大地促进我们对慢性感染期间粘膜组织中艾滋病毒与宿主关系的理解。

DESCRIPTION (provided by applicant): Because the gastrointestinal mucosa is a critical early site of viral replication and CD4 T-cell depletion, as well as the largest lymphoid organ in the body, assessment of the adaptive immune mechanisms functioning in this tissue may provide important new insights relevant to our understanding of the host-pathogen relationship. Our studies during the prior funding cycle indicated that a robust, often polyfunctional CD8 T-cell response is mounted in gut mucosa during chronic HIV infection. In the next funding cycle, we will build upon prior studies to test three complementary hypotheses concerning the role of mucosal immunity in HIV pathogenesis. Our studies will focus on (1) Polyfunctional mucosal T-cells as an immune correlate of non-progression; (2) The effects of antiretroviral therapy (ART) on CD8 T-cell phenotype and function in the gut; and (3) The role of mucosal regulatory T-cells in shaping polyfunctional adaptive immune responses. These studies will be conducted on paired blood and mucosal samples from HIV+ subjects on and off ART, including a well-characterized group of HIV controllers, and healthy controls. In Specific Aim 1, we will test the hypothesis that polyfunctional, HIV-specific CD8 T-cells in mucosal tissues are an immune correlate of non-progression. For the purposes of this study, we define polyfunctional T cells as those capable of secreting multiple cytokines/chemokines and releasing cytolytic granules upon in vitro stimulation. Our hypothesis predicts that mucosal T-cell responses in individuals characterized as Elite Controllers (EC, viral load <75) and Viremic Controllers (VC, viral load 75-2,000) are stronger, more functionally complex, and broader than in Non-Controllers (NC, viral load >10,000). For Specific Aim 2, we will focus on Non-Controllers who are beginning ART. We will test the hypotheses that (a) the gut microenvironment drives virus-specific memory CD8+ T-cells to immune senescence due to high antigen load, CD4 T-cell depletion, and local expression of ligands for PD- 1; and (b) ART will lead to only partial CD4 restoration and reversal of immune senescence in the gut. Finally, for Specific Aim 3, we will test the hypothesis that regulatory T-cells are present in mucosal tissues of HIV-infected individuals, and that these cells act locally within mucosal tissues to suppress HIV-specific effector functions. Taken together, these studies should greatly advance our understanding of the HIV-host relationship in mucosal tissues during chronic infection.