HIV-Specific T Cell Responses in Rectal Mucosa

直肠粘膜中 HIV 特异性 T 细胞反应

• 批准号: 7418720
• 负责人: Barbara L. Shacklett
• 金额: $ 37.01万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-11 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418720
• 关键词: Antibodies; Antigens; Avidity; Biological Preservation; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cells; Chronic; Clinical; Complex; Cross-Sectional Studies; Cytoplasmic Granules; Development; Exhibits; Frequencies; Functional disorder; Funding; Granzyme; HIV; HIV Infections; Highly Active Antiretroviral Therapy; IL2RA gene; Immune; Immune response; In Vitro; Individual; Infection; Lead; Ligands; Longitudinal Studies; Lymphoid; Measurement; Memory; Mucosal Immunity; Mucous Membrane; Organ; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Production; Purpose; Relative (related person); Role; Sampling; San Francisco; Shapes; Site; Specificity; T-Cell Depletion; T-Lymphocyte; Testing; Tissues; Viral; Viral Load result; Virus; Week; antiretroviral therapy; chemokine; cohort; cytokine; gastrointestinal; insight; pathogen; perforin; rectal; response; restoration; senescence

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.

描述（由申请方提供）：由于胃肠道粘膜是病毒复制和CD 4 T细胞耗竭的关键早期部位，也是体内最大的淋巴器官，因此评估该组织中的适应性免疫机制功能可能为我们理解宿主-病原体关系提供重要的新见解。我们在之前的资助周期中的研究表明，在慢性HIV感染期间，肠道粘膜中存在强大的，通常是多功能的CD 8 T细胞反应。在下一个资助周期中，我们将以先前的研究为基础，测试关于粘膜免疫在HIV发病机制中的作用的三个互补假设。我们的研究将集中在（1）多功能粘膜T细胞作为非进展的免疫相关性;（2）抗逆转录病毒治疗（ART）对肠道中CD 8 T细胞表型和功能的影响;（3）粘膜调节性T细胞在形成多功能适应性免疫应答中的作用。这些研究将对接受和未接受ART的HIV+受试者的配对血液和粘膜样本进行，包括一组特征良好的HIV控制者和健康对照。在具体目标1中，我们将检验粘膜组织中多功能的HIV特异性CD 8 T细胞是非进展的免疫相关性的假设。为了这项研究的目的，我们定义多功能T细胞为那些能够分泌多种细胞因子/趋化因子，并在体外刺激后释放溶细胞颗粒。我们的假设预测，以精英控制者（EC，病毒载量<75）和病毒血症控制者（VC，病毒载量75- 2，000）为特征的个体中的粘膜T细胞应答比非控制者（NC，病毒载量> 10，000）更强，功能更复杂，并且更广泛。对于特定目标2，我们将重点关注开始ART的非控制者。我们将检验以下假设：（a）肠道微环境驱动病毒特异性记忆CD 8 + T细胞免疫衰老，原因是高抗原负荷、CD 4 T细胞耗竭和PD- 1配体的局部表达;（B）ART仅导致肠道中部分CD 4恢复和免疫衰老逆转。最后，具体目标3，我们将测试的假设，即调节性T细胞存在于粘膜组织中的HIV感染者，这些细胞在粘膜组织中发挥作用，以抑制HIV特异性效应功能。综上所述，这些研究应大大提高我们的理解，在慢性感染的粘膜组织中的HIV-宿主的关系。