Viral control mechanisms of HIV-specific T cells in HIV-infected lymph node

HIV感染淋巴结中HIV特异性T细胞的病毒控制机制

• 批准号: 9089892
• 负责人: Michael R Betts
• 金额: $ 65.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089892
• 关键词: Activities of Daily Living; Address; Animal Model; Antigen-Presenting Cells; Antigens; Antiviral Agents; Automobile Driving; BLR1 gene; Biological; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cellular Immunity; Chronic; Cytoplasmic Granules; Cytotoxic T-Lymphocytes; Data; Development; Disease Progression; Engineering; Frequencies; Functional disorder; Goals; HIV; HIV Infections; HIV vaccine; Helper-Inducer T-Lymphocyte; Homing; Humoral Immunities; Immune; Immune response; Immunity; Individual; Infection; Inflammatory; Kinetics; Ligands; Lymphoid Follicle; Lymphoid Tissue; Maintenance; Mediating; Nature; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Property; Regulation; Shock; Site; Structure of germinal center of lymph node; Synapses; T cell response; T-Lymphocyte; Therapeutic; Transcriptional Regulation; Vaccines; Viral; Viremia; antiretroviral therapy; base; cytotoxic; design; improved; killings; lymph nodes; perforin; peripheral blood; prevent; public health relevance; receptor; response; trafficking; trend; vaccine development

 DESCRIPTION (provided by applicant: Lymphoid tissue is the key site for the initial seeding, dissemination, and long-term maintenance of the HIV reservoir. As such, understanding those T cell properties and mechanisms required for control and elimination of HIV directly within lymphoid tissue are of critical importance to the HIV cure, eradication, and vaccine agenda. The central question underlying this proposal is whether HIV-specific CD8+ and CD4+ T cells in the lymph node (LN) have or can acquire the functional capabilities necessary to control or eliminate HIV infected cells. These studies are predicated on the concept that cytotoxic CD8+ (and CD4+) T cells are normally absent from the lymph node in HIV- subjects or those without underlying inflammatory conditions. Intuitively, this makes biological sense: why would cytotoxic T cells be wanted in a LN? Cytotoxic T cells (either CD8+ or CD4+) in the LN would function in part to eliminate antigen presenting cells, thereby dampening immune responses. However, in HIV infection, HIV vaccines, and especially HIV cure-based strategies, cytotoxic HIV- specific CD8+ T cells within the LN would be needed to control or eliminate virally infected CD4+ T cells. Our preliminary data show the presence of dysregulated perforin+ HIV-specific CD8+ T cells in the LN from chronically infected subjects, with very low expression of CXCR5, a marker required for entry into the lymphoid follicle, where HIV-infected CD4+ T cells are concentrated. Unexpectedly, antiretroviral therapy appears to reverse this, with heightened CXCR5 expression on LN CD8+ T cells, but lower levels of perforin. This is opposite of what one would want as the "kill" component of an HIV "shock and kill" cure strategy. Our findings overall indicate that LN CD8+ T cells have fundamentally different functional abilities compared to the conventional wisdom driving the HIV cure and vaccine field. These considerations suggest that were an effective anti-HIV cytolytic T cell response present, it would not target the LN HIV reservoir in the majority of HIV-infected people. To address these issues, we will examine LN T cell responses against HIV in subjects with progressive HIV infection, ART-treated HIV infection, and elite control of HIV infection. Our studies will provide critical information for therapeutic manipulation, engineering, or vaccine-mediated strategies designed to induce HIV-specific CD8+ T cells capable of homing to appropriate regions of the LN in order to eliminate HIV reservoirs. In Aim 1 we will define the effect of antiretroviral therapy on LN total and HIV-specifc CD8+ and CD4+ T cells compared to HIV infected chronic progressors and elite controllers. In Aim 2, we will determine whether LN- and PBMC-derived CD8+ and CD4+ T cells from ART-treated HIV-infected individuals have effective cytolytic activity. Finally, in Aim 3, we will determine the effect of ART on LN CD8+ and CD4+ HIV-specific T cell transcriptional regulation, activation, cytotoxic properties, and LN retention/egress markers after activation.

 描述（通过应用提供：淋巴组织是初始播种，传播和长期维持HIV储层的关键部位。因此，了解直接控制和消除HIV所需的T细胞特性和机制，直接在淋巴组织中，对HIV疗法+ CURE和PAGINA CODSASE+ CDECASE cDECASE IS cODSASE+ cDECSASE IS cODSASE+ TENS cODSASE y hiv是至关重要的。在淋巴结（LN）中，可以获得或消除受HIV感染细胞所必需的功能能力，即在HIV受试者中通常没有淋巴结中的淋巴结中的淋巴结，或者在没有炎症的情况下，这些研究通常没有淋巴结。 LN中的细胞毒性T细胞（CD8+或CD4+）将部分发挥作用以消除抗原呈递细胞，从而抑制免疫物质。然而，在HIV感染，HIV疫苗，尤其是基于HIV的基于HIV治疗的策略中，需要在LN内进行细胞毒性HIV特异性CD8+ T细胞，以控制或消除几乎被感染的CD4+ T细胞。我们的初步数据表明，来自慢性感染受试者的LN中存在失调的穿孔蛋白+ HIV特异性CD8+ T细胞，其中CXCR5的表达非常低，CXCR5是进入淋巴样犬种所需的标记，其中浓缩了HIV感染的HIV感染的CD4+ T细胞。出乎意料的是，抗逆转录病毒疗法似乎扭转了这一点，在LN CD8+ T细胞上的CXCR5表达升高，但穿孔素水平较低。这与人们想要作为艾滋病毒的“杀死”组成部分“震惊和杀死”治愈策略相反。我们的发现总体表明LN CD8+ T细胞与驱动HIV治疗和疫苗场的传统智慧相比具有根本不同的功能能力。这些考虑因素表明，这是存在有效的抗HIV细胞溶解T细胞反应，它不会针对大多数HIV感染者的LN HIV储量。为了解决这些问题，我们将检查针对HIV感染，ART治疗的HIV感染和对HIV感染的精英控制的受试者中针对HIV的LN T细胞反应。我们的研究将提供关键的信息，以提供旨在诱导HIV特异性CD8+ T细胞诱导能够将LN归入适当区域以消除HIV储层的热操作，工程或疫苗介导的策略。在AIM 1中，我们将定义抗逆转录病毒疗法对HIV感染的慢性进度者和精英控制器相比，抗逆转录病毒疗法对LN总和HIV特异性CD8+和CD4+ T细胞的影响。在AIM 2中，我们将确定来自ART治疗的HIV感染的个体的LN和PBMC衍生的CD8+和CD4+ T细胞是否具有有效的溶细胞活性。最后，在AIM 3中，我们将确定ART对LN CD8+和CD4+ HIV特异性T细胞转录调控，激活，细胞毒性特性以及激活后LN保留/出口标记的影响。