Immunoregulatory networks and HIV pathogenesis

免疫调节网络和艾滋病毒发病机制

• 批准号: 7339459
• 负责人: Daniel E Kaufmann
• 金额: $ 44.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339459
• 关键词: Acquired Immunodeficiency Syndrome; Address; Antigen-Presenting Cells; Antigens; Antiviral Agents; Biopsy; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Defect; Disease; Disease Progression; Functional disorder; Gut associated lymphoid tissue; HIV; HIV Antigens; HIV Infections; Immune; Immune System Diseases; Immune response; Immune system; Immunotherapy; Impairment; In Vitro; Individual; Infection; Laboratories; Ligands; Mediating; Modeling; Mus; Pathogenesis; Pathway interactions; Peptides; Peripheral Blood Mononuclear Cell; Persons; Play; Population; Publishing; Regulatory Pathway; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Sorting - Cell Movement; Staging; T-Cell Proliferation; T-Lymphocyte; Up-Regulation; Viral Load result; Virus; base; design; exhaust; exhaustion; immune function; loss of function; peripheral blood; programs; prophylactic; receptor; response; therapeutic vaccine

DESCRIPTION (provided by applicant): Defective CD4 T cell responses are associated with disease progression in HIV-infected persons, and the mechanisms responsible for this dysfunction are poorly understood. A fundamental question is whether CD4 T cell impairment is due to an irreversible loss of functions or under control of inhibitory mechanisms that may be reverted by manipulation of regulatory pathways. Recent findings provide evidence that major defects in CD4 function in HIV+ subjects may be reversible: we and others showed that the Programmed Death 1 (PD-1) pathway plays a key role in T cell dysfunction in vitro, and that in persons with HIV infection, PD-1 expression on CD4 T cells is associated with disease progression. Our published report, for which the PI is the co-first author, and preliminary data in this application demonstrate that CD4 T cell proliferative capacity can be restored by blocking the interaction of PD-1 with its ligand PD-L1. In addition, our preliminary data show that expression of another inhibitory receptor, CTLA-4, is also a marker for reversible CD4 T cell dysfunction. In this application, we propose to elucidate the role of PD-1 in the impairment of HIV-specific CD4 T cell proliferation in HIV+ subjects. In Aim 1, building on previous results correlating PD-1 expression by CD4 T cells with CD4 count and viral load, we will first assess expression by CD4 T cells of PD-1 and CTLA-4 in HIV+ subjects at various stages of disease. To determine the effect of varying levels of inhibitory molecule expression on T cell function, we will use quantitative RT-PCR and sorted HIV-specific CD4 T cell populations to define the phenotypic and functional profile of PD-1low and PD-1high virus-specific CD4 T cells. Given that involvement of gut-associated lymphoid tissue (GALT) is central to HIV pathogenesis, we will also assess the expression of PD-1 and its ligands in biopsies of gut-associated lymphoid tissue, and identify these molecules on various cell populations and on HIV-infected cells. In Aim 2, we will determine whether there is a correlation between the degree to which CD4 T cell dysfunction can be reversed and two parameters: disease status, and level of expression of inhibitory receptors. Preliminary data are consistent with a model in which some PD-L1+ subsets of APCs take up HIV antigen and present it to HIV-specific T cells in a manner that inhibits efficient proliferation. In Aim 3, using selective depletion, we will identify APC subsets in peripheral blood of HIV+ subjects that inhibit CD4 T cell proliferation via PD-1, and determine whether PD1 ligand can alter HIV-specific CD4 T cell function when present on non-antigen-loaded cells (in trans) or only if presented on the same cell as antigenic peptide (in cis). Our previous studies have shown that cells of the immune system become "exhausted" in people infected with HIV. We are studying the mechanisms responsible for this exhaustion and looking for ways to restore normal immune function in HIV-infected persons.

描述（由申请人提供）：有缺陷的 CD4 T 细胞反应与 HIV 感染者的疾病进展相关，而造成这种功能障碍的机制知之甚少。一个基本问题是 CD4 T 细胞损伤是否是由于不可逆的功能丧失造成的，或者是由于受到抑制机制的控制而导致的，而抑制机制可以通过操纵调节途径来恢复。最近的研究结果提供了证据，表明 HIV+ 受试者中 CD4 功能的主要缺陷可能是可逆的：我们和其他人表明，程序性死亡 1 (PD-1) 通路在体外 T 细胞功能障碍中发挥着关键作用，并且在 HIV 感染者中，CD4 T 细胞上的 PD-1 表达与疾病进展相关。我们发表的报告（PI 是该报告的共同第一作者）和本申请中的初步数据表明，可以通过阻断 PD-1 与其配体 PD-L1 的相互作用来恢复 CD4 T 细胞的增殖能力。此外，我们的初步数据表明，另一种抑制性受体 CTLA-4 的表达也是可逆性 CD4 T 细胞功能障碍的标志物。在本申请中，我们建议阐明 PD-1 在 HIV+ 受试者中 HIV 特异性 CD4 T 细胞增殖受损中的作用。在目标 1 中，基于先前将 CD4 T 细胞的 PD-1 表达与 CD4 计数和病毒载量相关联的结果，我们将首先评估处于不同疾病阶段的 HIV+ 受试者中 CD4 T 细胞的 PD-1 和 CTLA-4 表达。为了确定不同水平的抑制分子表达对 T 细胞功能的影响，我们将使用定量 RT-PCR 和分选的 HIV 特异性 CD4 T 细胞群来定义 PD-1low 和 PD-1high 病毒特异性 CD4 T 细胞的表型和功能特征。鉴于肠道相关淋巴组织 (GALT) 的参与是 HIV 发病机制的核心，我们还将评估肠道相关淋巴组织活检中 PD-1 及其配体的表达，并在各种细胞群和 HIV 感染细胞上鉴定这些分子。在目标 2 中，我们将确定 CD4 T 细胞功能障碍可逆转的程度与两个参数（疾病状态和抑制性受体的表达水平）之间是否存在相关性。初步数据与模型一致，其中一些 APC 的 PD-L1+ 亚群吸收 HIV 抗原，并以抑制有效增殖的方式将其呈递给 HIV 特异性 T 细胞。在目标 3 中，我们将使用选择性耗竭技术，鉴定 HIV+ 受试者外周血中通过 PD-1 抑制 CD4 T 细胞增殖的 APC 亚群，并确定当 PD1 配体存在于非抗原负载细胞（反式）或仅与抗原肽存在于同一细胞上（顺式）时，是否可以改变 HIV 特异性 CD4 T 细胞功能。 我们之前的研究表明，感染艾滋病毒的人的免疫系统细胞会变得“疲惫不堪”。我们正在研究造成这种衰竭的机制，并寻找恢复艾滋病毒感染者正常免疫功能的方法。