Immunoregulatory networks and HIV pathogenesis

免疫调节网络和艾滋病毒发病机制

• 批准号: 8115205
• 负责人: Daniel E Kaufmann
• 金额: $ 43.67万
• 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/8115205
• 关键词: Acquired Immunodeficiency Syndrome; Address; Antigen-Presenting Cells; 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 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 response; T-Cell Proliferation; T-Lymphocyte; Up-Regulation; Viral Load result; Virus; base; design; exhaust; exhaustion; immune activation; 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）：CD4 T细胞反应缺陷与hiv感染者的疾病进展有关，而导致这种功能障碍的机制尚不清楚。一个基本的问题是，CD4 T细胞损伤是由于不可逆的功能丧失，还是受到抑制机制的控制，而抑制机制可能通过调节途径的操纵而恢复。最近的研究结果提供了证据，证明HIV+受试者中CD4功能的主要缺陷可能是可逆的：我们和其他人发现程序性死亡1 （PD-1）途径在体外T细胞功能障碍中起关键作用，并且在HIV感染者中，CD4 T细胞上PD-1的表达与疾病进展有关。我们发表的报告（PI是共同第一作者）和本应用程序的初步数据表明，通过阻断PD-1与其配体PD-L1的相互作用，可以恢复CD4 T细胞的增殖能力。此外，我们的初步数据显示，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。在这项应用中，我们建议阐明PD-1在HIV+受试者中HIV特异性CD4 T细胞增殖损伤中的作用。在Aim 1中，基于先前的CD4 T细胞表达PD-1与CD4计数和病毒载量相关的结果，我们将首先评估CD4 T细胞表达PD-1和CTLA-4在不同疾病阶段的HIV+受试者中的表达。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和分类hiv特异性CD4 T细胞群来定义PD-1low和PD-1high病毒特异性CD4 T细胞的表型和功能谱。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PD-1及其配体在肠道相关淋巴组织活检中的表达，并在各种细胞群和HIV感染细胞上鉴定这些分子。在Aim 2中，我们将确定CD4 T细胞功能障碍逆转的程度是否与两个参数相关：疾病状态和抑制受体的表达水平。初步数据与一种模型一致，即一些PD-L1+ apc亚群接受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Aim 3中，使用选择性消耗，我们将识别通过PD-1抑制CD4 T细胞增殖的HIV+受试者外周血中的APC亚群，并确定当PD1配体存在于非抗原负载细胞（反式）或仅作为抗原肽存在于同一细胞（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变得“耗尽”。我们正在研究导致这种衰竭的机制，并寻找恢复艾滋病毒感染者正常免疫功能的方法。