Activation-induced Non-responsiveness causes HIV Prog.

激活引起的无反应会导致 HIV 进展。

基本信息

批准号：
7610904
负责人：
HELEN HORTON
金额：
$ 32.46万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7610904
关键词：
Acquired Immunodeficiency Syndrome Address Alleles Anti-Retroviral Agents Antigens Apoptosis Appearance Autologous Avidity Biological Assay CD8B1 gene Cell Maturation Cells Characteristics Chronic Clonal Expansion Color Data Disease Disease Progression Down-Regulation Epitopes Evolution Flow Cytometry Frequencies HIV HIV vaccine HIV-1 HLA-A3 Antigen HLA-B27 Antigen IL2 gene IL4 gene Immune Immune response In Vitro Individual Infection Infection Control Interferon Type II Interleukin-10 Interleukin-2 Lead Ligation Link MHC Class I Genes Measures Modeling Mus Mutation Peripheral Blood Mononuclear Cell Persons Phenotype Proliferating Proteins Proteomics Research Personnel Resistance Sampling Sorting - Cell Movement Specificity T-Cell Activation T-Lymphocyte TCR Activation Technology Testing Therapeutic Intervention Time Tumor Immunity Vaccination Viral Virus Virus Diseases Virus Replication anergy cell mediated lymphocytolysis test cytokine design in vivo longitudinal analysis pressure prevent programs prophylactic receptor response therapeutic vaccine

项目摘要

DESCRIPTION (provided by applicant): The immune correlates of protection against HIV-1 are unknown making rationale design of efficacious, prophylactic and therapeutic vaccines difficult. This proposal will investigate whether induction of Activation- Induced Non-Responsiveness (AINR) in HIV-specific CD8+T cells leads to disease progression in persons chronically infected with HIV-1. Our preliminary data show that chronic infection with HIV-1 leads to the induction of AINR in HIV-specific T cells. Furthermore, individuals who are controlling chronic HIV-1 infection (long term non-progressors, LTNP) possess HIV-specific T cells that are resistant to AINR. Thus, induction of AINR in HIV-specific CD8+ T cells may be the cause of loss of viral control and progression to AIDS. In Aim 1 we will characterize the functional phenotype of AINR CD8+ HIV-specific T cells to determine which effector functions (apart from proliferative ability) are compromised in the AINR sate using IFN-gamma ELISpot, polychromatic (11 color) flow cytometry and proteomics technologies. Furthermore, longitudinal analysis of these T cell responses throughout the course of infection will allow us to determine when AINR appears in the context of natural infection and whether appearance of AINR CD8+ T cells correlates with disease progression. In Aim 2, we will determine whether HIV-specific AINR CD8+ T cells are compromised in their ability to prevent viral replication using in vitro infectivity assays. We will ascertain whether the presence of AINR HIV-specific T cells in vivo influences viral evolution by sequencing regions of the autologous virus that correspond to epitopes recognized by AINR CD8+ T cells. In addition, we will attempt to reverse the AINR state and determine if this leads to enhanced control of viral infection. In Aim 3, we will identify factors that contribute to induction of AINR. Since the proposed studies will potentially characterize an immune correlate of protection from HIV-1 disease progression they will have far reaching implications on therapeutic intervention in chronically-infected individuals and rationale design of HIV vaccines.

描述（由申请人提供）：针对 HIV-1 的保护的免疫相关性尚不清楚，这使得有效、预防性和治疗性疫苗的基本原理设计变得困难。该提案将调查 HIV 特异性 CD8+T 细胞中激活诱导无反应 (AINR) 的诱导是否会导致慢性 HIV-1 感染者的疾病进展。我们的初步数据表明，HIV-1 的慢性感染会导致 HIV 特异性 T 细胞中 AINR 的诱导。此外，控制慢性 HIV-1 感染的个体（长期非进展者，LTNP）拥有对 AINR 具有抗性的 HIV 特异性 T 细胞。因此，HIV 特异性 CD8+ T 细胞中 AINR 的诱导可能是病毒失去控制和进展为 AIDS 的原因。在目标 1 中，我们将使用 IFN-gamma ELISpot、多色（11 色）流式细胞术和蛋白质组学技术来表征 AINR CD8+ HIV 特异性 T 细胞的功能表型，以确定 AINR 状态下哪些效应功能（增殖能力除外）受到损害。。此外，对整个感染过程中这些 T 细胞反应的纵向分析将使我们能够确定 AINR 在自然感染情况下何时出现，以及 AINR CD8+ T 细胞的出现是否与疾病进展相关。在目标 2 中，我们将使用体外感染性测定来确定 HIV 特异性 AINR CD8+ T 细胞阻止病毒复制的能力是否受到损害。我们将通过对与 AINR CD8+ T 细胞识别的表位相对应的自体病毒区域进行测序，确定体内 AINR HIV 特异性 T 细胞的存在是否影响病毒进化。此外，我们将尝试逆转 AINR 状态，并确定这是否会增强对病毒感染的控制。在目标 3 中，我们将确定有助于诱导 AINR 的因素。由于拟议的研究将潜在地描述预防 HIV-1 疾病进展的免疫相关性，因此它们将对慢性感染者的治疗干预和 HIV 疫苗的合理设计产生深远的影响。