Functional Assessment of CTL Anergy in HIV Infection

HIV 感染中 CTL 无反应性的功能评估

基本信息

批准号：
8795665
负责人：
OTTO O YANG
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8795665
关键词：
Address Agonist Antiviral Agents Autoimmunity Avidity CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular Immunity Chronic Containment Cytomegalovirus Cytotoxic T-Lymphocytes Disease Progression Down-Regulation Epigenetic Process Epitopes Failure Functional disorder Funding Mechanisms Generations Genetic Recombination HIV Infections HIV-1 Health Immune Immune response Immune system Immunity Immunotherapy Induced Mutation Infection Lymphocytic choriomeningitis virus Measures Mutation Organism Persons Physiological Plasmodium Process Production Property Receptor Signaling Regulatory T-Lymphocyte Reporting Role Signal Pathway Signal Transduction T cell response T-Cell Receptor T-Lymphocyte Testing Therapeutic Thymus Gland Vaccines Variant Viral anergy arm base coping cytokine design exhaustion high risk humanized SCID mouse in vivo mouse model mutant novel pathogen prevent response senescence success therapeutic vaccine

项目摘要

DESCRIPTION (provided by applicant): This proposal addresses a novel concept regarding the failure of cytotoxic T lymphocytes in the immunopathogenesis of HIV-1 infection. While scattered reports have suggested that there may be examples of epitope variation causing CTL "antagonism" or anergy, the phenomenon has been poorly understood and it has been impossible to determine the degree to which this process is sporadic or widespread. We present a novel hypothesis and build the case that HIV-1 epitope mutation causing anergy of responding CTLs may be a generalized process. Tapping into the growing understanding of anergy in general, we will explore the effect of anergy in CTL control of HIV-1. Our specific aims are: Aim 1: To demonstrate epitope variants that induce anergy in HIV-1-specific CTLs. HIV-1-specific TCRs from infected persons will be used to generate phenotypically normal CTLs by transducing normal CD8+ T cells. These CTLs will be screened functionally against epitope variants from the same persons to identify anergy-inducing mutants, with confirmation using HIV-1-infected cells. Aim 2: To demonstrate the functional impact of anergy-inducing variants within HIV-1 in vivo. A humanized SCID mouse model with HIV-1-specific TCR-transduced CTLs will be tested for anergy induction by infection with HIV-1 containing epitope mutations.

描述（由申请人提供）：该提案提出了一个关于细胞毒性 T 淋巴细胞在 HIV-1 感染的免疫发病机制中失败的新概念。虽然零散的报告表明可能存在导致 CTL“拮抗”或无反应的表位变异的例子，但人们对这种现象知之甚少，并且不可能确定该过程是零星的还是广泛的程度。我们提出了一个新的假设，并证明 HIV-1 表位突变导致 CTL 反应无反应可能是一个普遍的过程。随着人们对无反应性的了解不断加深，我们将探讨无反应性在 CTL 控制 HIV-1 中的作用。我们的具体目标是：目标 1：证明在 HIV-1 特异性 CTL 中诱导无反应性的表位变体。来自感染者的 HIV-1 特异性 TCR 将用于通过转导正常 CD8+ T 细胞来产生表型正常的 CTL。这些 CTL 将针对来自同一个人的表位变体进行功能性筛选，以识别无反应性诱导突变体，并使用 HIV-1 感染的细胞进行确认。目标 2：证明 HIV-1 内无反应性诱导变异在体内的功能影响。将测试具有 HIV-1 特异性 TCR 转导 CTL 的人源化 SCID 小鼠模型，以检测感染含有表位突变的 HIV-1 引起的无反应性。