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）：该提案解决了一个新的概念，该概念涉及HIV-1感染的免疫发病发生中细胞毒性T淋巴细胞的失败。尽管散落的报告表明，可能存在引起CTL“拮抗”或反感的表位变化的例子，但这种现象的理解很差，并且无法确定该过程零星或广泛的程度。我们提出了一个新的假设，并建立了一种案例，即HIV-1表位突变引起反应CTL的反应可能是一个普遍的过程。一般来说，我们将探讨对Anergy日益增长的理解，我们将探讨Anergy在HIV-1控制中的影响。我们的具体目的是：目标1：展示诱导HIV-1特异性CTL中反感的表位变体。来自感染者的HIV-1特异性TCR将用于通过传输正常的CD8+ T细胞来产生表型正常的CTL。这些CTL将通过使用HIV-1感染的细胞进行确认，以鉴定同一人的表位变体的功能筛选。目标2：证明体内HIV-1内反应诱导变体的功能影响。具有HIV-1特异性TCR转导的CTL的人源化SCID小鼠模型将通过感染含有表位突变的HIV-1感染来测试是否诱导Anergy诱导。