Role of host factors and HLA-E T cell immunity in HIV rebound kinetics

宿主因素和 HLA-E T 细胞免疫在 HIV 反弹动力学中的作用

基本信息

批准号：
9332147
负责人：
CHRISTIAN BRANDER
金额：
$ 22.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-19 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332147
关键词：
Address Adenoviruses Affect Aftercare Anti-Retroviral Agents Antigens Biological Biological Markers Cells Characteristics Clinical Clinical Research Clinical Trials Complement DNA Data Dependence Development Epigenetic Process Epitope Mapping Exhibits Future Genetic Genome HIV HIV Infections HIV vaccine HIV-1 Human Human immunodeficiency virus test Immune Immunity Immunologic Factors Immunologics In Vitro Individual Infection Integration Host Factors Interruption Kinetics Link Lymphoid Macaca Measures Mediating Methylation Modeling Modification Monkeys Myelogenous Pan Genus Pattern Phase II Clinical Trials Phenotype Placebo Control Program Research Project Grants Recording of previous events Recrudescences Reporting Role SIV Sampling Series Surface T cell response T-Lymphocyte Testing Therapeutic Vaccination Vaccines Validation Viral Viral Load result Viral reservoir Virus Work base cell type cohort cytokine epigenetic regulation exhaustion experimental study immune function immunogenic in vivo methylome novel response successful intervention therapeutic vaccine transcriptome transcriptomics unnecessary treatment vaccine candidate vaccine trial vector viral rebound virology

项目摘要

Project summary: Establishing reliable predictors of viral rebound in HIV treatment interruption is a prerequisite to accelerating the development of effective HIV cure and eradication strategies. The definition of such predictors is, however, complicated by the diverse clinical histories of each infected individual and the variable levels of host immunity levied against the virus, As therapeutic vaccination is considered a critical component of the HIV cure agenda, immune predictors of virus control should ideally also be assessed in the context of the most advanced and potent vaccine strategies available and in individuals with maximally maintained immune function. In Project 1 of this P01 program we will take advantage of having conducted a series of clinical trials that provide an extraordinarily rich sample base from past, ongoing and future treatment interruption trials that, in some cases, are combined with the most immunogenic and promising therapeutic vaccine candidates to date. We will use this privileged situation to test the hypothesis that HLA-E restricted T cell responses impact viral reservoir activity and the kinetics of viral rebound and that additional host factors and viral reservoir characteristics enhance this effect. The hypothesis is based on intriguing data from the SIV model, where Mamu-E restricted T cell responses have been implicated in vaccine-mediated virus control, and our own extensive preliminary data linking epigenetic modification of critical host factors, including HLA-E, to viral control in untreated HIV infection. Together with data from Project 3 and validation experiments in monkey models in Project 2, we will address the question of whether strong HLA-E restricted responses discordantly affect myeloid and lymphoid reservoirs that leads to changes in reservoir and rebounding virus composition. If successful, the expected data will establish markers of successful therapeutic vaccination and effective control of viral rebound in HIV cure strategies.

项目概要：建立艾滋病毒治疗中断期间病毒反弹的可靠预测因素是加速艾滋病毒治疗的先决条件制定有效的艾滋病毒治疗和根除策略。此类预测变量的定义是，然而，由于每个感染者的不同临床病史和宿主水平的不同，情况变得更加复杂针对病毒的免疫力，因为治疗性疫苗接种被认为是艾滋病毒的重要组成部分治愈议程，理想情况下，病毒控制的免疫预测因素也应该在最严重的背景下进行评估先进且有效的疫苗策略可用于最大程度维持免疫的个体功能。在此 P01 计划的项目 1 中，我们将利用已进行的一系列临床试验提供了来自过去、正在进行和未来的治疗中断试验的极其丰富的样本库，在某些情况下，与最具免疫原性和最有希望的治疗性疫苗候选物相结合日期。我们将利用这种特殊情况来检验 HLA-E 限制 T 细胞反应影响的假设病毒库活性和病毒反弹动力学以及其他宿主因素和病毒库特性增强了这种效果。该假设基于 SIV 模型中有趣的数据，其中 Mamu-E 限制性 T 细胞反应与疫苗介导的病毒控制有关，而我们自己的将关键宿主因子（包括 HLA-E）的表观遗传修饰与病毒联系起来的大量初步数据控制未经治疗的艾滋病毒感染。结合项目 3 的数据和猴子验证实验在项目 2 中的模型中，我们将解决强 HLA-E 限制反应是否不一致的问题影响骨髓和淋巴储库，导致储库变化和病毒成分反弹。如果成功，预期数据将建立成功治疗性疫苗接种和有效控制的标志 HIV治疗策略中病毒反弹的影响。