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.

项目摘要：在HIV治疗中断中建立可靠的病毒反弹预测指标是加速的先决条件开发有效的HIV治疗和消除策略。此类预测指标的定义是，但是，每个受感染个体的临床历史和宿主的可变水平都复杂化由于治疗性疫苗接种被认为是艾滋病毒的关键成分，因此对病毒征收免疫力治疗议程，理想情况下，也应在最多的背景下评估病毒控制的免疫预测因子可用的先进和有效的疫苗策略以及具有最大维护免疫力的个体功能。在该P01计划的项目1中，我们将利用进行一系列临床试验的优势从过去，正在进行的和将来的治疗中断试验中提供了一个非常丰富的样本基础，在某些情况下，与最有前途和最有前途的治疗疫苗候选相结合日期。我们将利用这种特权情况来检验HLA-E限制T细胞反应影响的假设病毒储层活性和病毒反弹的动力学以及其他宿主因素和病毒储层特征增强了这种效果。该假设基于SIV模型的有趣数据，其中 MAMU-E受限的T细胞反应与疫苗介导的病毒控制有关，我们自己广泛的初步数据将关键宿主因子（包括HLA-E）与病毒的表观遗传修饰联系起来控制未治疗的HIV感染。以及来自项目3的数据和猴子中的验证实验项目2中的模型，我们将解决强大HLA-E是否不同意限制响应的问题影响髓样和淋巴样储层，导致储层变化和反弹病毒组成。如果成功，预期的数据将建立成功的治疗疫苗和有效控制的标志物艾滋病毒治疗策略中的病毒反弹。