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

• 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
• 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

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时病毒反弹的可靠预测指标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战略。这些预测因子的定义是， 然而，由于每个感染个体的不同临床病史和宿主的可变水平， 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关键组成部分， 治疗议程，病毒控制的免疫预测因子理想情况下也应该在大多数情况下进行评估。 先进和有效的疫苗策略，并在最大限度地维持免疫的个体中 功能在P01项目的项目1中，我们将利用进行一系列临床试验的优势， 这些试验提供了来自过去、正在进行和未来的治疗中断试验的非常丰富的样本基础， 在某些情况下，与最具免疫原性和最有希望的治疗性候选疫苗组合， 约会我们将利用这一特殊情况来检验HLA-E限制性T细胞反应影响免疫应答的假设。 病毒库活性和病毒反弹的动力学，以及额外的宿主因子和病毒库 特性增强了这种效果。这一假设是基于SIV模型的有趣数据， Mamu-E限制性T细胞反应与疫苗介导的病毒控制有关，我们自己的研究表明， 广泛的初步数据将关键宿主因子（包括HLA-E）的表观遗传修饰与病毒 控制未经治疗的艾滋病毒感染。结合项目3和猴验证实验的数据 在项目2的模型中，我们将讨论强HLA-E限制性反应是否不一致的问题， 影响骨髓和淋巴储库，导致储库和反弹病毒组成的变化。如果 如果成功，预期的数据将建立成功的治疗性疫苗接种和有效控制的标志物 艾滋病治疗策略中的病毒反弹。