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

项目总结： 在HIV治疗中断中建立可靠的病毒反弹预测指标是加速 制定有效的艾滋病毒治疗和根除战略。这类预测指标的定义是， 然而，由于每个感染者的不同临床病史和不同水平的宿主，情况复杂 对病毒征收免疫力，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，理想情况下，病毒控制的免疫预测指标也应该在大多数情况下进行评估 先进和有效的疫苗策略可用于最大限度保持免疫力的个人 功能。在P01计划的项目1中，我们将利用进行了一系列临床试验的优势 从过去的、正在进行的和未来的治疗中断试验中提供了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相结合 约会。我们将利用这一特殊情况来检验人类白细胞抗原-E限制性T细胞反应影响 病毒库的活性和病毒反弹的动力学以及额外的宿主因素和病毒库 这些特征增强了这一效果。这一假设基于SIV模型中耐人寻味的数据，其中 Mamu-E限制性T细胞反应与疫苗介导的病毒控制有关，我们自己的 广泛的初步数据将包括人类白细胞抗原-E在内的关键宿主因子的表观遗传修饰与病毒联系起来 控制未经治疗的艾滋病毒感染。结合项目3的数据和猴子的验证实验 在项目2中，我们将解决强烈的人类白细胞抗原-E限制性反应是否不协调的问题 影响髓系和淋巴系贮存库，导致贮存库变化和病毒成分反弹。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 艾滋病毒治疗策略中病毒反弹的可能性。

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.