High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir

摘要 实现艾滋病毒持续缓解的战略必须以艾滋病毒感染细胞的长期宿主为目标。 这些储存库仍然是研究的一个挑战，因为它们只占免疫细胞的很小一部分，可以 位于难以采样的解剖部位(例如，中枢神经系统[CNS])，通常较少 在接受治疗中断的个体中得到了很好的研究。在这里，我们旨在回答三个关键问题 问题：(A)什么是克隆扩张、HIV-1感染细胞的激活和病毒反弹的驱动因素 时机-是病毒因素(如HIV-1整合位点)为受感染细胞提供生存益处，还是 它是驱动HIV-1增殖的宿主因素(如对抗原或HIV刺激的免疫反应)- 感染细胞和病毒在治疗中断后反弹(项目1)？(B)艾滋病毒-1感染细胞如何持续存在 并在外周血液和中枢神经系统的解剖避难所之间分配(项目2)？(C)感染HIV-1 根除策略，如广谱中和抗体(BNAbs)，对宿主免疫效应器进行重新编程 从转录、表观遗传和功能上的反应(项目3)？总体而言，我们的目标是了解 使用几种独特的方法对HIV-1持久性的扩张动力学、组织分布和反弹预测因子 临床队列和创新方法，为HIV-1持续和感染的机制提供关键见解 根除艾滋病毒-1的战略。我们将使用这些样本来定义支配自发的机制 HIV-1在治疗中断期间的重新激活和尽管有效的抗逆转录病毒治疗仍存在的病毒血症 治疗(ART)，特别是探索可能影响病毒维护和免疫的病毒和免疫机制 反弹(项目1)。我们专注于建立、持续、克隆增殖和反弹能力 在HIV-1脑宿主感染的不同阶段，一个至关重要的病毒庇护所一直是 挑战详细学习(项目2)。最后，我们探讨了影响病毒库的免疫机制。 宿主表观遗传学和免疫细胞功能在控制和修剪HIV-1中的动态和作用 人类首例广谱中和抗体背景下的前病毒前景(项目3)。这些项目 将由一个管理核心和一个数据分析和建模核心提供支持。 1

SUMMARY Strategies for achieving sustained HIV remission must target the long-lived reservoir of HIV-infected cells. These reservoirs remain a challenge to study because they make up a very small fraction of immune cells, can be located in difficult to sample anatomic sites (e.g., the central nervous system [CNS]), and are generally less well studied in individuals who undergo treatment interruption. Here we aim at answering three critical questions: (A) what are the drivers of clonal expansion, activation of HIV-1-infected cells, and viral rebound timing – is it viral factors (such as HIV-1 integration site) that provide survival benefit of the infected cells, or is it host factors (such as immune responses to antigen or HIV stimulation) that drive the proliferation of HIV-1- infected cells and viral rebound after treatment interruption (Project 1)? (B) How do HIV-1-infected cells persist and distribute between peripheral blood and the anatomical sanctuary of the CNS (Project 2)? (C) Do HIV-1 eradication strategies, such as broadly neutralizing antibodies (bnAbs), reprogram host immune effector responses, transcriptionally, epigenetically, and functionally (Project 3)? Overall, we aim at understanding the expansion dynamics, tissue distribution, and rebound predictors of HIV-1 persistence using several unique clinical cohorts and innovative methods to provide critical insight to mechanisms of HIV-1 persistence and strategies for HIV-1 eradication. We will use these samples to define the mechanisms that govern spontaneous HIV-1 reactivation during treatment interruption and the persistence of viremia despite effective antiretroviral therapy (ART), specifically exploring virus and immune mechanisms that may impact viral maintenance and rebound (Project 1). We focus on the establishment, persistence, clonal proliferation, and rebound competence in different stages of infection of HIV-1 brain reservoirs, a critically important virus sanctuary that has been a challenge to study in detail (Project 2). Lastly, we explore the immune mechanisms that impact virus reservoir dynamics and the role of host epigenetics and immune cell function in the control and pruning of the HIV-1 proviral landscape in the context of a first-in-human broadly neutralizing antibody (Project 3). These Projects will be supported by an Administrative Core and a Data Analytics & Modeling Core. 1