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

HIV 储存库持续性和扰动的高清表征

• 批准号: 10654759
• 负责人: Ya-Chi Ho
• 金额: $ 172.18万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654759
• 关键词: Address; Aftercare; Anatomy; Antigens; Autopsy; Binding; Blood; Blood specimen; Brain; Cell physiology; Cell surface; Cells; Central Nervous System; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Clonal Expansion; Clonality; Competence; Data Analytics; Dimensions; Disease remission; Drug or chemical Tissue Distribution; Epigenetic Process; Evolution; Frequencies; Genetic Transcription; HIV; HIV Infections; HIV-1; Immune; Immune response; Immune system; Individual; Infection; Integration Host Factors; Interruption; Maintenance; Methods; Neurobiology; Participant; Peripheral; Population; Proliferating; Proteome; Proviruses; Research Personnel; Resolution; Role; Sampling; Techniques; Therapeutic Intervention; Tissues; Transcriptional Activation; Viral; Viral reservoir; Viremia; Virus; antiretroviral therapy; brain cell; cohort; data modeling; epigenome; first-in-human; fitness; immune function; innovation; insight; integration site; mathematical model; neutralizing antibody; novel; peripheral blood; pressure; programs; response; transcriptome; viral rebound; virology

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

概括 实现艾滋病毒持续缓解的策略必须针对艾滋病毒感染细胞的长寿命储存库。 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一小部分，可以 位于难以采样的解剖部位（例如中枢神经系统 [CNS]），并且通常较少 在接受治疗中断的个体中进行了深入研究，我们旨在回答三个关键问题。 问题：(A) 克隆扩增、HIV-1 感染细胞激活和病毒反弹的驱动因素是什么 时机 – 是病毒因素（例如 HIV-1 整合位点）为受感染细胞提供了生存益处，还是 它承载着驱动 HIV-1- 增殖的因素（例如对抗原或 HIV 刺激的免疫反应） 感染细胞和治疗中断后病毒反弹（项目 1）？(B) HIV-1 感染细胞如何持续存在？ 并在外周血和中枢神经系统的解剖保护区之间分布（项目 2）（C）HIV-1 存在吗？ 根除策略，例如广泛中和抗体（bnAb）、重新编程宿主免疫效应子 总体而言，我们的目标是了解转录、表观遗传和功能方面的反应（项目 3）。 使用几种独特的方法来预测 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 持久性机制提供重要见解 我们将使用这些样本来定义自发控制的机制。 尽管使用有效的抗逆转录病毒药物，治疗中断期间 HIV-1 重新激活以及病毒血症持续存在 疗法（ART），专门探索可能影响病毒维持和治疗的病毒和免疫机制 反弹（项目 1）。 HIV-1脑储存库是一个极其重要的病毒避难所，在感染的不同阶段 详细研究的挑战（项目 2）最后，我们探索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 HIV-1 控制和修剪中的动力学和作用 首个人类广泛中和抗体背景下的前病毒景观（项目 3）。 将得到管理核心和数据分析和建模核心的支持。 1