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: 10469108
• 负责人: Ya-Chi Ho
• 金额: $ 173.94万
• 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/10469108
• 关键词: Address; Aftercare; Anatomy; Antigens; Autopsy; Blood; Blood specimen; Brain; Cell physiology; Cell surface; Cells; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Trials; Clonal Expansion; Clonality; Competence; Data Analytics; 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; Lead; Maintenance; Methods; Neuraxis; Neurobiology; Participant; Peripheral; Population; 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; 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

总结 实现艾滋病毒持续缓解的战略必须针对艾滋病毒感染细胞的长寿库。 这些储库仍然是研究的一个挑战，因为它们构成免疫细胞的一小部分， 位于难以取样的解剖部位（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充分研究。在这里，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-是病毒因子（如HIV-1整合位点）提供感染细胞的存活益处，还是 它的宿主因子（如对抗原或HIV刺激的免疫反应）驱动HIV-1的增殖， 治疗中断后感染细胞和病毒反弹（项目1）？(B)HIV-1感染细胞如何持续存在 分布在外周血和中枢神经系统的解剖保护区之间（项目2）？(C)做HIV-1 根除策略，如广泛中和抗体（bnAbs），重编程宿主免疫效应物 反应，转录，表观遗传学和功能（项目3）？总的来说，我们的目标是了解 扩张动力学，组织分布和HIV-1持久性的反弹预测，使用几个独特的 临床队列和创新方法，为HIV-1持续存在的机制提供重要见解， 艾滋病毒-1根除战略。我们将使用这些样本来定义自发的机制， 治疗中断期间HIV-1再活化和尽管抗逆转录病毒有效但病毒血症持续存在 抗逆转录病毒疗法（ART），特别是探索可能影响病毒维持和 反弹（项目1）。我们着重于建立，持续，克隆增殖，和反弹能力 在HIV-1脑储库感染的不同阶段，这是一个至关重要的病毒避难所， 详细研究的挑战（项目2）。最后，我们探讨了影响病毒库的免疫机制 动态和宿主表观遗传学和免疫细胞功能在HIV-1的控制和修剪中的作用 第一次在人类广泛中和抗体的背景下的前病毒景观（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