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 实现持续HIV缓解的策略必须针对感染HIV感染细胞的长寿命库。 这些储层仍然是研究的挑战，因为它们构成了很小的免疫细胞，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人中进行了很好的研究。在这里，我们旨在回答三个关键 问题：（a）克隆扩张的驱动因素是什么，HIV-1感染细胞的激活以及病毒反弹 时机 - 是病毒因素（例如HIV-1整合位点），它提供了感染细胞的生存优势，还是 它宿主因素（例如对抗原或HIV刺激的免疫回应），这些因素驱动HIV-1-的增殖 治疗中断后感染的细胞和病毒反弹（项目1）？ （b）HIV-1感染的细胞如何持续 并分布在外围血和中枢神经系统的解剖学庇护所（项目2）之间？ （c）做HIV-1 根除策略，例如广泛中和抗体（BNAB），重编程宿主免疫效应子 响应，转录，表观遗传和功能（项目3）？总体而言，我们旨在了解 使用几种独特 临床人群和创新方法，以对HIV-1持久性机制和 消除HIV-1的策略。我们将使用这些样品来定义自发的机制 HIV-1在治疗中断期间的重新激活和拼命有效抗逆转录病毒的病毒血症的持久性 治疗（ART），专门探索可能影响病毒维持和的免疫力学 反弹（项目1）。我们专注于建立，持久性，克隆扩散和反弹能力 在HIV-1脑储层的不同阶段，这是一个至关重要的病毒保护区 详细研究的挑战（项目2）。最后，我们探索影响病毒储层的免疫机制 动力学以及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 在人类的第一范围内广泛中和抗体的背景下（项目3）。这些项目 将由管理核心和数据分析和建模核心支持。 1