Understanding and Reversing T Cell Dysfunction to Control and Eliminate Persistent HIV Reservoirs

了解和逆转 T 细胞功能障碍以控制和消除持续的 HIV 病毒库

• 批准号: 10523539
• 负责人: Bruce D Walker
• 金额: $ 42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-23 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523539
• 关键词: AIDS prevention; Address; Antigens; Binding; Biological Markers; Blood; Bone Marrow; CCR5 gene; CD8-Positive T-Lymphocytes; CXCR4 gene; Cell Therapy; Cells; Chronic; Clinical; Containment; Couples; Data; Development; Disease; Disease remission; Epigenetic Process; Epitopes; Evaluation; Functional disorder; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; HIV; HIV Infections; Heterogeneity; Immune response; Immunobiology; Immunotherapy; Impairment; In Situ; Individual; Infection; Intervention; Intrinsic factor; Knowledge; Lymphocyte Activation; Lymphocyte Function; Lymphoid Tissue; Maintenance; Malignant Neoplasms; Mediating; Mission; Molecular; Molecular Target; Monitor; Mutation; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Prevention; Prevention strategy; Provirus Integration; Public Health; Regulation; Regulatory Pathway; Research; Resolution; Risk; Sampling; Signal Transduction; Specimen; Systemic infection; Systems Biology; T-Cell Development; T-Lymphocyte; Therapeutic Intervention; Tissue Stains; Tissues; Transplantation; United States National Institutes of Health; Validation; Variant; Viral; Viral reservoir; Viremia; antiretroviral therapy; biobank; checkpoint receptors; chronic infection; clinical trial participant; combat; comparative; cost; cytotoxic CD8 T cells; epigenetic profiling; exhaustion; experimental study; human disease; immune activation; immune checkpoint; immune checkpoint blockade; improved; innovation; insight; multiple omics; novel; pharmacologic; posttranscriptional; predictive marker; prevent; rational design; response; restoration; specific biomarkers; success; superinfection; viral rebound

PROJECT SUMMARY Antiviral cytotoxic CD8+ T lymphocytes (CTLs) are critical for controlling viremia and are central to HIV cure/remission strategies. However, there is a fundamental gap in understanding the molecular determinants underlying the onset and persistence of HIV-specific CTL dysfunction in individuals who fail to control viremia, preventing strategies to restore CTL function for HIV prevention and durable remission. The objective of this application is to define molecular regulation and biomarkers of HIV-specific CTL dysfunction. Based upon strong preliminary evidence, we hypothesize that initiation of CTL dysfunction preceding loss of virologic control and maintenance of CTL dysfunction during antiretroviral therapy are mediated by cell-intrinsic mechanisms, identification of which will inform therapeutic interventions to combat HIV persistence. We will define regulatory mechanisms of CTL dysfunction using an integrative, multi-omics systems biology approach at intra-patient, antigen-specific, and single-cell resolution, and validate using gene editing for restoration of antiviral CTL function. The rationale of the proposed studies is that a more precise understanding of the molecular mechanisms governing durable versus failed CTL-mediated HIV control will be needed to advance CTL-based HIV cure strategies. Aim 1 will define mechanisms by which CTL dysfunction is initiated preceding breakthrough viremia in HIV controllers. Preliminary data demonstrate that a progressive loss of antiviral CTL function precedes viral rebound in patients who lose HIV control. Experiments in this aim will elucidate regulatory pathways governing the initiation of CTL dysfunction by evaluating changes in epigenetic, transcriptional, and post-transcriptional signatures using longitudinal specimens preceding loss of HIV control. Regulatory pathways will be disrupted using gene editing for mechanistic validation. Aim 2 will define mechanisms by which CTL dysfunction is maintained during pharmacologic HIV suppression and the extent to which function can be restored. Preliminary evidence indicates that CTL dysfunction is not restored by antiretroviral therapy or immune checkpoint blockade. Experiments in this aim will identify molecular mechanisms by which dysfunction is maintained in non-escaped HIV-specific CTLs during antiretroviral therapy using a multi-omics approach, and determine the extent to which CTL function can be restored by inhibition and gene editing of identified regulatory networks. This approach is innovative because it couples controlled intra-patient comparisons of epitope-specific CTLs by population and single-cell transcriptional, post-transcriptional, and epigenetic profiling with gene editing in primary cells to interrogate the molecular mechanisms that underlie HIV-specific CTL dysfunction. The proposed research is significant because it will provide the mechanistic groundwork for development and evaluation of interventions that aim to harness CTLs for eradication or functional cure of HIV infection.

项目摘要 抗病毒细胞毒性CD8+ T淋巴细胞（CTL）对于控制病毒血症至关重要，对HIV至关重要 治愈/缓解策略。但是，了解分子决定因素存在根本差距 在无法控制病毒血症的个体中，HIV特异性CTL功能障碍的发作和持久性的基础 防止策略恢复CTL功能以预防HIV和持久的缓解。这个目的 应用是定义HIV特异性CTL功能障碍的分子调节和生物标志物。基于强 初步证据，我们假设启动病毒学控制丧失之前的CTL功能障碍 抗逆转录病毒治疗期间CTL功能障碍的维持是由细胞中性机制介导的 识别其将为治疗干预措施提供依据，以打击艾滋病毒的持久性。我们将定义监管 CTL功能障碍的机制，使用患者内部的集成，多摩学系统生物学方法， 抗原特异性和单细胞分辨率，并使用基因编辑验证抗病毒病毒CTL 功能。提出的研究的理由是，对分子的更精确理解 控制耐用与失败的CTL介导的HIV控制的机制将需要基于CTL的HIV控制 艾滋病毒治愈策略。 AIM 1将定义CTL功能障碍在突破之前开始的机制 HIV控制器中的病毒血症。初步数据表明，抗病毒CTL功能的逐渐丧失 在失去艾滋病毒控制的患者中，先于病毒反弹。此目标的实验将阐明调节 通过评估表观遗传学，转录和 使用艾滋病毒控制损失之前的纵向标本的转录后特征。监管途径 使用基因编辑进行机理验证，将被破坏。 AIM 2将定义CTL的机制 在药物HIV抑制期间保持功能障碍以及功能的程度 恢复。初步证据表明，抗逆转录病毒疗法或免疫无法恢复CTL功能障碍 检查点封锁。此目标中的实验将确定功能障碍的分子机制 使用多摩学方法和 确定可以通过抑制和基因编辑来恢复CTL功能的程度 网络。这种方法具有创新性，因为它伴侣控制了表位特异性的患者内比较 人口和单细胞转录，转录后和表观遗传分析的CTL和基因编辑 在原代细胞中，询问HIV特异性CTL功能障碍的分子机制。这 拟议的研究很重要，因为它将为开发和 评估旨在利用CTL的干预措施，以消除或功能治愈HIV感染。