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: 10308059
• 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/10308059
• 关键词: AIDS prevention; Address; Antigens; 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; 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; Pharmacology; Population; Prevention; Prevention strategy; Proviruses; Public Health; Regulation; Regulatory Pathway; Research; Resolution; Risk; Sampling; Seeds; 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 reservoir; Viremia; antiretroviral therapy; base; 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; 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.

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.