Epigenetic Control of CD8 T-Cell Differentiation in Human Lymph Nodes

人类淋巴结 CD8 T 细胞分化的表观遗传控制

• 批准号: 9767954
• 负责人: Zaza Mtine Ndhlovu
• 金额: $ 14.47万
• 依托单位: KWAZULU-NATAL RESEARCH INSTITUTE TB-HIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-07 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767954
• 关键词: ATAC-seq; Accounting; Acute; Address; Adherence; Animals; Area; B-Lymphocytes; BLR1 gene; Binding; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Caring; Cells; Chromatin; Chronic; Chronic Disease; DNA; Data; Detection; Development; Education; Epidemic; Epigenetic Process; Exclusion; Failure; Female; Flow Cytometry; Foundations; Frequencies; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; HIV; HIV Infections; HIV-1; Health; Heart; Helper-Inducer T-Lymphocyte; High-Throughput Nucleotide Sequencing; Home environment; Human; Image; Immune; Immune response; Immune system; Immunotherapeutic agent; In Vitro; Individual; Infection; Interleukin-12; Interleukin-15; Interruption; Intervention; Knowledge; Lead; Life; Logistics; Longitudinal cohort; Lymph Node Tissue; Lymph node excision; Lymphoid Tissue; MADH4 gene; Mediating; Methods; Molecular; Molecular Conformation; Monitor; Mus; Oral; Persons; Phenotype; Plasma; Population; Problem Solving; RNA; Regulation; Sampling; Site; Source; South Africa; Structure of germinal center of lymph node; T cell differentiation; TCF Transcription Factor; TCF3 gene; Testing; Tissues; Transcription Initiation Site; Transforming Growth Factor beta; Transposase; Tumor-infiltrating immune cells; Ursidae Family; Viral Load result; Viremia; Virus; antiretroviral therapy; base; cell motility; chemokine receptor; chronic infection; cohort; cost; cytokine; cytotoxic; differential expression; epigenetic drug; epigenome; follow-up; genome-wide; human tissue; immune clearance; immune function; innovation; interleukin-23; lymph nodes; novel; novel strategies; pill; pre-exposure prophylaxis; preservation; programs; recruit; repository; transcription factor; transcriptome sequencing; transmission process; treatment program; young woman

PROJECT SUMMARY The development of potent antiretroviral therapies, now delivered as a single pill once a day, has transformed HIV infection into a chronic disease. Globally, over 19 million people are now on life-long treatment, and test- and-treat strategies as was well as oral PrEP have the ability to further reduce HIV transmissions. However, despite these remarkable advances, prolonged ART mediated suppression of plasma viral loads to undetectable levels does not eradicate the virus, which rapidly rebounds upon treatment interruption. The many logistical limitations and cost challenges that come with providing life-long care to those living with HIV highlights the need for novel strategies of controlling the virus in the absence of therapy. Emerging data indicate that lymph nodes are a major source of HIV persistence during ART mainly because infected T follicular helper cells are protected from immune elimination due to partial exclusion of cytotoxic CD8 T cells (CTL) from germinal centers (GC). The molecular mechanisms that regulate CXCR5 expression which allows CTL migration into GCs are not known, mainly due to the difficulty associated with obtaining lymph node samples for such studies. Through innovative recruitment strategies, we have now solved this problem. We propose to use stored lymph node samples obtained from persons identified and treated at the onset of plasma viremia, in many when plasma viral loads are less than 1,000 RNA copies/ml to investigate why CTLs are largely excluded from GCs. Our preliminary ATAC-Seq studies suggest that CXCR5 expression on lymph node CTLs is epigenetically regulated. To follow up on this observation we propose to conduct chromatin accessibility analysis and transcriptional profiling of sorted HIV-specific CD8 T cells to identify epigenetic mechanisms that regulate CXCR5 expression. Our experimental approach will involve pairwise chromatin accessibility and transcription analysis of sorted follicular and extrafollicular HIV-specific CD8 T cells. This strategy will help to identify novel epigenetic and transcription factors that are different between the two populations. Finally, we will manipulate some of the differentially expressed genes using exogenous agents namely cytokines and epigenetic modifying drugs to determine the optimal conditions to induce CXCR5 expression on CD8 T cells. Our results will lead to novel strategies for redirecting CTL to follicular areas where they are needed to kill HIV infected cells. If successful, our studies will lead to novel strategies for redirecting CTL to follicular areas to eradicate HIV infection as part of a cure strategy.

项目总结