Epigenetic Regulation of T-cell Exhaustion During Treated Chronic HIV Infection

治疗慢性 HIV 感染期间 T 细胞耗竭的表观遗传调控

• 批准号: 8998914
• 负责人: Benjamin Alan Youngblood
• 金额: $ 42.4万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998914
• 关键词: Acute; Adoptive Transfer; Alleles; Antigen-Presenting Cells; Antigens; Antiviral Agents; Antiviral Response; Autologous; Biological Assay; Biological Preservation; Blocking Antibodies; CD8B1 gene; Cell Culture Techniques; Cells; Chronic; Coupled; Cytomegalovirus; DNA Methylation; DNA Modification Methylases; Epigenetic Process; Foundations; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Goals; HIV; HIV Antigens; HIV Infections; Health; Highly Active Antiretroviral Therapy; ID2 gene; Immune System Diseases; Immune response; Individual; Infection; Interleukin-15; Interleukin-2; Interleukin-7; Kinetics; Ligation; Maintenance; Measures; Mediating; Memory; Methods; Methylation; Molecular; Morbidity - disease rate; Nucleic Acid Regulatory Sequences; Peptides; Reporting; Research; Signal Transduction; Staging; T cell response; T-Lymphocyte; Therapeutic; Time; Transcriptional Regulation; Viral; Virus; cell killing; design; epigenetic regulation; exhaust; exhaustion; insight; killings; longitudinal analysis; mortality; novel; programs; promoter; research study; response; sample fixation; therapeutic vaccine; whole genome

 DESCRIPTION: Control of HIV infection in individuals treated with highly active antiretroviral therapy (HAART) is the most effective means for reducing mortality and morbidity of chronically infected individuals. We are now challenged with the goal of functionally curing individuals that have HAART suppressed HIV. The HIV reservoir in HAART treated individuals' remains elusive to our current therapeutic strategies so new strategies are now focused on exploiting the inherent potential of HIV-specific CD8 T cells to target and kill infected cells in order to fully resolve the infection or at least maintain control without the use of HAART. In order to utilize th host repertoire of HIV-specific CD8 T cells to achieve the goal of curing HIV infected individuals, we have to develop strategies that can stably rejuvenate nonfunctional HIV-specific CD8 T cells so that they re-acquire and retain antiviral functions after expansion. To achieve this goal, we have developed a research program that focuses on understanding the mechanism for acquisition and maintenance of acquired gene expression programs in exhausted HIV-specific CD8 T cells. The following aims are designed to identify genes that are targeted for stable epigenetic programming, develop methods for modifying these programs to erase the transcriptional memory of the HIV-specific CD8 T cell, and reactivate the cells in way that facilitates an effective antiviral response during encounter with an HIV-antigen presenting cell. The specific aims of this proposal are: Aim 1. To determine if gene expression program preservation in exhausted HIV-specific CD8 T cells is coupled to maintenance of DNA methylation at transcriptional regulatory regions. a) To identify T-cell exhaustion gene expression programs that are epigenetically preserved following HAART mediated viral control. b) To identify epigenetically poised transcriptional programs in HIV-specific CD8 T cells from HAART treated donors. Aim 2. To identify DNA methylation programs acquired during differentiation of functional HIV-specific CD8 T cells. a) To identify DNA methylation programs specific to functional HIV-specific CD8 T cells in elite controllers. b) To determine if the functional DNA methylation program in EC HIV-specific CD8 T cells is preserved in virus-specific CD8 T cells from other chronic infections. c) To identify the stage of differentiation whe the functional methylation program is lost during progressive exhaustion of HIV-specific CD8 T cells. Aim 3. To determine if modulation of DNA methylation reprogramming of HIV-specific CD8 T cells by - chain signaling and PD-1 signal blockade rescues HIV specific CD8 function and killing. a) To determine if IL-15 mediated differentiation of exhausted CD8 T cells results in short and long term heritable changes in gene regulations. b) To determine if inhibition of PD-1 engagement enhances DNA methylation re- programming of HIV-specific CD8 T cells.

 描述：用高度活跃的抗逆转录病毒（HAART）治疗的螺旋菌是最有效的减少疗法的方法。 HAART治疗的个体仍然难以捉摸我们的策略，因此新策略集中在HIV特异性CD8 T细胞靶向和杀死感染细胞的潜力上，以使感染完全解决感染或至少保持控制，而无需使用一半。为了达到HIV特异性CD8 T细胞，以实现固化HIV HIV HIV HIV HIV HIV固化的目标 我们必须制定能够稳定的稳定的非功能性CD8 T细胞，因此它们会在扩展中重新启用抗病毒功能，以实现这一目标。细胞旨在识别基因靶向表观遗传编程，开发用于将程序修改为HIV特异性CD8 T细胞的转录记忆提案的MS是：确定在耗尽的HIV特异性CD8 T细胞中的基因表达程序是在转录调节区域维持DNA甲基化的CD8。 。 The Stage of ONWHE THE THE THE THE THE THE THYLAM IS LOST DURING PURING PROGRESSIVE EXHAUSTION OF HIV-SPECIFIC CD8 T CELLS. AIM 3. To Determine IF METHYLATION OF HIV-SPECIFIC CD8-CHAIN ​​Signaling and PD-1 Signal Blockade RESCUES IFIC CD8功能和杀戮。