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

 描述：在接受高效抗逆转录病毒疗法(HAART)治疗的个人中控制艾滋病毒感染是降低慢性感染者死亡率和发病率的最有效手段。我们现在面临的挑战是从功能上治愈那些HAART抑制了艾滋病毒的人。对于我们目前的治疗策略，HAART治疗的个体中的HIV储存库仍然难以捉摸，因此新的策略现在专注于开发HIV特异性CD8 T细胞的内在潜力来靶向并杀死感染细胞，以便完全解决感染问题，或者至少在不使用HAART的情况下保持控制。为了利用HIV特异性CD8 T细胞的宿主库来达到治愈HIV感染者的目标， 我们必须开发一种策略，能够稳定地恢复不起作用的HIV特异性CD8 T细胞的活力，以便它们在扩增后重新获得并保留抗病毒功能。为了实现这一目标，我们开发了一项研究计划，重点是了解在耗尽的HIV特异性CD8T细胞中获得和维持获得性基因表达程序的机制。以下目标旨在识别稳定的表观遗传编程的目标基因，开发修改这些程序的方法以擦除HIV特异性CD8 T细胞的转录记忆，并以便于在与HIV抗原呈递细胞相遇期间有效的抗病毒反应的方式重新激活细胞。这项建议的具体目的是：目的1.确定在疲惫的HIV特异性CD8T细胞中基因表达程序的保存是否与转录调节区DNA甲基化的维持有关。A)确定在HAART介导的病毒控制后表观遗传保存的T细胞耗竭基因表达程序。B)从HAART治疗的捐献者中确定HIV特异性CD8 T细胞中表观遗传平衡的转录程序。目的2.鉴定在功能性HIV特异性CD8T细胞分化过程中获得的DNA甲基化程序。A)在精英控制员中确定针对功能性HIV特异性CD8 T细胞的DNA甲基化程序。B)确定EC HIV特异性CD8T细胞中的功能性DNA甲基化程序是否保存在其他慢性感染的病毒特异性CD8T细胞中。C)确定在HIV特异性CD8 T细胞进行性耗竭过程中功能甲基化程序丢失的分化阶段。目的3.确定链信号和PD-1信号阻断对HIV特异性CD8T细胞DNA甲基化重编程的调节是否能挽救HIV特异性CD8功能和杀伤。A)确定IL-15介导的耗尽CD8 T细胞的分化是否会导致基因调控的短期和长期可遗传变化。B)确定抑制PD-1参与是否增强了HIV特异性CD8 T细胞的DNA甲基化重编程。

 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.