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

 产品说明：在接受高效抗逆转录病毒疗法（HAART）治疗的个体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功能性治愈HAART抑制HIV的个体。HAART治疗的个体中的HIV储库对于我们目前的治疗策略来说仍然是难以捉摸的，因此新的策略现在集中于利用HIV特异性CD 8 T细胞的固有潜力来靶向和杀死感染的细胞，以便完全解决感染或至少在不使用HAART的情况下保持控制。为了利用HIV特异性CD 8 T细胞的宿主库来实现治愈HIV感染个体的目标， 我们必须开发出一种策略，可以稳定地恢复无功能的HIV特异性CD 8 T细胞，使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，我们开发了一个研究项目，重点是了解在耗尽的HIV特异性CD 8 T细胞中获得和维持获得性基因表达程序的机制。以下目的旨在鉴定针对稳定的表观遗传编程的基因，开发用于修改这些程序以消除HIV特异性CD 8 T细胞的转录记忆的方法，并以在与HIV抗原呈递细胞相遇期间促进有效抗病毒应答的方式重新激活细胞。本提案的具体目标是：目标1。确定耗尽的HIV特异性CD 8 T细胞中的基因表达程序保存是否与转录调控区的DNA甲基化维持相关联。a）鉴定在HAART介导的病毒控制后表观遗传学上保留的T细胞耗竭基因表达程序。B）鉴定来自HAART处理的供体的HIV特异性CD 8 T细胞中的表观遗传学平衡转录程序。目标二。鉴定HIV特异性CD 8 T细胞分化过程中获得的DNA甲基化程序。a）鉴定精英控制者中对功能性HIV特异性CD 8 T细胞特异的DNA甲基化程序。B）确定EC HIV特异性CD 8 T细胞中的功能性DNA甲基化程序是否保留在来自其他慢性感染的病毒特异性CD 8 T细胞中。c）鉴定在HIV特异性CD 8 T细胞进行性耗竭期间功能性甲基化程序丧失的分化阶段。目标3：确定通过β-链信号传导和PD-1信号阻断调节HIV特异性CD 8 T细胞的DNA甲基化重编程是否挽救HIV特异性CD 8功能和杀伤。a）确定IL-15介导的耗尽的CD 8 T细胞的分化是否导致基因调控的短期和长期可遗传变化。B）确定PD-1接合的抑制是否增强HIV特异性CD 8 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.