Epigenetic Control of the CD8+ T-cell Response to HIV

描述(由申请人提供)：总体目标是确定抗病毒CD8+T细胞的特性，这些特性应由HIV-1疫苗(预防和治疗)激发，或作为HIV-1治愈的治疗策略的一部分而激发。CD8+T细胞在“病毒控制者”中维持对HIV-1病毒血症的长期控制，病毒控制者被定义为HIV-1感染患者在不治疗的情况下自然能够控制病毒复制。在HIV-1CD8+T细胞中表达的几个基因已被鉴定为与控制者的HIV-1抑制相关或介导。然而，基因表达的调节以及介导CD8+T细胞的HIV抑制活性的全部基因谱系尚不清楚。目前对CD8+T细胞抗病毒应答知识的这一空白限制了开发有效疫苗和根治疗法的能力，这些疫苗和治疗方法可以利用CD8+T细胞介导的抗病毒机制提供的免疫保护。 Tomaras实验室此前发现，抗病毒CD8+T细胞介导的反应受表观遗传机制调节，为诱导有效的CD8+T细胞介导的HIV-1抑制提供了新的范式。此外，我们的实验室发现，HIV-1疫苗诱导的CD8+T细胞介导的HIV-1抑制作用在记忆细胞亚群中发现了最大的活性。综上所述，这些数据表明，表观遗传学在调节CD8+T细胞对HIV的记忆反应中发挥了作用，当遇到HIV-1抗原时，允许转录机制访问适当的基因。该项目主要建立在最近发表的工作的基础上，使用CD8+T细胞病毒抑制分析、流式细胞术和细胞分类的创新组合策略，以及分子技术来确定在CD8+T细胞反应中发挥作用的基因和表观遗传调节机制。为了实现这一目标，将检测从同一患者中分离出来的具有和不具有活性的CD8+T细胞的表观遗传标记和基因表达。该项目的完成将提供关键数据，从而能够识别自然控制HIV-1感染的患者(病毒控制者)中功能最强的CD8+T细胞的基因表达谱和表观遗传机制。

DESCRIPTION (provided by applicant): The overall goal is to define the properties of anti-viral CD8+ T-cells that should be elicited by an HIV-1 vaccine (preventative and therapeutic) or elicited as part of a therapeutic strategy for an HIV-1 cure. CD8+ T-cells maintain long-term control of HIV-1 viremia in "virus controllers", defined as HIV-1 infected patients naturally able o control virus replication without therapy. Several genes expressed in HIV-1 CD8+ T-cells have been identified as correlating or mediating HIV-1 inhibition in controllers. However, the regulation of gene expression as well as the full repertoire of genes that mediate CD8+ T-cells' HIV inhibitory activity are unknown. This gap in the current knowledge of CD8+ T-cell antiviral responses limits the ability to develop efficacious vaccines and curative therapies that can harness the immunological protection provided by CD8+ T-cell mediated antiviral mechanisms. The Tomaras lab previously found that the antiviral CD8+ T-cell mediated response is modulated by epigenetic mechanisms, providing a new paradigm for the induction of effective CD8+ T-cell mediated inhibition of HIV-1. Moreover, our lab identified that HIV-1 vaccination elicits CD8+ T-cell mediated HIV-1 inhibition with the greatest activity found in memory cell subpopulations. Taken together, these data indicate epigenetics play a role in mediating the memory CD8+ T-cell response to HIV by allowing the transcriptional machinery access to appropriate genes when HIV-1 antigens are encountered. This project builds significantly upon recently published work using the innovative combined strategies of CD8+ T-cell virus inhibition assays, flow cytometry with cell sorting, and molecular techniques to define the genes and epigenetic regulatory mechanisms that play a role in the CD8+ T-cell response. To achieve this goal, epigenetic marks and gene expression in CD8+ T- cells, sorted from the same patient, with and without activity will be examined. Completion of the project will provide key data that will enable identification of the gene expression profiles and epigenetic mechanisms responsible for the most functional CD8+ T-cells from patients naturally controlling HIV-1 infection (virus controllers).