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

描述（由申请方提供）：总体目标是定义HIV-1疫苗（预防性和治疗性）应引发或作为HIV-1治愈治疗策略的一部分引发的抗病毒CD 8 + T细胞的特性。在“病毒控制者”中，CD 8 + T细胞维持对HIV-1病毒血症的长期控制，所述“病毒控制者”定义为HIV-1感染的患者在没有治疗的情况下自然地能够控制病毒复制。在HIV-1 CD 8 + T细胞中表达的几个基因已被鉴定为与控制者中的HIV-1抑制相关或介导。然而，基因表达的调节以及介导CD 8 + T细胞HIV抑制活性的完整基因库尚不清楚。目前对CD 8 + T细胞抗病毒应答的认识中的这种差距限制了开发有效疫苗和治愈性疗法的能力，所述有效疫苗和治愈性疗法可以利用由CD 8 + T细胞介导的抗病毒机制提供的免疫保护。 Tomaras实验室先前发现，抗病毒CD 8 + T细胞介导的反应是由表观遗传机制调节的，为诱导有效的CD 8 + T细胞介导的HIV-1抑制提供了新的范例。此外，我们的实验室确定，HIV-1疫苗接种可增强CD 8 + T细胞介导的HIV-1抑制，在记忆细胞亚群中具有最大活性。总之，这些数据表明表观遗传学在介导记忆CD 8 + T细胞对HIV的应答中发挥作用，当遇到HIV-1抗原时，表观遗传学允许转录机制访问适当的基因。该项目建立在最近发表的工作，使用CD 8 + T细胞病毒抑制试验，流式细胞术与细胞分选和分子技术的创新组合策略，以确定在CD 8 + T细胞应答中发挥作用的基因和表观遗传调控机制。为了实现这一目标，将检查从同一患者分选的具有和不具有活性的CD 8 + T细胞中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，从而能够识别基因表达谱和表观遗传机制，这些基因表达谱和表观遗传机制负责自然控制HIV-1感染的患者（病毒控制者）中最具功能的CD 8 + T细胞。

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).