Project 1

摘要 为了在ART停止后有效控制HIV，HIV特异性T细胞对 治疗性疫苗接种不仅必须增加规模，而且还必须长期-- 住过，有能力到库址坚持不懈，有T细胞记忆力 强大的增殖和执行效应器功能以响应抗原的能力(即，它们 需要克服残留在先前存在的HIV特异性T细胞中的T细胞耗尽 尽管ART抑制了病毒载量)，并重新聚焦于具有显性反应的 瞄准易受攻击的表位。由于标准T细胞分析的局限性，尽管 来自临床试验的新数据显示，接种后艾滋病毒至少得到了部分控制，但几乎没有 已知HIV治疗性疫苗方案无效的机制 将预先存在的HIV特异性T细胞免疫转化为有效的抗病毒反应。在这个项目中，我们 将利用我们执行集成多模式系统免疫学分析的经验 与配对的单细胞转录组和TCR测序(scRNA/TCRseq)数据和高 多维流式细胞仪数据。我们将对HIV/SIV治疗进行克隆水平分析 疫苗诱导的高度独特和临床相关的人类和猕猴CD8+T细胞 治疗性疫苗对改变的HIV/SIV队列产生了可测量的影响 治疗中断后病毒载量动力学问：目前在多大程度上是首选 能够招募新的和/或先前存在的T细胞克隆的治疗性疫苗方案 最佳的类似记忆的属性(功能和分化状态；目标1和2)，以及目标是什么 疫苗诱导的T细胞反应的记忆样特征(或其他特征)的程度 与艾滋病毒治疗后控制相关(目标3)？这些研究将使我们能够表征 在前所未有的深度，不同的治疗性疫苗方案对危重和 以前无法测量的-病毒特异性T细胞反应质量的各个方面。我们的结果 将为我们开发可靠的病毒特异性T细胞克隆测量方法奠定基础 结构和分化状态，这将为人类和猕猴的迭代研究提供信息。

ABSTRACT In order to effectively control HIV after ART is stopped, HIV-specific T cell responses to therapeutic vaccination must not only be increased in magnitude, but they also must be long- lived, have the capacity to home to sites of reservoir persistence, have the T cell memory-like capacity to robustly proliferate and execute effector functions in response to antigen (i.e., they need to overcome the residual T cell exhaustion that persists in pre-existing HIV-specific T cells despite viral load suppression with ART), and be refocused to have dominant responses that target vulnerable epitopes. Due to the limitations of standard T cell assays, and despite emerging data from clinical trials showing at least partial control of HIV post-vaccination, little is known about the mechanisms by which HIV therapeutic vaccine regimens transform ineffective pre-existing HIV-specific T cell immunity into an effective antiviral response. In this Project, we will leverage our experience performing integrated multi-modal systems immunology analysis with paired single cell transcriptome and TCR sequencing (scRNA/TCRseq) data and high- dimensional flow cytometry data. We will perform clonal-level analysis on HIV/SIV therapeutic vaccine-elicited CD8+ T cells from highly unique and clinically relevant human and macaque HIV/SIV cohorts in which therapeutic vaccines have exerted a measurable effect on altering viral load kinetics after treatment interruption to ask: to what extent are current top-candidate therapeutic vaccine regimens capable of recruiting new and/or pre-existing T cell clones with optimal memory-like properties (function and differentiation state; Aims 1 and 2), and to what extent do memory-like features (or other features) of the vaccine-elicited T cell response correlate with post-treatment control of HIV (Aim 3)? These studies will allow us to characterize in unprecedented depth the impact of different therapeutic vaccine regimens on critical – and previously unmeasurable – facets of the quality of the virus-specific T cell response. Our results will lay the groundwork for us to develop reliable measurements of virus-specific T cell clonal structure and differentiation state that will inform iterative studies in humans and macaques.