Project 1: Systemic analysis of the origin and tissue effects of the 68-1 RhCMV/SIV vaccine efficacy-predictive whole blood transcriptomic signature

项目1：68-1 RhCMV/SIV疫苗功效预测全血转录组特征的起源和组织效应的系统分析

• 批准号: 10723639
• 负责人: Louis J. Picker
• 金额: $ 40.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723639
• 关键词: Acute; Address; Bioinformatics; Blood; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Cells; Characteristics; Chronic Phase; Cytomegalovirus; Data; Dependence; Epitopes; Exhibits; Gene Expression Regulation; Generations; Genetic Transcription; Goals; HIV/SIV vaccine; Homeostasis; Homing; Homing Behavior; Immune; Immune response; Immunity; Immunologics; In Vitro; Infection; Inflammasome; Intercept; Interleukin-15; Knowledge; Link; Lymphoid Tissue; Macaca mulatta; Maintenance; Major Histocompatibility Complex; Mediating; Memory; Modality; Modification; Molecular; Mucous Membrane; Natural Killer Cells; Outcome; Pathogenicity; Pathway interactions; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Population; Program Research Project Grants; Regulation; Rhesus; Role; SIV; SIV Vaccines; Signal Induction; Signal Transduction; Site; Stimulus; System; Systems Biology; T cell response; T memory cell; Time; Tissues; Toll-like receptors; Vaccinated; Vaccination; Vaccinee; Vaccines; Whole Blood; cell type; clinical translation; clinically significant; cytokine; data integration; effector T cell; efficacy evaluation; immunoregulation; in vivo; monocyte; predictive signature; programs; response; transcriptomics; vaccine efficacy; vector

Project 1 Summary Vaccination of Rhesus macaques (RMs) with SIV insert-expressing 68-1 Rhesus Cytomegalovirus vectors (RhCMV/SIV) elicits an immune response that in 59% of vaccinees can intercept and effectively arrest an early spreading primary SIV infection. The vast majority of vaccinated RM that manifest SIV replication arrest go to completely clear SIV infection, a remarkable outcome with enormous potential clinical significance. This unique pattern of “arrest and clear” efficacy has been linked to major histocompatibility complex (MHC)-E-restricted SIV- specific CD8+ T cell responses and in RMs with MHC-E-restricted CD8+ T cell responses, a protection-predictive innate immune transcriptional response to vaccination in whole blood (the whole blood protection-predictive signature or wbPPTS) that includes a central IL-15 signaling component. RhCMV/SIV vaccinated RM destined for arrest and clear efficacy manifest low baseline IL-15 signaling (IL-15 quiescence) and high post vaccination IL-15 signaling which persists through to SIV challenge. Since IL-15 is the major cytokine regulator of effector memory T cell physiology, including regulation of effector function, activation thresholds, population homeostasis, and homing behavior, these observations that correlation between the magnitude and persistence of IL-15 signaling induction and protection might reflect an IL-15-mediated modulation of the SIV-specific MHC- E-restricted CD8+ T cells, but IL-15 is not the only pathway in the wbPPTS and its unclear whether IL-15 or other components of the wbPPTS contribute to the tissue-based immune programming that enables vaccine efficacy. In this project, we seek to delineate the origin and tissue correlates of the wbPPTS and its IL-15 dependence in order the delineate the fundamental components of vaccine-induced innate immune programming required for efficacy. We will achieve this goal by determining 1) the systemic transcriptomic correlates of the RhCMV/SIV vaccine-induced wbPPTS in peripheral and mucosal lymphoid tissues and its dependence on IL-15 signaling (S.A.1), 2) the specific spatial transcriptomic response to RhCMV/SIV-infected cells in tissues and the direct contribution of vector-infected cells to the local and systemic transcriptomic responses linked to wbPPTS programming (S.A.2), and 3) the mechanisms underlying the association between IL-15 signaling quiescence and generation of the wbPPTS (S.A.3). We expect these data to implicate an underlying immune mechanism for RhCMV/SIV vaccine-induced arrest and clear protection, to provide validated tissue-based immune correlates for clinical translation, and, potentially, to lead to vaccine modifications that would increase the efficacy of CMV- based SIV/HIV vaccines.

项目1概要 使用表达 SIV 插入片段的 68-1 恒河猴巨细胞病毒载体对恒河猴 (RM) 进行疫苗接种 (RhCMV/SIV) 会引发免疫反应，59% 的疫苗接种者可以拦截并有效阻止早期免疫反应。 传播原发性 SIV 感染。绝大多数表现出 SIV 复制停滞的接种疫苗 RM 完全清除SIV感染，这是一个具有巨大潜在临床意义的显着结果。这种独特的 “逮捕和清除”功效的模式与主要组织相容性复合体（MHC）-E-限制性 SIV-有关 特异性 CD8+ T 细胞反应以及在具有 MHC-E 限制的 CD8+ T 细胞反应的 RM 中，这是一种保护预测 全血中疫苗接种的先天免疫转录反应（全血保护预测 签名或 wbPPTS），其中包括中央 IL-15 信号传导成分。 RhCMV/SIV 疫苗接种 RM 注定 对于逮捕和明确的功效表现出低基线 IL-15 信号传导（IL-15 静止）和高疫苗接种后 IL-15 信号传导持续到 SIV 攻击。由于IL-15是效应子的主要细胞因子调节剂 记忆 T 细胞生理学，包括效应器功能的调节、激活阈值、群体 稳态和归巢行为，这些观察结果表明幅度和持久性之间的相关性 IL-15 信号诱导和保护的作用可能反映了 IL-15 介导的 SIV 特异性 MHC- 调节 E-限制性 CD8+ T 细胞，但 IL-15 并不是 wbPPTS 中的唯一途径，并且尚不清楚 IL-15 或其他途径 wbPPTS 的组成部分有助于基于组织的免疫编程，从而实现疫苗功效。 在这个项目中，我们试图描述 wbPPTS 的起源和组织相关性及其 IL-15 依赖性 命令描述疫苗诱导的先天免疫编程的基本组成部分 功效。我们将通过确定 1) RhCMV/SIV 的系统转录组相关性来实现这一目标 疫苗诱导的外周和粘膜淋巴组织中的 wbPPTS 及其对 IL-15 信号传导的依赖性 (S.A.1), 2) 对组织中 RhCMV/SIV 感染细胞的特异性空间转录组反应以及直接 载体感染细胞对与 wbPPTS 相关的局部和全身转录组反应的贡献 编程 (S.A.2) 和 3) IL-15 信号静止之间关联的机制 以及 wbPPTS (S.A.3) 的生成。我们期望这些数据能够暗示潜在的免疫机制 RhCMV/SIV 疫苗诱导的抑制和明确的保护，提供经过验证的基于组织的免疫相关性 用于临床转化，并有可能导致疫苗修改，从而提高 CMV 的功效 基于 SIV/HIV 的疫苗。