Immunologic and Virologic Basis of RhCMV/SIV Vaccine-Induced Replication Arrest Efficacy

总体--项目摘要 大约20年前，我们的研究小组开始开发基于持久性β的疫苗载体- 疱疹病毒巨细胞病毒(CMV)由于具有诱导和无限期维持高水平的能力 不同组织中频率、效应器分化的T细胞反应。使用恒河猴(RM)模型， 我们已经证明，不仅RhCMV/SIV疫苗对高致病性病毒具有优越的疗效 SIV疫苗比传统SIV疫苗更具挑战性(总体而言，59%的RhCMV/SIV疫苗接种了废除的RM疫苗 进行性SIV感染)，这种疗效是一种全新的模式--早期SIV复制停止，然后 最终病毒清除-由一种新的免疫反应-MHC-E-受限的效应器记忆-介导- 分化的CD8+T细胞(到目前为止，这种细胞只能由具有特定遗传程序的CMV载体诱导)。 我们还知道，MHC-E靶向CD8+T细胞反应的有效性是通过全血预测的 以IL-15信号为特征的转录切割签名，但负责完全阻止和 新生的SIV感染的后续清除没有定义，包括为什么MHC-E-限制的问题 有效的表位识别是必需的，这些细胞是如何介导复制停止的，以及如何保护 全血转录信号影响这些独特的效应器反应。在这个节目中，我们寻求 两人都回答了这些问题，并为指导正在进行的“复制阻止”的有效性制定了详细的标准 人巨细胞病毒/艾滋病毒疫苗的I/II期临床测试。拟议的计划将包括以下3个方面 项目：1)RhCMV/SIV疫苗介导的SIV复制停滞的免疫学和病毒学特性 有效性，2)体内T细胞(和整体免疫)拦截原发SIV感染的特征 差异应答程序化RhCMV/SIV载体(MHC-E-vs.MHC-II-vs.MHC-Ia-)免疫接种 限制)和传统的加强免疫SIV疫苗(MHC-Ia限制)，以及3)最低限度的测定 MHC-E限制性SIV表位靶向是RhCMV/SIV疫苗介导的SIV复制抑制所必需的 功效。这些项目将由4个核心支持：A)管理、B)NHP、C)高级空间分析、 和d)`OMICS、生物信息学和数据管理。除了指导当前和未来的临床试验 HMCV/HIV疫苗，了解“SIV复制抑制”效果的免疫学基础和SIV的作用 在这一过程中，MHC-E限制的CD8+T细胞将对HIV的治愈方法以及 告知使用MHC-E限制性CD8+T细胞作为通用(非MHC单倍型)效应器 针对其他传染病或癌症的免疫疗法。

OVERALL - PROJECT SUMMARY Almost 2 decades ago our research group began development of vaccine vectors based on the persistent β- herpesvirus Cytomegalovirus (CMV) because of the ability of CMV to elicit and indefinitely maintain high frequency, effector-differentiated T cell responses in diverse tissues. Using the rhesus macaque (RM) model, we have demonstrated that not only do RhCMV/SIV vaccines provide superior efficacy against highly pathogenic SIV challenge than conventional SIV vaccines (in aggregate, 59% of RhCMV/SIV vaccinated RM with abrogation of progressive SIV infection), this efficacy is of an entirely new pattern – early SIV replication arrest followed by eventual viral clearance – and is mediated by a novel immune response – MHC-E-restricted, effector memory- differentiated CD8+ T cells (which to date can only be elicited by CMV vectors with specific genetic programming). We also know that the efficacy of MHC-E targeted CD8+ T cell responses is predicted by a whole blood transcriptomic signature featuring IL-15 signaling, but the mechanisms responsible for complete arrest and subsequent clearance of nascent SIV infection are not defined, including the questions of why MHC-E-restricted epitope recognition is required for efficacy, how these cells mediate replication arrest, and how the protective whole blood transcriptomic signature influences these unique effector responses. In this program, we seek to both answer these questions and develop detailed criteria for “replication arrest” efficacy for guiding ongoing phase I/II clinical testing of human CMV/HIV vaccines. The proposed program will include the following 3 projects: 1) Immunologic and virologic characterization of RhCMV/SIV vaccine-mediated SIV “replication arrest” efficacy, 2) Characterization of the in vivo T cell (and overall immune) interception of primary SIV infection after vaccination with differentially response programmed RhCMV/SIV vectors (MHC-E- vs. MHC-II- vs. MHC-Ia- restricted) and a conventional prime-boost SIV vaccine (MHC-Ia-restricted), and 3) Determination of the minimal MHC-E-restricted SIV epitope targeting required for RhCMV/SIV vaccine-mediated SIV “replication arrest” efficacy. These projects will be supported by 4 cores: A) Administration, B) NHP, C) Advanced Spatial Analysis, and D) `Omics, Bioinformatics, and Data Management. In addition to guiding current and future clinical testing of HMCV/HIV vaccines, the understanding the immunologic basis of “SIV replication arrest” efficacy and the role of MHC-E-restricted CD8+ T cells in this process will have broad implications for HIV cure approaches, as well as inform the use of MHC-E-restricted CD8+ T cells as universal (MHC haplotype independent) effectors for immunotherapies directed at other infectious diseases or cancer.