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- 巨细胞病毒（CMV），因为CMV的能力，以引发和无限期地保持高 频率，效应分化的T细胞反应在不同的组织。使用恒河猴（RM）模型， 我们已经证明，RhCMV/SIV疫苗不仅对高致病性病毒具有上级效力， 与常规SIV疫苗相比，SIV攻毒（总体而言，59%的RhCMV/SIV疫苗接种RM废除了 进行性SIV感染），这种疗效是一种全新的模式-早期SIV复制停滞，随后是 最终的病毒清除-并由一种新的免疫应答- MHC-E限制性效应记忆-介导， 分化的CD 8 + T细胞（迄今为止只能由具有特异性遗传编程的CMV载体引发）。 我们还知道，MHC-E靶向CD 8 + T细胞应答的功效是通过全血细胞计数来预测的。 转录组特征的IL-15信号，但机制负责完全逮捕和 新生SIV感染的随后清除尚未确定，包括为什么MHC-E限制性抗原 表位识别是有效性所必需的，这些细胞如何介导复制停滞，以及保护性细胞如何介导复制停滞。 全血转录组标志影响这些独特的效应子应答。在这个项目中，我们寻求 都回答了这些问题，并制定了详细的标准，“复制抑制”的疗效，以指导正在进行的 人类CMV/HIV疫苗的I/II期临床试验。拟议方案将包括以下3项 项目：1）RhCMV/SIV疫苗介导的SIV“复制停滞”的免疫学和病毒学表征 2）在免疫后，原发性SIV感染的体内T细胞（和总体免疫）拦截的表征 用差异应答程序化的RhCMV/SIV载体（MHC-E- vs. MHC-II- vs. MHC-Ia-vs. 限制性的）和常规初免-加强SIV疫苗（MHC-Ia限制性的），和3）确定最小免疫应答（MHC-Ia限制性的）。 RhCMV/SIV疫苗介导的SIV“复制停滞”所需的MHC-E限制性SIV表位靶向 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）`组学，生物信息学和数据管理。除了指导当前和未来的临床试验外， HMCV/HIV疫苗，了解“SIV复制阻滞”功效的免疫学基础和作用， MHC-E限制性CD 8 + T细胞在这一过程中将对HIV治疗方法产生广泛的影响， 告知使用MHC-E限制性CD 8 + T细胞作为通用（MHC单倍型非依赖性）效应子， 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.