Project 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

项目 2：用差异反应编程的 RhCMV/SIV 载体接种疫苗后，体内 T 细胞（和整体免疫）拦截原发性 SIV 感染的表征

• 批准号: 10619303
• 负责人: Scott G Hansen
• 金额: $ 75.55万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619303
• 关键词: Autopsy; CD8-Positive T-Lymphocytes; Cells; Characteristics; Cytomegalovirus; Development; Fibroblast Growth Factor; GTP-Binding Protein alpha Subunits, Gs; Genetic Programming; Genetic Transcription; Goals; HIV vaccine; Immune; Immune response; Immunologics; Infection; Intercept; Interleukin-15; Link; Macaca mulatta; Major Histocompatibility Complex; Mediating; Memory; Modeling; Pattern; Phenotype; Process; Rhesus; SIV; SIV Vaccines; Signal Transduction; T cell response; T-Cell Receptor; T-Lymphocyte; Technology; Tissues; Vaccinated; Vaccination; Vaccinee; Vaccines; Viral; Viremia; Virus Activation; base; clinical translation; genetic manipulation; immune activation; in vivo; insight; programs; response; unvaccinated; vector

PROJECT 2 - PROJECT 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. This unique pattern of “replication arrest” efficacy has been linked to three 68- 1 RhCMV/SIV immune characteristics, including its ability to generate and maintain: 1) high magnitude, circulating and tissue-based, effector memory-biased CD8+ T cell responses, 2) major histocompatibility complex (MHC)-E-restricted SIV-specific CD8+ T cell responses and 3) in RMs with MHC-E-restricted CD8+ T cell responses, a protection-predictive innate immune transcriptional response to vaccination that includes a central IL-15 signaling component; however, the specific immune mechanism(s) underlying replication arrest protection are unknown. RhCMV/SIV vectors can now be programmed by genetic manipulation to elicit SIV-specific CD8+ T cell responses that are restricted by MHC-E-only, MHC-II-only and MHC-Ia-only, and while the latter 2 response types are similar in magnitude and phenotype to the MHC-E-restricted responses, they, as well as conventional prime-boost vaccine elicited MHC-Ia-restricted CD8+ T cell responses, are unable to mediate SIV replication arrest. This indicates that the protective (IL-15/innate-modulated) MHC-E-restricted SIV-specific CD8+ T cells must manifest a different response upon interception of primary SIV infection than the other T cell response types, possibly being more efficient in detecting and responding to SIV-infected cells in vivo and/or manifesting a different (more effective) functional program upon infected cell recognition. In this project, we will use sophisticated `omics technologies that enable detailed characterization of tissue immune responses (including specific analyses of T cell receptor-defined, SIV-specific CD8+ T cells) to define these differences in vivo in the actual RM tissues hosting an early spreading SIV infection. In S.A.1, we will define the systemic viral and immune activation trajectories of unvaccinated vs. (long-term, previously protected and functionally cured) 68-1 RhCMV/SIV vaccinated RMs by analysis of serial necropsies with the goal identifying the optimal post challenge timepoint(s) to study the cellular immune interception of viral spread prior to progressive viremia or stable establishment of replication arrest. In S.A.2, we will use this optimized RM model to identify the unique characteristics of RhCMV/SIV-elicited MHC-E-restricted CD8+ T cell responses in vaccinated naïve RMs that mediate SIV replication arrest efficacy by comparison of the viral:immune intercept of these responses vs. MHC- II-only and MHC-Ia-only SIV-specific CD8+ T cell responses elicited in naïve RMs by differentially programmed RhCMV vectors and vs. MHC-Ia-restricted CD8+ T cell responses elicited by the conventional ChAdOx1/MVA vaccine. These contrasts will provide important insight into the immune processes responsible for replication arrest efficacy and facilitate development of immune mechanism-based correlates of efficacy that will guide clinical translation of a CMV-based HIV vaccine.

项目2-项目摘要 用SIV插入表达68-1恒河状病毒载体的恒河猕猴（RMS）疫苗接种 （RHCMV/SIV）引起免疫反应，其中有59％的疫苗可以拦截并有效地停止早期 传播原发性SIV感染。这种独特的“复制逮捕”效率模式与三个68-- 1个RHCMV/SIV免疫特征，包括其生成和维护的能力：1）高幅度， 循环和基于组织的效应器记忆偏置的CD8+ T细胞反应，2）主要的组织相容性复合物 （MHC） - 限制的SIV特异性CD8+ T细胞响应，3）在具有MHC-E限制CD8+ T细胞的RMS中 反应，一种预测性的先天免疫对疫苗接种的转录反应，其中包括一个中心 IL-15信号分量；但是，具体的免疫机制基础复制逮捕保护 是未知的。现在，可以通过遗传操纵来编程RHCMV/SIV载体以引起SIV特异性CD8+ T细胞响应受仅MHC-E，仅MHC-II的限制，仅MHC-IA，而后2 响应类型的大小和表型与MHC-E限制响应相似，它们以及 常规的促进疫苗引起的MHC-IA限制CD8+ T细胞反应无法介导SIV 复制逮捕。这表明受保护（IL-15/先天性调制）MHC-E限制的SIV特异性CD8+ 与其他T细胞相比，T细胞在原发性SIV感染时必须表现出不同的反应 响应类型，在体内和/或对SIV感染的细胞检测和响应时可能更有效 在感染的细胞识别后表现出不同的（更有效）功能程序。在这个项目中，我们将 使用精致的``omics技术'' （包括对T细胞受体定义的特定分析，SIV特异性CD8+ T细胞），以定义这些差异 实际的RM组织中的体内有早期扩散的SIV感染。在S.A.1中，我们将定义全身病毒 和未接种疫苗的免疫激活轨迹（长期，先前受保护和功能治愈） 68-1 RHCMV/SIV接种RMS通过分析连续尸检的目标，其目标识别最佳柱 挑战时间点要研究在进行性病毒血症或 稳定建立复制逮捕。在S.A.2中，我们将使用此优化的RM模型来识别唯一 RHCMV/SIV吸收的MHC-E限制CD8+ T细胞反应在接种幼稚的RMS中的特征 通过比较病毒的介导SIV复制停滞效率：这些反应的免疫截距与MHC- 仅II二和仅MHC-IA仅SIV特异性CD8+ T细胞响应在幼稚的RMS中通过差异编程引起 RHCMV载体和VS. MHC-IA限制的CD8+ T细胞响应由常规Chadox1/MVA引起 疫苗。这些对比将提供对负责复制的免疫过程的重要见解 阻止效率并促进基于免疫力学的效率相关性的发展，这将指导 基于CMV的HIV疫苗的临床翻译。