Multi-Omics Correlates of Therapeutic Vaccine Efficacy

摘要 治疗性疫苗接种的目标是加强对HIV-1的宿主免疫控制，以实现持久的病毒学 在没有抗逆转录病毒治疗的情况下进行控制，这被定义为“功能性治愈”。然而，中国的治疗性疫苗研究 到目前为止，人类在很大程度上没有成功。相比之下，在之前的治疗性疫苗接种研究中， SIV/SIV感染非人类灵长类动物(NHP)，一组动物实现了病毒控制，包括减少 淋巴器官中的病毒水平，表明干预措施具有抗蓄积作用。了解 治疗性疫苗疗效的潜在机制和识别与抗-HBs相关的免疫标志 体内储存库的活性是优化其治疗HIV的基本前提。 在项目2中，我们假设导致病毒学控制的组合免疫策略 诱导独特的外周和组织免疫特征，包括病毒组织内的重组 储集层，可利用空间多组学方法进行识别。我们进一步假设 这种保护性免疫反应主要在淋巴组织中发挥作用。对这些进行评估 假设，我们提出了两个具体目标： 目的1.确定SIV/SIV感染恒河猴病毒学控制的免疫学相关性 遵循主动免疫和组合免疫战略。我们将进行全面的病毒学研究， 3例非人灵长类和1例临床标本的免疫学和多组学分析 研究产生关于长期病毒学控制与短期病毒学控制的相关性的假设。 目的2.明确淋巴组织中外周和组织病毒库的控制机制 新城疫病毒感染恒河猴的治疗性疫苗接种。我们将进行干预性研究以测试 组合疫苗策略可以诱导针对病毒库的免疫反应的假设 在新城疫病毒感染的恒河猴的淋巴结和胃肠粘膜中。 我们将应用尖端的、高通量的、多组学分析平台，详细说明请参阅Core B(多OMICS 核心)，以界定治疗性疫苗接种的影响。然后，我们将在Core C中集成多组学数据 (计算分析核心)生成全面的病毒格局和监管网络 治疗性疫苗接种后的宿主和宿主免疫反应。这些数据将定义 在具有复制能力的病毒库上以前所未有的分辨率接种治疗性疫苗， 这将为下一代HIV-1治疗努力提供关键的见解。

SUMMARY The goal of therapeutic vaccination is to increase host immune control of HIV-1 to achieve durable virologic control in the absence of ART, which is defined as a “functional cure”. However, therapeutic vaccine studies in humans have to date been largely unsuccessful. In contrast, in previous therapeutic vaccination studies in SIV/SHIV infected non-human primates (NHPs), a subset of animals achieved viral control including reduced viral levels in lymphoid organs, suggesting an anti-reservoir effect of the interventions. Understanding the mechanisms underlying therapeutic vaccine efficacy and identifying immune signatures that associate with anti- reservoir activity in vivo is a fundamental prerequisite towards their optimization for HIV cure. In Project 2, we hypothesize that combinatorial immunization strategies that result in virological control induce unique peripheral and tissue immune signatures, including reorganization within viral tissue reservoirs, which can be identified using spatial multi-omics approaches. We further hypothesize that such protective immune responses mediate their efficacy primarily in lymphoid tissues. To evaluate these hypotheses, we propose two Specific Aims: Aim 1. Identify the immunological correlates of virologic control in SIV/SHIV-infected rhesus macaques following active and combinatorial immunization strategies. We will perform a comprehensive virologic, immunologic, and multi-omics analysis of existing specimens from three non-human primate and one clinical studies study to generate hypotheses regarding correlates of long term vs. short term virologic control. Aim 2. Define mechanisms of peripheral and tissue viral reservoir control in lymphoid tissues following therapeutic vaccination of SHIV-infected rhesus macaques. We will perform interventional studies to test the hypothesis that combinatorial vaccine strategies can induce immune responses that target the viral reservoir in lymph nodes and gastrointestinal mucosa in SHIV-infected rhesus macaques. We will apply cutting-edge, high-throughput, multi-omics profiling platforms detailed in Core B (Multi-Omics Core) to define the impact of therapeutic vaccination. We will then integrate the multi-omics data in Core C (Computational Analysis Core) to generate a comprehensive landscape and regulatory network of the viral reservoir and host immune responses following therapeutic vaccination. These data will define the impact of therapeutic vaccination on the replication-competent viral reservoir at an unprecedented level of resolution, which will provide critical insights for next generation HIV-1 cure efforts.