Multi-Omics Correlates of Therapeutic Vaccine Efficacy

总结 治疗性疫苗接种的目标是增加宿主对HIV-1的免疫控制，以实现持久的病毒学治疗。 在没有ART的情况下进行控制，其被定义为“功能性治愈”。然而，治疗性疫苗研究在 人类迄今为止基本上是不成功的。相反，在先前的治疗性疫苗接种研究中， SIV/SHIV感染的非人灵长类动物（NHP），一个动物子集实现了病毒控制，包括减少的 淋巴器官中的病毒水平，表明干预措施具有抗储库效应。了解 治疗性疫苗功效的潜在机制和鉴定与抗- 体内的储库活性是其优化用于HIV治疗的基本先决条件。 在项目2中，我们假设导致病毒学控制的组合免疫策略 诱导独特外周和组织免疫特征，包括病毒组织内重组 储层，可以使用空间多组学方法来识别。我们进一步假设， 这种保护性免疫应答主要在淋巴组织中介导它们的功效。评估这些 假设，我们提出两个具体目标： 目标1. SIV/SHIV感染恒河猴病毒学控制的免疫学相关性研究 采取主动和组合免疫策略。我们会进行全面的病毒学检查， 对来自三种非人灵长类动物和一种临床灵长类动物现有标本进行免疫学和多组学分析 研究旨在产生关于长期与短期病毒学控制相关性的假设。 目标2.定义淋巴组织中外周和组织病毒储库控制的机制， SHIV感染恒河猴的治疗性疫苗接种。我们将进行干预性研究， 组合疫苗策略可以诱导靶向病毒库的免疫应答的假设 淋巴结和胃肠道粘膜中的SHIV感染恒河猴。 我们将应用核心B（多组学）中详细介绍的尖端、高通量、多组学分析平台 核心），以确定治疗性疫苗接种的影响。然后，我们将在Core C中整合多组学数据 （计算分析核心），以生成病毒的全面景观和监管网络， 治疗性疫苗接种后的储库和宿主免疫应答。这些数据将定义 以前所未有的分辨率水平对具有复制能力的病毒储库进行治疗性疫苗接种， 这将为下一代HIV-1治疗工作提供重要的见解。

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.