Multi-Omics Analysis of Broadly Neutralizing Antibodies and Therapeutic Vaccination

总结 该P01项目的目标是确定广泛中和抗体（bNAb）的有效性机制， 在一个高度合作和多方面的研究计划中，为HIV-1提供治疗性疫苗。我们的整体 有一种假说认为，HIV-1治疗免疫策略通过靶向HIV-1病毒， 水库和增加宿主的抗病毒免疫力。我们将评估治疗效果的机制， 人类和非人类灵长类动物（NHP）使用协调的病毒学，免疫学和多组学 这些方法的目标是开发改进的下一代HIV-1治愈策略。我们会进行切割- 边缘，高通量，多组学分析平台，并整合这些数据集，以生成一个全面的 病毒库和宿主免疫反应的组织景观和调控网络。 该计划建立在我们过去几年在人类和NHP评估中的现有研究基础上 bNAb和治疗性疫苗延迟抗逆转录病毒治疗中断后病毒反弹的能力 治疗（ART）。我们将首先利用这些研究中现有的样本来产生关于以下方面的假设： 延迟病毒反弹的相关因素然后，我们将在NHP中进行新的干预性研究， 在淋巴结和胃肠道粘膜组织中进行组学分析，以检验假设， 通过bNAb和治疗性疫苗的储库靶向机制。 该项目的意义在于有可能确定导致延迟病毒反弹的生物学途径 在ART停止后。对部分有效的bNAb和治疗性疫苗的更好理解 在人类和NHPs中的应用将导致基础研究的进步，这将允许开发改进的下一个 第二代HIV-1治疗方法。为了实现P01计划的目标，我们提出以下建议 项目和核心： 项目1。广泛中和抗体效力的多组学相关性 项目2.治疗性疫苗效力的多组学相关性 核心A。行政核心 核心B。多组学核心 核心C。计算分析核心 核心D。NHP核心

SUMMARY The goal of this P01 program is to define mechanisms of efficacy of broadly neutralizing antibodies (bNAbs) and therapeutic vaccines for HIV-1 in a highly collaborative and multifaceted research program. Our overall hypothesis is that immunologic strategies for HIV-1 cure delay viral rebound both by targeting the viral reservoir and by increasing host antiviral immunity. We will evaluate mechanisms of therapeutic efficacy in both humans and nonhuman primates (NHPs) using coordinated virologic, immunologic, and multi-omic approaches with the goal of developing improved next generation HIV-1 cure strategies. We will apply cutting- edge, high-throughput, multi-omic profiling platforms and integrate these data sets to generate a comprehensive tissue landscape and regulatory network of the viral reservoir and host immune responses. This program builds on our existing studies over the past several years in both humans and NHPs evaluating the ability of bNAbs and therapeutic vaccines to delay viral rebound following discontinuation of antiretroviral therapy (ART). We will first utilize existing samples from these studies to generate hypotheses regarding correlates of delayed viral rebound. We will then perform new interventional studies in NHPs with spatial multi- omic analyses in lymph nodes and gastrointestinal mucosal tissues to test hypotheses in order to define mechanisms of reservoir targeting by bNAbs and therapeutic vaccines. The significance of this program is the potential to define the biologic pathways that lead to delayed viral rebound following ART discontinuation. An improved understanding of partially effective bNAbs and therapeutic vaccines in humans and NHPs will lead to basic research advances that will allow the development of improved next generation HIV-1 cure approaches. To accomplish the goals of this P01 program, we propose the following Projects and Cores: Project 1. Multi-Omics Correlates of Broadly Neutralizing Antibody Efficacy Project 2. Multi-Omics Correlates of Therapeutic Vaccine Efficacy Core A. Administrative Core Core B. Multi-Omics Core Core C. Computational Analysis Core Core D. NHP Core