Multi-Omics Analysis of Broadly Neutralizing Antibodies and Therapeutic Vaccination

摘要 本P01计划的目标是确定广谱中和抗体(BNAbs)和 HIV-1治疗性疫苗正在进行高度合作和多方面的研究计划。我们的整体 假设HIV-1治愈的免疫学策略通过靶向病毒来延缓病毒反弹 通过提高宿主的抗病毒免疫力。我们将评估其治疗效果的机制 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 旨在制定改进的下一代艾滋病毒-1治疗战略的方法。我们将应用切割- 边缘、高通量、多基因组图谱平台并集成这些数据集，以生成全面的 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评估方面的现有研究基础上 BNAbs和治疗性疫苗延缓抗逆转录病毒停药后病毒反弹的能力 治疗(ART)。我们将首先利用这些研究的现有样本来生成以下假设 病毒反弹延迟的相关因素。然后，我们将在NHP中进行新的干预性研究，使用空间多维 对淋巴结和胃肠粘膜组织进行组学分析，以验证假设，以确定 BNAbs和治疗性疫苗靶向水库的机制。 这个项目的意义在于有可能确定导致病毒延迟反弹的生物途径。 随着艺术的中断。提高对部分有效的bNAbs和治疗性疫苗的认识 将导致基础研究的进步，从而使下一步改进的开发成为可能 一代HIV-1的治愈方法即将到来。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个OMICS相关性 项目2.治疗性疫苗疗效的多个OMICS相关性 核心A.行政核心 核心B.多OMICS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