Multi-Omics Analysis of Broadly Neutralizing Antibodies and Therapeutic Vaccination

广泛中和抗体和治疗性疫苗的多组学分析

• 批准号: 10724219
• 负责人: Dan H. Barouch
• 金额: $ 141.27万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724219
• 关键词: Basic Science; Biological; Biological Assay; Cellular Immunity; Computer Analysis; Data Set; Development; Goals; HIV-1; Human; Immune; Immune response; Immunologics; Intervention Studies; Lymphoid Tissue; Macaca mulatta; Mediating; Mucous Membrane; Pathway interactions; Peripheral; Program Research Project Grants; Research; SIV; Sampling Studies; Testing; Tissues; Treatment Efficacy; Vaccine Therapy; Vaccines; Viral; Viral reservoir; animal resource; anti-viral efficacy; antiretroviral therapy; antiviral immunity; combinatorial; data integration; gastrointestinal; improved; lymph nodes; multiple omics; neutralizing antibody; next generation; nonhuman primate; programs; simian human immunodeficiency virus; therapeutic vaccine; vaccination strategy; vaccine efficacy; viral rebound

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

概括 该 P01 计划的目标是定义广泛中和抗体 (bNAb) 的功效机制和 在高度协作和多方面的研究计划中开发 HIV-1 治疗性疫苗。我们的整体 假设是治疗 HIV-1 的免疫策略通过靶向病毒来延缓病毒反弹 病毒库并通过增加宿主的抗病毒免疫力。我们将评估治疗效果的机制 使用协调的病毒学、免疫学和多组学方法对人类和非人灵长类动物 (NHP) 进行研究 方法的目标是开发改进的下一代 HIV-1 治疗策略。我们将应用切割- 边缘、高通量、多组学分析平台，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节网络。 该计划建立在我们过去几年对人类和 NHP 进行评估的现有研究的基础上 bNAb 和治疗性疫苗在抗逆转录病毒药物停用后延缓病毒反弹的能力 治疗（ART）。我们将首先利用这些研究中的现有样本来生成关于 病毒反弹延迟的相关性。然后，我们将在 NHP 中进行新的介入研究，具有空间多 对淋巴结和胃肠粘膜组织进行组学分析以检验假设，以确定 bNAb 和治疗性疫苗的储库靶向机制。 该计划的意义在于有可能确定导致病毒反弹延迟的生物途径 ART 终止后。更好地了解部分有效的 bNAb 和治疗性疫苗 人类和 NHP 的研究将带来基础研究的进步，从而开发出改进的下一代药物 一代 HIV-1 治愈方法。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. 广泛中和抗体功效的多组学关联 项目 2. 治疗性疫苗功效的多组学关联 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