Multi-Omics Correlates of Broadly Neutralizing Antibody Efficacy

广泛中和抗体功效的多组学关联

• 批准号: 10724224
• 负责人: Dan H. Barouch
• 金额: $ 23.25万
• 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/10724224
• 关键词: Antibody Therapy; Cell surface; Cells; Cellular Immunity; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chromatin; Clinical; Clinical Trials; Computer Analysis; Data; Dose; Drug Kinetics; Effectiveness; Genetic Transcription; Genomics; HIV-1; Human; Immune response; Immunologics; In Situ; Individual; Infusion procedures; Intervention Studies; Lymphoid Tissue; Macaca; Macaca mulatta; Measures; Molecular Profiling; Mucous Membrane; Multiomic Data; Participant; Phenotype; Property; Proteins; Proteomics; Reporting; Resistance; Resolution; Specimen; Testing; Therapeutic; Tissue Sample; Tissues; Transcript; Vaccine Therapy; Vaccines; Viral; Viral Physiology; Viral reservoir; Virus; Virus Replication; anti-viral efficacy; gastrointestinal; insight; lymph nodes; multiple omics; neutralizing antibody; next generation; nonhuman primate; protein biomarkers; simian human immunodeficiency virus; single-cell RNA sequencing; transcriptomics; viral DNA; viral RNA; viral detection; viral rebound

SUMMARY Accumulating data suggests that administration of broadly neutralizing antibodies (bNAbs) in ART-suppressed, SHIV-infected nonhuman primates (NHPs) and HIV-1-infected humans can delay viral rebound following ART discontinuation. However, the mechanism underlying the efficacy of bNAbs remains to be determined. Multiple mechanisms may contribute to the effectiveness of bNAbs in delaying viral rebound, including direct antiviral activity against replicating virus, targeting of the replication-competent viral reservoir, and indirect effects such as augmenting cellular immune responses via the “vaccinal” effect. Understanding the mechanism of action underlying bNAb efficacy will lead to optimization of these and other HIV-1 cure strategies. In Project 1, we hypothesize that bNAbs can directly target the viral reservoir in addition to providing direct antiviral effects, both of which contribute to the observed long-term virologic control following ART discontinuation. An alternative hypothesis is that bNAbs contribute to long-term antiviral efficacy by modulating host cellular immunity via the vaccinal effect. To evaluate these hypotheses, we propose two Specific Aims: Aim 1. To determine multi-omics correlates of bNAb based virologic control in HIV-1-infected humans. We will perform a comprehensive virologic, immunologic, and multi-omics analysis of existing clinical specimens from the T003 study to generate hypotheses regarding correlates of long term vs. short term virologic control. Aim 2. To define mechanisms of bNAb efficacy in lymphoid tissues in SHIV-infected rhesus macaques. We will perform interventional studies to test the hypothesis that bNAbs can 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 bNAb therapy. 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 bNAb therapy. These data will define the impact of bNAbs on the replication- competent viral reservoir at an unprecedented level of resolution, which will provide critical insights for next generation HIV-1 cure efforts.

概括 积累的数据表明，在 ART 抑制中施用广泛中和抗体 (bNAb)， 感染 SHIV 的非人类灵长类动物 (NHP) 和感染 HIV-1 的人类可以延缓 ART 后的病毒反弹 停产。然而，bNAb 功效的机制仍有待确定。多种的 机制可能有助于 bNAb 延迟病毒反弹的有效性，包括直接抗病毒 对抗复制病毒的活性，针对具有复制能力的病毒库，以及间接影响，例如 通过“疫苗”效应增强细胞免疫反应。了解作用机制 bNAb 的潜在功效将导致这些和其他 HIV-1 治疗策略的优化。 在项目 1 中，我们假设 bNAb 除了提供病毒库外还可以直接靶向病毒库 直接抗病毒作用，这两者都有助于观察到的长期病毒学控制 ART 终止。另一种假设是 bNAb 有助于长期抗病毒功效 通过疫苗效应调节宿主细胞免疫。为了评估这些假设，我们建议 两个具体目标： 目标 1. 确定 HIV-1 感染者中基于 bNAb 的病毒学控制的多组学相关性。 我们将对现有临床标本进行全面的病毒学、免疫学和多组学分析 从 T003 研究中生成有关长期与短期病毒学控制相关性的假设。 目标 2. 明确 bNAb 在感染 SHIV 的恒河猴淋巴组织中的功效机制。 我们将进行介入研究来检验 bNAb 可以靶向淋巴中病毒库的假设 感染 SHIV 的恒河猴的淋巴结和胃肠粘膜。 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）来定义 bNAb 治疗的影响。然后我们将在 Core C（计算 分析核心）生成病毒库和宿主的全面景观和调控网络 bNAb 治疗后的免疫反应。这些数据将定义 bNAb 对复制的影响 具有前所未有的分辨率水平的病毒库，这将为下一步提供重要的见解 一代 HIV-1 治愈努力。