Antiviral Activity In Situ

原位抗病毒活性

• 批准号: 10475294
• 负责人: GEORGIA Doris TOMARAS
• 金额: $ 85.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475294
• 关键词: Active Immunization; Address; Animals; Antibodies; Autopsy; Biodistribution; Cell Communication; Cells; Collaborations; Complement; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Effector Cell; Environment; Event; FCGR3B gene; Fc Receptor; Female; Genetic; HIV; HIV Antibodies; HIV-1; Heterogeneity; Human; IgG3; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; In Situ; In Vitro; Individual; Infection; Infusion procedures; Interruption; Label; Length; Lentivirus; Macaca mulatta; Mediating; Mediator of activation protein; Modeling; Monitor; Monoclonal Antibodies; Mucous Membrane; Natural Killer Cells; PET/CT scan; Passive Immunization; Phagocytosis; Phase; Phenotype; Plasma; Play; Population; Process; Property; Role; SIV; Signal Transduction; Specificity; System; Testing; Therapeutic; Time; Tissues; Vaccination; Vaccines; Viral Antibodies; Viremia; Virus Replication; base; cell type; differential expression; gastrointestinal; in vivo; in vivo evaluation; insight; monocyte; mucosal site; neutralizing antibody; nonhuman primate; novel; prevent; receptor expression; recruit; reproductive tract; sample collection; simian human immunodeficiency virus; trafficking; transcriptomics; transmission process; vaccination strategy; vaccine response; vaccine trial

ABSTRACT_Project 3 Anti-HIV antibodies can interact with a variety of Fc-receptors (FcRs) that are differentially expressed on host effector cells and exert a broad range of functions including antibody-dependent cell phagocytosis (ADCP) and antibody-dependent cell mediated cytotoxcity (ADCC). Passive as well as active vaccination in human and non human primate (NHP) studies have indicated that ADCC as well as phagocytosis are consistent correlates of protection. However, testing of the mechanistic relevance of IgG subclasses and allotypes on antiviral activity remains extremely limited. FcR-bearing cells also have a broad distribution which can vary widely by cell type, tissue, and species, and remain incompletely characterized in NHP, particularly in mucosal sites of lentivirus transmission. Further, compartmental considerations on the relative contributions of ADCC and ADCP to interruption of early HIV and SIV replication remain underexplored. Importantly, we have demonstrated disparate expansion of transient and tissue-resident NK cells in both HIV and SIV infections, but the relevance of these populations, as well as tissue-resident or trafficking subpopulations of other FcR- bearing cells remains unclear. Defining the events that take place in these early mucosal foci will provide critical insights into functional interactions that inhibit ongoing virus replication and spread in a highly dynamic mucosal environment that includes a range of genetic variability of the IgG and FcR repertoires and the significant heterogeneity of NHP FcR compared to humans. This Project will explore the specific hypothesis that optimal antiviral antibody activity is impacted by the tissue distribution of effector cells and FcR expression, which can be tuned to enhance vaccine responses and subsequent protection against SHIV challenge. The specific aims for Project 3 are as follows: Aim 1: Define the In vivo recognition of SIV/SHIV-infected cells by antibody and FcR-bearing cells in the GI and FRT mucosae. Aim 2. Define the antiviral properties of human immunoglobulin subclasses in vivo. Aim 3. Define the relative contribution of FcR-bearing cells to protection against mucosal SHIV challenge.

Abstract_project 3 抗HIV抗体可以与在宿主上不同表达的多种FC受体（FCR）相互作用 效应细胞并发挥广泛的功能，包括抗体依赖性细胞吞噬作用（ADCP） 和抗体依赖性细胞介导的细胞毒素（ADCC）。人类的被动和主动疫苗 非人类灵长类动物（NHP）研究表明，ADCC和吞噬作用是一致的 保护的关联。但是，测试IgG亚类和同型的机理相关性 抗病毒活性仍然非常有限。带有FCR的细胞也具有广泛的分布，可以改变 通过细胞类型，组织和物种广泛，并保持不完全的NHP表征，尤其是在粘膜中 慢病毒传播部位。此外，对ADCC的相对贡献的分室考虑 和ADCP中断早期艾滋病毒和SIV复制的中断尚未得到充分反思。重要的是，我们有 在HIV和SIV感染中均显示出瞬时和组织居民NK细胞的不同扩展，但 这些人群的相关性以及其他FCR-的组织居民或贩运亚群 轴承细胞仍然不清楚。定义这些早期粘膜焦点中发生的事件将提供 对功能相互作用的批判性见解，这些功能相互作用抑制正在进行的病毒复制并传播在高度动态的 粘膜环境包括IgG和FCR曲目的一系列遗传变异性以及 与人类相比，NHPFCR的显着异质性。该项目将探讨特定的假设 最佳的抗病毒抗体活性受效应细胞的组织分布和FCR表达的影响， 可以调整以增强疫苗反应并随后对SHIV挑战的保护。这 项目3的具体目标如下： AIM 1：定义通过抗体和FCR细胞中对SIV/SHIV感染细胞的体内识别 gi和frt粘膜。 AIM 2。定义体内人类免疫球蛋白亚类的抗病毒特性。 AIM 3。定义含FCR细胞对防止粘膜SHIV的相对贡献 挑战。