Antiviral Activity In Situ

原位抗病毒活性

基本信息

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
项目类别：
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

项目摘要

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.

摘要_项目 3 抗 HIV 抗体可以与宿主上差异表达的多种 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）以及抗体依赖性细胞介导的细胞毒性（ADCC）在人体中的被动和主动疫苗接种。和非人类灵长类动物 (NHP) 研究表明 ADCC 以及吞噬作用是一致的然而，测试 IgG 亚类和同种异型的机制相关性。携带 FcR 的细胞的抗病毒活性仍然极其有限，而且分布广泛且各不相同。广泛的细胞类型、组织和物种，并且在 NHP 中仍然不完全表征，特别是在粘膜中此外，对 ADCC 的相对贡献进行分区考虑。重要的是，我们尚未充分探索 ADCP 阻断早期 HIV 和 SIV 复制的作用。 HIV 和 SIV 感染中均表现出短暂性和组织驻留 NK 细胞的不同扩增，但是这些人群以及其他 FcR- 的组织驻留或贩运亚群的相关性承载细胞仍不清楚，这些早期粘膜病灶中发生的事件仍不清楚。对抑制病毒持续复制和高度动态传播的功能相互作用的重要见解粘膜环境，包括 IgG 和 FcR 库的一系列遗传变异性以及与人类相比，NHP FcR 具有显着的异质性，该项目将探讨具体的假设。最佳抗病毒抗体活性受到效应细胞的组织分布和 FcR 表达的影响，可以对其进行调整以增强疫苗反应和随后针对 SHIV 挑战的保护。项目3的具体目标如下：目标 1：定义抗体和携带 FcR 的细胞对 SIV/SHIV 感染细胞的体内识别 GI 和 FRT 粘膜。目标 2. 确定人免疫球蛋白亚类的体内抗病毒特性。目标 3. 确定携带 FcR 的细胞对预防粘膜 SHIV 的相对贡献挑战。