Antiviral Activity In Situ

摘要_项目3 抗HIV抗体可以与宿主细胞上差异表达的多种Fc受体（FcRs）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性（ADCC）。人类被动和主动接种疫苗 和非人灵长类动物（NHP）的研究表明，ADCC以及吞噬作用是一致的 保护的相关性。然而，检测IgG亚类和同种异型对免疫缺陷的机制相关性， 抗病毒活性仍然非常有限。携带FcR的细胞也具有广泛的分布，其可以变化 广泛地通过细胞类型、组织和物种，并且在NHP中仍然不完全表征，特别是在粘膜中， 慢病毒的传播途径。此外，对ADCC相对贡献的房室考虑 和ADCP阻断早期HIV和SIV复制的作用仍有待研究。重要的是我们有 证明了在HIV和SIV感染中瞬时和组织驻留NK细胞的不同扩增，但 这些群体以及其他FcR的组织驻留或贩运亚群的相关性， 生育细胞尚不清楚。明确这些早期粘膜病灶中发生的事件将提供 关键的洞察功能的相互作用，抑制正在进行的病毒复制和传播的高度动态的 粘膜环境，包括一系列的遗传变异性的IgG和Fc γ R库和 与人类相比，NHP Fc β R具有显著异质性。本项目将探讨具体的假设 最佳的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， 其可以被调节以增强疫苗应答和随后的针对SHIV攻击的保护。的 项目3的具体目标如下： 目的1：确定抗体和FcR携带细胞对SIV/SHIV感染细胞的体内识别， GI和FRT粘膜。 目标2.定义人免疫球蛋白亚类在体内的抗病毒特性。 目标3。确定携带FcR的细胞对粘膜SHIV保护的相对贡献 挑战.

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.