Antiviral Activity In Situ

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，发挥广泛的功能，包括抗体依赖细胞吞噬(ADCP) 抗体依赖细胞介导的细胞毒作用(ADCC)。人类的被动和主动疫苗接种 非人灵长类动物(NHP)的研究表明，ADCC和吞噬作用是一致的 保护的关联性。然而，对免疫球蛋白亚类和同种异型的机械相关性的测试 抗病毒活性仍然极其有限。携带FCR的细胞也有广泛的分布，这可能会有所不同 广泛存在于细胞类型、组织和物种中，但在NHP中仍未完全表现出特征，特别是在粘膜中 慢病毒传播的场所。此外，关于ADCC的相对贡献的分部考虑 而ADCP对阻断早期HIV和SIV复制的作用仍未得到充分探索。重要的是，我们有 在HIV和SIV感染中，瞬时和组织驻留的NK细胞表现出不同的扩张，但 这些人口以及其他FCR组织居留或贩运亚群的相关性-- 目前尚不清楚是否有轴承细胞。确定在这些早期粘膜病灶中发生的事件将提供 对抑制病毒持续复制并以高度动态的方式传播的功能交互的关键见解 粘膜环境，包括一系列免疫球蛋白和FcR谱系的遗传变异性以及 与人类相比，NHP FcR具有显著的异质性。本项目将探索具体的假设 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， 可以对其进行调整，以增强疫苗反应和随后对SIV挑战的保护。这个 项目3的具体目标如下： 目的1：明确抗体和FCR细胞对SIV/SHV感染细胞的体内识别作用。 GI和FRT粘膜。 目的2.确定人免疫球蛋白亚类的体内抗病毒特性。 目的3.确定携带FCR的细胞对黏膜移位病毒的保护作用 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.