Mechanisms of Antibody Fc Mediated Protection

摘要_项目1 开发艾滋病毒疫苗和其他免疫预防方法的主要努力是基于以下前提： 抗Env抗体（Ab）应答将保护人类和非人灵长类动物免受HIV、SIV或SHIV的侵害 (NHP)如果在暴露前存在话。体液反应包括必须考虑的两种Ab功能 HIV预防：通过表位-互补位相互作用实现的直接中和活性; 抗病毒效应细胞（NK细胞、单核细胞、粒细胞），通过Fc-Fc受体相互作用。虽然 已经详尽地研究了中和活性的应用，抗体Fc介导的中和活性的效用已经被证明是有效的。 艾滋病毒预防的职能只是部分界定。此外，这些功能如何允许非中和 提供保护性人类免疫的抗体（nnAb）是一个尚未解决但重要的问题， nnAb识别不变表位，可以通过疫苗接种产生，并在免疫应答中募集Fc介导的效应子功能。 实验设置。过去在建立保护和nnAb之间的明确联系方面的局限性可能是 FC介导的功能可以通过对靶表位敏感性的不完全理解来解释， Ab的应用和/或用于功效测试的动物模型的使用。因此，本项目的目标是 填补这些信息空白，并确定是否以及如何Fc介导的免疫功能可以最 有效地用于合理设计艾滋病毒预防方法。我们将利用动物实验的最新进展 模型和Fc-Fc CD 4 R依赖性免疫，以建立能够桥接表位呈递的新方法 模式、效应细胞募集和靶细胞原位杀伤以及体内保护功效。我们将验证 我们的数据表明Fc介导的免疫在预防HIV感染中的两种假设情况。第一章 非中和抗体将根据以下可识别的性质在人免疫背景中表现出功效： 表位靶向、同种型和Fc介导的效应器机制。2)bnAbs和cross- 反应性nnAb将在人免疫背景中提供比单独的任一Ab类型更有效的保护; 从而在体内提供保护效力，否则其将是限制性滴度。这些将使用 新的体外系统和免疫缺陷小鼠重建以产生人背景和效应物 机制，以及在RM免疫背景下的比较实验。具体目标是： 目标1。确定原发感染系统中Fc介导活动的脆弱性窗口。 目标2.证明nnAb及其Fc依赖性功能，单独使用和/或与亚效 bnAb滴度，在体内防止HIV感染。

ABSTRACT_Project 1 Major efforts to develop HIV vaccines and other immunoprevention approaches are based on the premise that anti-Env antibody (Ab) responses will protect against HIV, SIV or SHIV in humans and nonhuman primates (NHP) if present before exposure. Humoral responses comprise two Ab functions that must be considered for HIV prevention: direct neutralizing activity, enabled by epitope-paratope interactions; and the recruitment of antiviral effector cells (NK cells, monocytes, granulocytes), via Fc-Fc receptor interactions. Although applications of neutralizing activity have been exhaustively studied, the utility of antibody Fc-mediated functions in HIV prevention is only partially defined. Further, how these functions allow non-neutralizing antibodies (nnAbs) to afford protective human immunity is an unresolved but significant question as many nnAbs recognize invariant epitopes, can be raised by vaccination, and recruit Fc-mediated effector functions in experimental settings. It is likely that past limitations in establishing clear links between protection and nnAb FC-mediated functions may be explained by an incomplete understanding of target epitope sensitivity, optimal applications of Abs and/or usage of animal models for efficacy testing. Accordingly, the goal of this project is to fill these information gaps and determine whether and how Fc-mediated immune functions can be most effectively employed for the rational design of HIV prevention methods. We will use recent advances in animal models and Fc-FcR dependent immunity to build new approaches that can bridge epitope presentation patterns, effector cell recruitment and target cell killing in situ, and protective efficacy in vivo. We will validate two hypothetical scenarios for Fc-mediated immunity in preventing HIV infection suggested by our data. 1) Non-neutralizing Abs will exhibit efficacy in a human immune background according to identifiable qualities of epitope targeting, isotype and Fc-mediated effector mechanism. 2) Polyclonal mixtures of bnAbs and cross- reactive nnAbs will afford more potent protection in a human immune background than either Ab type alone; thus affording protective efficacy in vivo at what would otherwise be limiting titers. These will be tested using novel in vitro systems and immunodeficient mice reconstituted to produce human backgrounds and effector mechanisms, as well as comparative experiments in RM immune backgrounds. The Specific Aims are: Aim 1. Identify windows of vulnerability to Fc-mediated activities in a primary infection system. Aim 2. Demonstrate that nnAbs and their Fc-dependent functions, alone and/or with sub-efficacious bnAb titers, protect against HIV infection in vivo.