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这样一个前提： 在人类和非人类灵长类动物中，抗环境抗体(Ab)反应将保护人们免受HIV、SIV或SIV的感染 (NHP)，如果在暴露前存在。体液反应包括两个必须考虑的AB函数 艾滋病毒预防：通过表位-副表位相互作用实现的直接中和活动；以及招募 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 已经对中和活性的应用进行了详尽的研究，抗体Fc介导的用途 在预防艾滋病毒方面的作用仅有部分定义。此外，这些功能如何允许非中和 提供保护性人体免疫的抗体(NnAbbs)是一个悬而未决但意义重大的问题 NnAb识别不变表位，可通过疫苗接种而提高，并在 实验环境。过去在保护和NNAB之间建立明确联系方面的限制很可能是 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，最优 应用抗体和/或使用动物模型进行疗效测试。因此，该项目的目标是 填补这些信息空白，并确定Fc介导的免疫功能是否以及如何最 有效地用于合理设计艾滋病毒预防方法。我们将利用动物方面的最新进展 模型和Fc-FcR依赖免疫建立新的方法，可以桥接表位呈递 模式，效应细胞募集和靶细胞原位杀伤，以及体内的保护效果。我们将验证 我们的数据提出了Fc介导的免疫预防HIV感染的两种假设情景。1) 根据可识别的特性，非中和抗体将在人类免疫背景中显示效力 表位靶向、同型和Fc介导的效应机制。2)bNAbs和Crox的多克隆混合物 反应性nnAbbs在人类免疫背景下将提供比任何一种单独的Ab型更有效的保护； 从而在体内提供保护性效果，否则将是限制滴度。这些将使用以下工具进行测试 用于产生人类背景和效应器的新型体外系统和免疫缺陷小鼠 机制，以及在RM免疫背景下的对比实验。具体目标是： 目的1.确定在初级感染系统中对FC介导的活动的脆弱性窗口。 目的2.证明nnAbbs及其Fc依赖功能，单独和/或不起作用 BNab滴度，预防体内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.