Mechanisms of Antibody Fc Mediated Protection

抗体 Fc 介导的保护机制

基本信息

批准号：
10258150
负责人：
GEORGIA Doris TOMARAS
金额：
$ 60.67万
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/10258150
关键词：
AIDS prevention Animal Model Antibodies Antibody Binding Sites Antibody Response Antibody titer measurement Antibody-mediated protection Antiviral Agents Biophysics CD4 Positive T Lymphocytes Cell physiology Cells Complement Data Databases Differentiation Antigens Effector Cell Epitopes Exhibits Fc Receptor Flow Cytometry Goals HIV HIV Infections HIV vaccine Human Humoral Immunities Immune Immune system Immunity Immunodeficient Mouse Immunoprevention In Situ In Vitro Infection Knowledge Link Macaca mulatta Measures Mediating Methods Modeling Mouse Strains Natural Killer Cells Nature Neutralization Tests Outcome Pattern Phagocytosis Primary Infection SIV Surface System Testing Therapeutic Vaccination Virus antibody test antibody-dependent cell cytotoxicity base cell killing comparative confocal imaging cross reactivity design efficacy testing exhaustion experimental study granulocyte humanized mouse imaging modality immune function in vivo monocyte neutralizing antibody nonhuman primate novel novel strategies preservation prevent programs protective effect protective efficacy reactivation from latency reconstitution recruit response simian human immunodeficiency virus

项目摘要

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.

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基于以下前提：抗 Env 抗体 (Ab) 反应将预防人类和非人类灵长类动物感染 HIV、SIV 或 SHIV (NHP) 如果在暴露前存在体液反应，则必须考虑包含两种抗体功能的情况。艾滋病毒预防：通过表位-互补位相互作用和招募来实现直接中和活动；通过 Fc-Fc 受体相互作用，产生抗病毒效应细胞（NK 细胞、单核细胞、粒细胞）。中和活性的应用已被详尽地研究，抗体 Fc 介导的效用 HIV 预防中的功能仅部分定义。此外，这些功能如何实现非中和。提供保护性人类免疫力的抗体（nnAbs）是一个尚未解决但重要的问题，因为许多人 nnAb 识别不变表位，可通过疫苗接种产生，并在体内招募 Fc 介导的效应功能过去在保护和 nnAb 之间建立明确联系方面可能存在局限性。 FC 介导的功能可能是由于对靶表位敏感性、最佳因此，该项目的目标是应用抗体和/或使用动物模型进行功效测试。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发挥最大作用我们将利用动物方面的最新进展模型和 Fc-FcR 依赖性免疫来构建可以桥接表位呈递的新方法我们将验证模型、效应细胞募集和原位靶细胞杀伤以及体内保护功效。我们的数据表明 Fc 介导的免疫预防 HIV 感染的两种假设情景 1)。非中和抗体将根据可识别的质量在人类免疫背景中表现出功效表位靶向、同种型和 Fc 介导的效应机制 2) bnAb 和交叉抗体的多克隆混合物。反应性 nnAb 在人类免疫背景下比单独的任一抗体类型提供更有效的保护；从而在体内提供保护功效，否则将使用限制滴度。新型体外系统和免疫缺陷小鼠重组以产生人类背景和效应物 RM 免疫背景的机制以及比较实验的具体目标是：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/或与亚效一起使用 bnAb 滴度，可防止体内 HIV 感染。