Bridging Antibody Fc-mediated Antiviral Functions Across Humans and Non-human Primates

 描述(由申请人提供)：HIV-1疫苗效力试验和多项动物研究，包括与HIV治愈策略有关的研究表明，抗体与细胞的相互作用--由抗体恒定(Fc)区介导--可以利用免疫系统的多个方面，通过中和以外的机制提供保护。然而，目前尚不清楚包括Fc介导的抗体功能诱导的候选HIV-1疫苗方案是否可以在恒河猴(RM)非人类灵长类(NHP)身上以一种可以移植到人类的方式进行测试。为了更有效地将从RM研究中获得的见解转化到临床上，有必要充分定义Fc介导的抗体功能在恒河猴和人类中的保护性特征。我们提出的工作将绘制人类和RMS中的抗体(Ab)和Fc受体(FCR)生物学图，目标是使RMS中观察到的保护反应更能预测人类反应，从而加速最有希望的疫苗概念成功地推进到临床。我们的中心假设是，通过阐明影响物种特异性FcγR依赖的效应器功能的关键变量(即抗体表位特异性、免疫复合体形成、同型/亚类、糖基化和FCR型/表型)，RM模型可以显著改进以抗体为基础的干预措施和疫苗。为了测试这一点，我们提出了三个协同的、相互关联的科学项目，由三个核心支持，以实现以下总体目标：总体目标1.表征跨RM到人类的有效抗HIV-1 Fc-FCR生物学。总体目的2.定义HIV-1病毒粒子和感染细胞表位用于抗体识别。总体目标3.确定产生最大抗HIV-1活性的抗体的Fv和Fc特征。

 DESCRIPTION (provided by applicant): HIV-1 vaccine efficacy trials and multiple animal studies, including those related to HIV-cure strategies, have shown that antibody interactions with cells - mediated by the antibody constant (Fc) region - can harness multiple aspects of the immune system to provide protection through mechanisms other than by neutralization. However, it is unknown whether candidate HIV-1 vaccine regimens that include induction of Fc-mediated antibody functions can be tested in the rhesus macaque (RM) nonhuman primate (NHP) in a way that can be translated to humans. In order to more effectively translate insights gained from RM studies to the clinic, there is a need to fully define the protective signatures of Fc-mediated antibody functions across rhesus macaques and humans. The work we propose will map antibody (Ab) and Fc-receptor (FcR) biology across humans and RMs with the goal of making observed protective responses in RMs more predictive of human responses, thus accelerating the most promising vaccine concepts to be advanced to the clinic with success. Our central hypothesis is that the RM model can be substantially improved for testing antibody-based interventions and vaccines through elucidation of key variables that impact species-specific FcγR-dependent effector functions (i.e. antibody epitope specificity, immune complex formation, isotype/subclass, glycosylation, and FcR genotype/phenotype). To test this, we propose three synergistic, inter-related scientific Projects supported by three Cores to achieve the following Overall Aims: Overall AIM 1. Characterize effective anti-HIV-1 Fc-FcR biology across RM to humans. Overall AIM 2. Define HIV-1 virion and infected cell epitopes for antibody recognition. Overall AIM 3. Determine the Fv and Fc features of antibodies yielding maximal anti-HIV-1 activity.