Linking Antibody Cooperativity and Effector Cell Engagement

摘要_项目2 HIV-1疫苗设计的一个关键目标是诱导广泛中和反应。虽然这一目标已 尚未实现，在非人灵长类动物中的临床前研究已经确定了几种疫苗策略， 在不诱导广泛中和抗体的情况下实现了一定水平的保护。这些发现和 来自该领域的新数据表明，一条可实现的前进道路是利用多克隆反应， 由多种抗体反应组成，这些抗体反应共同作用以消除病毒复制。一个关键的差距， 知识是疫苗引发的多克隆抗体应答的性质， 在非人灵长类动物的粘膜组织内的感染，以转化为对人类的保护 临床试验此外，缺乏关于如何最好地设计非- 中和抗体和中和抗体以在粘膜区室募集携带Fc受体的细胞， 利用不同的抗体组合来改善保护。我们的中心假设是， 多克隆抗体应答的组成显著影响单核细胞和NK细胞的募集， Fc介导的功能的合作。为了检验我们的主要假设，我们将评估以下组合： 单克隆抗体和多克隆疫苗诱导的血浆抗体，因为它们能够更有效地杀死 通过检查感染细胞的抗体依赖性细胞介导的杀伤和/或吞噬作用来检测感染细胞。 我们将定义通过有效的多克隆抗体募集的携带Fc受体的细胞的转录组学特征， 制备，以了解最佳的FcR-轴承细胞，应招募有效的疫苗诱导 抗体的这些特征将有助于了解物种特异性FcR和细胞多样性如何影响 从恒河猴到人类。最后，我们将确定 通过最佳mAb组合招募的携带FcR的细胞，因为它们能够消除感染的细胞并分泌 具有有限促炎特征的抗病毒细胞因子。这些问题将在下文中讨论 目的： 目标1.定义IgG 1、IgG 3和伊加对感染细胞和病毒颗粒识别的贡献。 目标2.鉴定由IgG 1、IgG 3和多克隆抗体募集的效应细胞亚群的功能特性 抗体组合。 目标3：确定单核细胞和NK细胞是否连续募集以消除受感染的细胞。

ABSTRACT_Project 2 A key goal for HIV-1 vaccine design is the induction of broadly neutralizing responses. Although this goal has not been achieved, preclinical studies in non-human primates have identified several vaccine strategies that achieved some level of protection without inducing broadly neutralizing antibodies. These findings and emerging data from the field indicate that an achievable path forward is to leverage a polyclonal response comprised of multiple antibody responses that work together to eliminate virus replication. A critical gap in knowledge is the nature of vaccine-elicited polyclonal antibody responses that can achieve protection against infection within mucosal tissues in the non-human primates in order to translate into protection in human clinical trials. Moreover, there is a lack of information on how best to design polyclonal combinations of non- neutralizing and neutralizing antibodies to recruit Fc-Receptor bearing cells at the mucosal compartment to leverage different antibody combinations for improved protection. Our central hypothesis is that the composition of polyclonal Ab responses significantly impacts recruitment of monocytes and NK cells and their cooperation for Fc-mediated functions. To test our primary hypothesis, we will evaluate combinations of monoclonal antibody and polyclonal vaccine-induced plasma antibodies for their ability to more efficiently kill infected cells by examining antibody-dependent cellular mediated killing and/or phagocytosis of infected cells. We will define the transcriptomic profile of Fc-receptor bearing cells recruited by effective polyclonal preparations to understand the optimal FcR-bearing cells that should be recruited by effective vaccine-induced antibodies. These signatures will enable to understand how species-specific FcR and cellular diversity impact translation from rhesus macaques to humans. Lastly, we will determine differences in the interaction between FcR-bearing cells recruited by optimal mAb combinations for their ability to eliminate infected cells and secrete antiviral cytokines with limited pro-inflammatory profile. These questions will be addressed in the following Aims: Aim 1. Define contribution of IgG1, IgG3, and IgA for recognition of infected cells and virus particles. Aim 2. Identify the functional properties of effector cell subsets recruited by IgG1, IgG3, and polyclonal Ab combinations. Aim 3. Determine whether monocytes and NK cells are serially recruited to eliminate infected cells.