Impact of Antibody Effector Function Diversity on Antiviral Activity In Situ

抗体效应子功能多样性对原位抗病毒活性的影响

• 批准号: 10475274
• 负责人: GEORGIA Doris TOMARAS
• 金额: $ 426.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10475274
• 关键词: Acquired Immunodeficiency Syndrome; Animal Model; Antibodies; Antibody Specificity; Autologous; Biological Models; Biophysics; COVID-19 impact; Cells; Cellular biology; Clinical; Clinical Research; Collaborations; Communicable Diseases; Educational process of instructing; Effector Cell; Elements; Environment; Epitopes; Fc Receptor; Fc domain; Genetic Determinism; Genotype; Goals; HIV Infections; HIV-1; Heterogeneity; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin Allotypes; In Situ; In Vitro; Infection; Joints; Knowledge; Learning; Macaca mulatta; Mediating; Methods; Modeling; Monoclonal Antibodies; Outcome; Phagocytes; Population; Positioning Attribute; Pre-Clinical Model; Prevention; Property; Public Health; Receptor Cell; Recording of previous events; Resources; Role; Sampling; Serum; Source; Specimen; Structure; Testing; Therapeutic; Vaccines; Viral Antibodies; Virus; Virus Replication; Work; antiviral immunity; base; cohort; defined contribution; efficacy trial; experimental study; fighting; global health; human model; humanized mouse; immunoprophylaxis; improved; in vivo; mouse model; neutralizing antibody; pandemic disease; pathogen; polyclonal antibody; preclinical study; prevent; programs; prophylactic; protective efficacy; rational design; response; treatment planning; vaccine efficacy; vaccine strategy

ABSTRACT_Overall Preventing HIV-1 acquisition and extinguishing virus replication is a key goal for vaccine and immunoprophylaxis strategies. Diverse antibody (Ab) Fc receptor (FcR)-mediated functions and multiple effector cell populations engage in vivo in a joint merger to thwart infection. An improved understanding of specific functional and qualitative features of the humoral response and how they contribute to protective efficacy is needed. Results from immune correlates analyses of vaccine efficacy trials, immunoprophylaxis trials and preclinical studies indicate that antibody constant (Fc) region mediated antiviral activity is an untapped source of antiviral functions to afford broad and potent protection against HIV infection. Full exploitation of this potential demands a more complete understanding of Fc-mediated immune mechanisms in humans and animal models. Rational design of prevention methods requires more information regarding epitope targets, cognate polyclonal antibody (Ab) isotypes and subclasses, diverse FcR and effector cell populations, and most important, how these elements can be pulled together for the greatest antiviral impact. The goal of this program is to define how Fc-mediated immunity can be used for preventing, treating, curing HIV infection. We propose to determine the combined impact of antibody Fc and effector cells on antiviral outcomes in situ, thus informing how antibody Fc effector functions can be used to improve antibody- based vaccine strategies, increase the relative antiviral activity of HIV-1 specific antibody subclasses, and augment bnAb- based prophylactic and therapeutic approaches. Our central hypothesis is that antibody antiviral potency is maximal when multiple antibody specificities and subclasses are combined and that their antiviral functions are modulated by the in vivo localization of FcR-bearing effector cells and host genetic determinants of Fc-FcR engagement. Harnessing Fc function will improve bnAb vaccine strategies given the need to increase the antiviral functions of neutralizing antibodies (nAbs) at sub-efficacious levels. Toward this end, we propose three synergistic, inter-related Projects supported by two Cores and an Administrative Core to achieve the following Overall Aims: 1. Identify combinations of bnAb and nnAb antibody specificities with maximal antiviral activity. 2. Define the contribution of antibody Fc domain (subclass, allotype) on antiviral functions. 3. Determine FcR and effector cell populations responsible for maximal Ab Fc antiviral functions in situ.

摘要_总体 预防HIV-1的获得和消灭病毒复制是疫苗和 免疫预防策略。不同的抗体（Ab）Fc受体（FcR）介导的功能和多种 效应细胞群在体内参与联合融合以阻止感染。更好地理解 体液反应的特定功能和定性特征，以及它们如何有助于保护 需要有效性。疫苗有效性试验的免疫相关性分析结果，免疫预防 试验和临床前研究表明，抗体恒定区（Fc）介导的抗病毒活性是一种抗病毒药物， 这种尚未开发的抗病毒功能来源，可提供广泛而有效的保护，防止艾滋病毒感染。充分 开发这种潜力需要更全面地了解Fc介导的免疫机制， 人类和动物模型。合理设计预防方法需要更多的信息， 表位靶点、同源多克隆抗体（Ab）同种型和亚类、不同的FcR和效应细胞 人群，最重要的是，如何将这些元素聚集在一起以产生最大的抗病毒效果。 该计划的目标是定义Fc介导的免疫如何用于预防，治疗， 治愈艾滋病病毒感染。我们建议确定抗体Fc和效应细胞对细胞增殖的联合影响。 原位抗病毒结果，从而告知抗体Fc效应子功能如何可用于改善抗体- 基于疫苗策略，增加HIV-1特异性抗体亚类的相对抗病毒活性， 增强基于bnAb的预防和治疗方法。我们的核心假设是抗体 当多种抗体特异性和亚类组合时， 抗病毒功能通过携带FcR的效应细胞的体内定位和宿主基因表达来调节。 Fc-FcR接合的决定因素。利用Fc功能将改善bnAb疫苗策略， 需要在亚有效水平增加中和抗体（nAb）的抗病毒功能。朝着这个 最后，我们建议三个互相配合、互相关连的项目，由两个核心项目和一个行政核心项目支援， 实现以下总体目标： 1.鉴定具有最大抗病毒活性的bnAb和nnAb抗体特异性的组合。 2.定义抗体Fc结构域（亚类，同种异型）对抗病毒功能的贡献。 3.确定负责最大Ab Fc抗病毒功能的FcR和效应细胞群 原地。