Structure-Function Analytics Core

摘要_核心 2 大量证据表明多种抗体 (Ab) 活性发挥作用，包括 Fc 受体 (FcR) - 介导的病毒载量减少和阻止 HIV-1 获得的功能。尽管 FcR 效应子的作用 抗病毒活性的功能跨多个模型系统和抗体，机制见解很复杂 通过物种特异性解决方案来平衡有效的抗体效应子活性与破坏性炎症，不同 表位、效应器和抗体特异性因素，以及可用效应器机制之间的区别 在血液和组织中。 尽管在进化上接近，恒河猴 (RM) 和人类抗体之间仍存在显着差异 生物学表现在 Ab 同种型和亚类、FcR 表达的不同功能特征 先天免疫细胞及其生物相互作用。该计划将扩展抗病毒地图 抗 HIV-1 的活性是通过不同的效应机制来完成的，涉及不同的参与 可溶性因子和效应细胞群，以及免疫复合物中独特的免疫球蛋白类型 人类和 RM 的整体结构和生物活性各不相同。仍然需要 在人类和动物模型中定义这种生物学，以便有效地转化从新兴技术中获得的见解 临床保护和治疗研究，并促进有效的抗体免疫预防、治疗策略和 疫苗设计。 结构-功能分析核心将支持项目 1、2 和 3，并在实现 计划目标是提供抗体特征的统一结构、生物物理、生化和数据分析 Fv 和 Fc 相互作用支撑有效的抗病毒活性。 目标 1. 确定有效抗病毒抗体活性的生物物理基础。 目标 2：确定有效抗病毒抗体活性的结构基础。 目标 3. 对免疫细胞和抗体特征的知识进行建模，以确定最佳的抗病毒活性。

ABSTRACT_Core 2 Considerable evidence suggests a role for diverse antibody (Ab) activities, including Fc receptor (FcR)- mediated functions in viral load reduction and in blocking HIV-1 acquisition. Although the role of FcR-effector function in antiviral activity holds across multiple model systems and Abs, mechanistic insights are complicated by species-specific solutions to balancing potent Ab effector activity with damaging inflammation, distinct epitope-, effector-, and Ab-specific factors, as well as distinctions between the effector mechanisms available in blood and tissue. Despite evolutionary proximity, significant differences between Rhesus macaque (RM) and human Ab biology that manifest in different functional characteristics of the Ab isotypes and subclasses, FcRs expressed on innate immune cells, and their biological interplay. This program will expand this map of how antiviral activity against HIV-1 is accomplished by diverse effector mechanisms, involving engagement of different soluble factors and effector cell populations, and distinctive immunoglobulin types in immune-complexes that vary in their overall architecture and biological activity, in both humans and RM. There is a continuing need to define this biology in humans and animal models in order to effectively translate insights gained from emerging protective and therapeutic studies to the clinic, and fuel impactful Ab immunoprophylaxis, cure strategies, and vaccine designs. The Structure-Function Analytics Core will support Projects 1, 2, and 3 and play a key role in achieving Program Goals by providing unifying structural, biophysical, biochemical, and data analysis of the Ab features and Fv and Fc interactions that underpin potent antiviral activities. Aim 1. Define the biophysical basis of potent antiviral Ab activity. Aim 2: Define the structural basis of potent antiviral Ab activity. Aim 3. Model the knowledge of immune cells and Ab features to define optimal antiviral activities.