Structure-Function Analytics Core

摘要_核心2 大量证据表明，不同的抗体(Ab)活动，包括Fc受体(Fcr)- 在减少病毒载量和阻止HIV-1感染方面的中介作用。尽管FCR效应器的作用 抗病毒活性的作用跨多个模型系统和抗体，机制洞察是复杂的 通过物种特定的解决方案来平衡有效的抗体效应器活性和破坏性炎症，独特 表位、效应器和抗体特异性因子，以及可用的效应器机制之间的区别 在血液和组织中。 尽管进化上很接近，但恒河猴(Rm)和人类抗体之间存在显著差异 表现在不同功能特征的抗体亚型和亚类、FCR表达的生物学 与生俱来的免疫细胞，以及它们的生物相互作用。该程序将扩展如何抗病毒的地图 抗HIV-1活性是通过不同的效应器机制完成的，涉及不同的 可溶性因子和效应细胞群，以及免疫复合体中独特的免疫球蛋白类型 在人类和RM中，它们的整体结构和生物学活动都不同。有持续的需要 在人类和动物模型中定义这种生物学，以便有效地将从新兴事物中获得的见解转化为 对临床的保护和治疗研究，以及燃料冲击性抗体免疫预防、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，并在实现以下目标方面发挥关键作用 通过提供对抗体特征的统一结构、生物物理、生化和数据分析来实现计划目标 以及Fv和Fc的相互作用，这是强大的抗病毒活性的基础。 目的1.明确有效的抗病毒抗体活性的生物物理基础。 目的2：确定有效的抗病毒抗体活性的结构基础。 目的3.对免疫细胞和抗体特性进行建模，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.