Harvard Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, United States.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.
Front Immunol. 2022 Jun 17;13:904609. doi: 10.3389/fimmu.2022.904609. eCollection 2022.
The dynamic interplay between virus and host plays out across many interacting surfaces as virus and host evolve continually in response to one another. In particular, epitope-paratope interactions (EPIs) between viral antigen and host antibodies drive much of this evolutionary race. In this review, we describe a series of recent studies examining aspects of epitope complexity that go beyond two interacting protein surfaces as EPIs are typically understood. To structure our discussion, we present a framework for understanding epitope complexity as a spectrum along a series of axes, focusing primarily on 1) epitope biochemical complexity (e.g., epitopes involving N-glycans) and 2) antigen conformational/dynamic complexity (e.g., epitopes with differential properties depending on antigen state or fold-axis). We highlight additional epitope complexity factors including epitope tertiary/quaternary structure, which contribute to epistatic relationships between epitope residues within- or adjacent-to a given epitope, as well as epitope overlap resulting from polyclonal antibody responses, which is relevant when assessing antigenic pressure against a given epitope. Finally, we discuss how these different forms of epitope complexity can limit EPI analyses and therapeutic antibody development, as well as recent efforts to overcome these limitations.
病毒和宿主之间的动态相互作用在许多相互作用的表面上展开，因为病毒和宿主不断相互进化以适应对方。特别是，病毒抗原和宿主抗体之间的表位-配体相互作用（EPIs）推动了这场进化竞赛。在这篇综述中，我们描述了一系列最近的研究，这些研究考察了表位复杂性的各个方面，超出了通常理解的 EPIs 仅限于两个相互作用的蛋白质表面。为了组织我们的讨论，我们提出了一个理解表位复杂性的框架，作为一系列轴上的一个谱，主要集中在 1）表位生化复杂性（例如，涉及 N-糖基化的表位）和 2）抗原构象/动态复杂性（例如，根据抗原状态或折叠轴具有不同特性的表位）。我们强调了其他表位复杂性因素，包括表位三级/四级结构，这有助于给定表位内或附近的表位残基之间的上位关系，以及多克隆抗体反应导致的表位重叠，这在评估针对给定表位的抗原压力时很重要。最后，我们讨论了这些不同形式的表位复杂性如何限制 EPI 分析和治疗性抗体的开发，以及最近克服这些限制的努力。
