Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD, United States.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, United States.
Front Immunol. 2018 May 28;9:1117. doi: 10.3389/fimmu.2018.01117. eCollection 2018.
Hepatitis C virus (HCV) is a major global health concern, and though therapeutic options have improved, no vaccine is available despite decades of research. As HCV can rapidly mutate to evade the immune response, an effective HCV vaccine must rely on identification and characterization of sites critical for broad immune protection and viral neutralization. This knowledge depends on structural and mechanistic insights of the E1 and E2 envelope glycoproteins, which assemble as a heterodimer on the surface of the virion, engage coreceptors during host cell entry, and are the primary targets of antibodies. Due to the challenges in determining experimental structures, structural information on E1 and E2 and their interaction is relatively limited, providing opportunities to model the structures, interactions, and dynamics of these proteins. This review highlights efforts to model the E2 glycoprotein structure, the assembly of the functional E1E2 heterodimer, the structure and binding of human coreceptors, and recognition by key neutralizing antibodies. We also discuss a comparison of recently described models of full E1E2 heterodimer structures, a simulation of the dynamics of key epitope sites, and modeling glycosylation. These modeling efforts provide useful mechanistic hypotheses for further experimental studies of HCV envelope assembly, recognition, and viral fitness, and underscore the benefit of combining experimental and computational modeling approaches to reveal new insights. Additionally, computational design approaches have produced promising candidates for epitope-based vaccine immunogens that specifically target key epitopes, providing a possible avenue to optimize HCV vaccines versus using native glycoproteins. Advancing knowledge of HCV envelope structure and immune recognition is highly applicable toward the development of an effective vaccine for HCV and can provide lessons and insights relevant to modeling and characterizing other viruses.
丙型肝炎病毒 (HCV) 是一个全球性的主要健康问题，尽管治疗选择有所改善，但经过几十年的研究仍没有疫苗可用。由于 HCV 可以迅速突变以逃避免疫反应，因此有效的 HCV 疫苗必须依赖于识别和表征对广泛免疫保护和病毒中和至关重要的位点。这方面的知识取决于 E1 和 E2 包膜糖蛋白的结构和机制见解，这些糖蛋白在病毒粒子表面组装成异二聚体，在宿主细胞进入过程中与核心受体结合，并且是抗体的主要靶标。由于确定实验结构的挑战，关于 E1 和 E2 及其相互作用的结构信息相对有限，为模拟这些蛋白质的结构、相互作用和动力学提供了机会。这篇综述重点介绍了模拟 E2 糖蛋白结构、功能性 E1E2 异二聚体组装、人核心受体的结构和结合以及关键中和抗体的识别的努力。我们还讨论了最近描述的全 E1E2 异二聚体结构模型的比较、关键表位位点动力学的模拟以及糖基化的建模。这些建模工作为进一步研究 HCV 包膜组装、识别和病毒适应性提供了有用的机制假设，并强调了将实验和计算建模方法相结合以揭示新见解的好处。此外，计算设计方法已经产生了针对关键表位的基于表位的疫苗免疫原的有希望的候选物，为针对 HCV 疫苗的优化提供了可能的途径，而不是使用天然糖蛋白。丙型肝炎病毒包膜结构和免疫识别知识的进步非常适用于开发有效的 HCV 疫苗，并且可以为建模和表征其他病毒提供相关的经验和见解。
