Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, United Kingdom.
Department of Genetics, University of Cambridge, Cambridge, United Kingdom.
PLoS Comput Biol. 2019 Mar 18;15(3):e1006905. doi: 10.1371/journal.pcbi.1006905. eCollection 2019 Mar.
The mechanism by which hepatitis C virus (HCV) gains entry into cells is a complex one, involving a broad range of host proteins. Entry is a critical phase of the viral lifecycle, and a potential target for therapeutic or vaccine-mediated intervention. However, the mechanics of HCV entry remain poorly understood. Here we describe a novel computational model of viral entry, encompassing the relationship between HCV and the key host receptors CD81 and SR-B1. We conduct experiments to thoroughly quantify the influence of an increase or decrease in receptor availability upon the extent of viral entry. We use these data to build and parameterise a mathematical model, which we then validate by further experiments. Our results are consistent with sequential HCV-receptor interactions, whereby initial interaction between the HCV E2 glycoprotein and SR-B1 facilitates the accumulation CD81 receptors, leading to viral entry. However, we also demonstrate that a small minority of viruses can achieve entry in the absence of SR-B1. Our model estimates the impact of the different obstacles that viruses must surmount to achieve entry; among virus particles attaching to the cell surface, around one third of viruses accumulate sufficient CD81 receptors, of which 4-8% then complete the subsequent steps to achieve productive infection. Furthermore, we make estimates of receptor stoichiometry; in excess of 10 receptors are likely to be required to achieve viral entry. Our model provides a tool to investigate the entry characteristics of HCV variants and outlines a framework for future quantitative studies of the multi-receptor dynamics of HCV entry.
丙型肝炎病毒 (HCV) 进入细胞的机制非常复杂，涉及广泛的宿主蛋白。进入是病毒生命周期的关键阶段，也是治疗或疫苗介导干预的潜在目标。然而，HCV 进入的机制仍知之甚少。在这里，我们描述了一种新的病毒进入计算模型，包括 HCV 与关键宿主受体 CD81 和 SR-B1 之间的关系。我们进行实验来彻底量化受体可用性的增加或减少对病毒进入程度的影响。我们使用这些数据来构建和参数化一个数学模型，然后通过进一步的实验进行验证。我们的结果与 HCV-受体的顺序相互作用一致，即 HCV E2 糖蛋白与 SR-B1 的初始相互作用促进了 CD81 受体的积累，从而导致病毒进入。然而，我们也证明了一小部分病毒可以在没有 SR-B1 的情况下实现进入。我们的模型估计了病毒必须克服的不同障碍对进入的影响；在附着在细胞表面的病毒颗粒中，大约三分之一的病毒积累了足够的 CD81 受体，其中 4-8%的病毒随后完成了后续步骤以实现有效的感染。此外，我们还对受体的化学计量进行了估计；可能需要超过 10 个受体才能实现病毒进入。我们的模型为研究 HCV 变体的进入特征提供了一种工具，并为未来 HCV 进入的多受体动力学的定量研究提供了一个框架。
