Building a mechanistic mathematical model of hepatitis C virus entry

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（hepatitis C virus, HCV）侵入宿主细胞的机制极为复杂，涉及多种宿主蛋白。病毒侵入是病毒生命周期的关键阶段，同时也是治疗干预或疫苗介导防控的潜在靶点。然而，目前人们对HCV侵入的具体机制仍知之甚少。本文报道一种全新的病毒侵入计算模型，该模型涵盖了HCV与关键宿主受体CD81、SR-B1之间的相互作用关系。我们开展实验，系统量化了受体表达水平上调或下调对病毒侵入程度的影响。基于上述实验数据，我们构建并参数化了一个数学模型，并通过额外实验对该模型进行验证。我们的研究结果支持HCV与受体的序贯相互作用模式：HCV E2糖蛋白与SR-B1的初始结合，可促进CD81受体的募集，进而介导病毒侵入。不过，我们同时证实，仅有极少数病毒可在缺乏SR-B1的情况下完成侵入过程。本模型估算了病毒完成侵入所需克服的各类障碍：在附着于细胞表面的病毒颗粒中，约三分之一可募集足够数量的CD81受体；其中4%至8%的病毒能够完成后续步骤，最终建立产性感染。此外，我们还对受体化学计量比进行了估算：病毒完成侵入所需的受体数量大概率超过10个。本模型为研究不同HCV变异株的侵入特性提供了研究工具，同时也为未来开展HCV侵入过程的多受体动态定量研究搭建了理论框架。