Building a mechanistic mathematical model of hepatitis C virus entry
Building a mechanistic mathematical model of hepatitis C virus entry
复制标题
DOI：
10.1371/journal.pcbi.1006905
复制
发表时间：
2019-03-01
影响因子：
4.3
通讯作者：
Illingworth, Christopher J. R.
中科院分区：
文献类型：
--
作者：
Kalemera, Mphatso;Mincheva, Dilyana;Illingworth, Christopher J. R.
丙型肝炎病毒 (HCV) 进入细胞的机制非常复杂，涉及多种宿主蛋白。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，人们对于丙型肝炎病毒进入的机制仍然知之甚少。在这里，我们描述了一种新的病毒进入计算模型，涵盖 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数学模型，然后通过进一步的实验进行验证。我们的结果与连续的 HCV-受体相互作用一致，即 HCV E2 糖蛋白和 SR-B1 之间的初始相互作用促进 CD81 受体的积累，导致病毒进入。然而，我们还证明，少数病毒可以在没有 SR-B1 的情况下进入。我们的模型估计了病毒进入时必须克服的不同障碍的影响；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%然后完成后续步骤以实现有效感染。此外，我们对受体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。我们的模型提供了一个研究 HCV 变体进入特征的工具，并概述了未来 HCV 进入多受体动力学定量研究的框架。 作者摘要 丙型肝炎病毒影响着全世界大约 7000 万人，对人类健康产生了重大影响。该病毒通过与人类细胞表面蛋白质的一系列复杂的相互作用来启动感染。在这里，我们将实验方法与新的数学模型相结合来研究病毒进入的过程。我们的模型成功地捕捉了实验行为，显示了细胞表达的人类蛋白质 CD81 和 SR-B1 数量的变化如何改变病毒进入细胞的概率。我们的模型表明，需要超过 10 个 CD81 受体才能进入细胞，并表明病毒进入是一项艰巨的任务，许多病毒在进入过程的不同阶段都失败了。我们的模型为进一步定量研究 HCV 病毒进入过程奠定了基础。
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 virus 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.Author summary Hepatitis C virus affects approximately 70 million people worldwide, resulting in a significant impact on human health. The virus initiates infection through a complex set of interactions with proteins on the surface of human cells. Here we combine experimental approaches with a new mathematical model to study the process of viral entry. Our model is successful in capturing the behaviour of experiments, which show how changes in the amount of the human proteins CD81 and SR-B1 expressed by a cell alter the probability of a virus getting into a cell. Our model suggests that more than 10 CD81 receptors are needed to gain entry into a cell, and shows that viral entry is a difficult task, with many viruses failing at different stages of the entry process. Our model sets out a basis for further quantitative research into the process of HCV viral entry.