Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma
Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma
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DOI：
10.1371/journal.pbio.3000562
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发表时间：
2020-07-01
期刊：
影响因子：
9.8
通讯作者：
Watashi, Koichi
中科院分区：
文献类型：
--
作者：
Iwanami, Shoya;Kitagawa, Kosaku;Watashi, Koichi
病毒增殖涉及受感染细胞内的基因复制和向新靶细胞的传播。一旦正链RNA病毒感染细胞，病毒基因组就作为复制的模板（“停留策略”）或包装成将在细胞外释放的子代病毒体（“离开策略”）。基因组复制和病毒体释放之间的平衡决定了病毒的产生和传播效力。随之而来的权衡尚未得到很好的描述。在这项研究中，我们使用丙型肝炎病毒（HCV）作为一个模型系统来研究这两种策略的平衡。结合病毒感染细胞培养试验与数学建模，我们表征了两种不同的HCV毒株（JFH-1，临床分离株，和Jc 1-n，实验室菌株），这具有不同的病毒释放特性的动力学。我们发现，分别有0.63%和1.70%的JFH-1和Jc 1-n细胞内病毒RNA用于产生和释放子代病毒粒子。HCV基因组的马尔萨斯参数的分析（即，初始增殖率）和新生感染的数量（即，初始传播率）表明离开策略为Jc 1-n提供了更高水平的初始传播，而相比之下，停留策略为JFH-1提供了更高的初始增殖率。因此，病毒动力学的理论-实验分析使我们能够更好地了解病毒的增殖策略，这有助于有效控制病毒的传播。我们的研究是第一次分析病毒生命周期中的停留-离开权衡以及复制-释放转换机制对病毒增殖的意义。
Virus proliferation involves gene replication inside infected cells and transmission to new target cells. Once positive-strand RNA virus has infected a cell, the viral genome serves as a template for copying ("stay-strategy") or is packaged into a progeny virion that will be released extracellularly ("leave-strategy"). The balance between genome replication and virion release determines virus production and transmission efficacy. The ensuing trade-off has not yet been well characterized. In this study, we use hepatitis C virus (HCV) as a model system to study the balance of the two strategies. Combining viral infection cell culture assays with mathematical modeling, we characterize the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral release characteristics. We found that 0.63% and 1.70% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial proliferation rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leave-strategy provides a higher level of initial transmission for Jc1-n, whereas, in contrast, the stay-strategy provides a higher initial proliferation rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses, which contributes to the efficient control of virus transmission. Ours is the first study to analyze the stay-leave trade-off during the viral life cycle and the significance of the replication-release switching mechanism for viral proliferation.