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.

病毒增殖涉及受感染细胞内部的基因复制以及向新靶细胞的传播。一旦正链RNA病毒感染了细胞，病毒基因组就会作为复制的模板（“保持策略”）或被包装到将在细胞外释放的子代病毒体中（“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功效。随后的权衡尚未很好地表征。在这项研究中，我们使用丙型肝炎病毒（HCV）作为模型系统来研究两种策略的平衡。结合病毒感染细胞培养测定与数学模型，我们表征了具有不同病毒释放特性的两种不同HCV菌株（临床分离株JFH-1和实验室菌株Jc1-n）的动力学特性。我们发现JFH-1和Jc1-n细胞内病毒RNA的分别为0.63％和1.70％，用于产生和释放子代病毒体。对HCV基因组的马尔萨斯参数（即初始增殖率）和从头感染的数量（即初始传播性）的分析表明，休假策略为Jc1-n提供了更高水平的初始传播。相反，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，从而有助于有效控制病毒的传播。