Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma

PLoS Biol. 2020 Jul 30;18(7):e3000562. doi: 10.1371/journal.pbio.3000562. eCollection 2020 Jul.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Genome, Viral*
  • Hepacivirus / genetics*
  • Hepatitis C
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Models, Biological
  • Virus Replication / genetics

Grant support

This study was supported by funding from the following sources: a Grant-in-Aid for JSPS Research Fellows 19J12319 (to S. Iwanami), 19J21395 (to KK), Scientific Research (KAKENHI) B 18KT0018 (to S. Iwami), 18H01139 (to S. Iwami), 16H04845 (to S. Iwami), 17H04085 (to KW), Scientific Research in Innovative Areas 20H05042 (to S. Iwami), 19H04839 (to S. Iwami), 18H05103 (to S. Iwami); AMED CREST 19gm1310002 (to S. Iwami); AMED J-PRIDE 19fm0208006s0103 (to S. Iwami), 19fm0208014h0003 (to S. Iwami), 19fm0208019h0103 (to S. Iwami), 19fm0208019j0003 (to KW); AMED Research Program on HIV/AIDS 19fk0410023s0101 (to S. Iwami); Research Program on Emerging and Re-emerging Infectious Diseases 19fk0108050h0003 (to S. Iwami); Program for Basic and Clinical Research on Hepatitis 19fk0210036h0502 (to S. Iwami), 19fk0210036j0002 (to KW); Program on the Innovative Development and the Application of New Drugs for Hepatitis B 19fk0310114h0103 (to S. Iwami), 19fk0310114j0003 (to KW), 19fk0310101j1003 (to KW), 19fk0310103j0203 (to KW); JST MIRAI 18077147 (to S. Iwami and KW); Mitsui Life Social Welfare Foundation (to S. Iwami and KW); Shin-Nihon of Advanced Medical Research (to S. Iwami); Suzuken Memorial Foundation (to S. Iwami); Life Science Foundation of Japan (to S. Iwami); SECOM Science and Technology Foundation (to S. Iwami); The Japan Prize Foundation (to S. Iwami); Toyota Physical and Chemical Research Institute (to S. Iwami); The Yasuda Medical Foundation (to KW); Smoking Research Foundation (to KW); and The Takeda Science Foundation (to KW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.