Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release

PLoS Comput Biol. 2020 Nov 5;16(11):e1008421. doi: 10.1371/journal.pcbi.1008421. eCollection 2020 Nov.


Hepatitis C virus (HCV) causes acute hepatitis C and can lead to life-threatening complications if it becomes chronic. The HCV genome is a single plus strand of RNA. Its intracellular replication is a spatiotemporally coordinated process of RNA translation upon cell infection, RNA synthesis within a replication compartment, and virus particle production. While HCV is mainly transmitted via mature infectious virus particles, it has also been suggested that HCV-infected cells can secrete HCV RNA carrying exosomes that can infect cells in a receptor independent manner. In order to gain insight into these two routes of transmission, we developed a series of intracellular HCV replication models that include HCV RNA secretion and/or virus assembly and release. Fitting our models to in vitro data, in which cells were infected with HCV, suggests that initially most secreted HCV RNA derives from intracellular cytosolic plus-strand RNA, but subsequently secreted HCV RNA derives equally from the cytoplasm and the replication compartments. Furthermore, our model fits to the data suggest that the rate of virus assembly and release is limited by host cell resources. Including the effects of direct acting antivirals in our models, we found that in spite of decreasing intracellular HCV RNA and extracellular virus concentration, low level HCV RNA secretion may continue as long as intracellular RNA is available. This may possibly explain the presence of detectable levels of plasma HCV RNA at the end of treatment even in patients that ultimately attain a sustained virologic response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antiviral Agents / pharmacology
  • Computational Biology
  • Computer Simulation
  • Exosomes / virology
  • Hepacivirus / genetics*
  • Hepacivirus / pathogenicity
  • Hepacivirus / physiology*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / virology
  • Host Microbial Interactions / genetics
  • Host Microbial Interactions / physiology
  • Humans
  • Mathematical Concepts
  • Models, Biological*
  • RNA, Viral / biosynthesis
  • RNA, Viral / genetics
  • Viral Replication Compartments / physiology
  • Virion / genetics
  • Virion / physiology
  • Virus Assembly / drug effects
  • Virus Assembly / genetics
  • Virus Assembly / physiology
  • Virus Release / genetics
  • Virus Release / physiology
  • Virus Replication / drug effects
  • Virus Replication / genetics
  • Virus Replication / physiology


  • Antiviral Agents
  • RNA, Viral