Internal disequilibria and phenotypic diversification during replication of hepatitis C virus in a noncoevolving cellular environment

Elena Moreno, Isabel Gallego, Josep Gregori, Adriana Lucía-Sanz, María Eugenia Soria, Victoria Castro, Nathan M. Beach, Susanna Manrubia, Josep Quer, Juan Ignacio Esteban, Charles M. Rice, Jordi Gómez, Pablo Gastaminza, Esteban Domingo, Celia Perales

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

Abstract

© 2017 American Society for Microbiology. Viral quasispecies evolution upon long-term virus replication in a noncoevolving cellular environment raises relevant general issues, such as the attainment of population equilibrium, compliance with the molecular-clock hypothesis, or stability of the phenotypic profile. Here, we evaluate the adaptation, mutant spectrum dynamics, and phenotypic diversification of hepatitis C virus (HCV) in the course of 200 passages in human hepatoma cells in an experimental design that precluded coevolution of the cells with the virus. Adaptation to the cells was evidenced by increase in progeny production. The rate of accumulation of mutations in the genomic consensus sequence deviated slightly from linearity, and mutant spectrum analyses revealed a complex dynamic of mutational waves, which was sustained beyond passage 100. The virus underwent several phenotypic changes, some of which impacted the virus-host relationship, such as enhanced cell killing, a shift toward higher virion density, and increased shutoff of host cell protein synthesis. Fluctuations in progeny production and failure to reach population equilibrium at the genomic level suggest internal instabilities that anticipate an unpredictable HCV evolution in the complex liver environment.
Original languageEnglish
Article numbere02505-16
JournalJournal of Virology
Volume91
Issue number10
DOIs
Publication statusPublished - 1 May 2017

Keywords

  • Mutant spectrum
  • Population instability
  • Quasispecies
  • RNA virus

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