Evolution of a cell culture-derived genotype 1a hepatitis C Virus (H77S.2) during persistent infection with chronic hepatitis in a Chimpanzee

Min Kyung Yi, Fengyu Hu, Michael Joyce, Vikas Saxena, Christoph Welsch, Deborah Chavez, Bernadette Guerra, Daisuke Yamane, Ronald Veselenak, Rick Pyles, Christopher M. Walker, Lorne Tyrrell, Nigel Bourne, Robert E. Lanford, Stanley M. Lemon

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Persistent infection is a key feature of hepatitis C virus (HCV). However, chimpanzee infections with cell culture-derived viruses (JFH1 or related chimeric viruses that replicate efficiently in cell culture) have been limited to acute-transient infections with no pathogenicity. Here, we report persistent infection with chronic hepatitis in a chimpanzee challenged with cell culture-derived genotype 1a virus (H77S.2) containing 6 cell culture-adaptive mutations. Following acute-transient infection with a chimeric H77/JFH1 virus (HJ3-5), intravenous (i.v.) challenge with 106 FFU H77S.2 virus resulted in immediate seroconversion and, following an unusual 4-to 6-week delay, persistent viremia accompanied by alanine aminotransferase (ALT) elevation, intrahepatic innate immune responses, and diffuse hepatopathy. This first persistent infection with cell culture-produced HCV provided a unique opportunity to assess evolution of cell culture-adapted virus in vivo. Synonymous and nonsynonymous nucleotide substitution rates were greatest during the first 8 weeks of infection. Of 6 cell culture-adaptive mutations in H77S.2, Q1067R (NS3) had reverted to Q1067 and S2204I (NS5A) was replaced by T2204 within 8 weeks of infection. By 62 weeks, 4 of 6 mutations had reverted to the wild-type sequence, and all reverted to the wild-type sequence by 194 weeks. The data suggest H77S.2 virus has greater potential for persistence and pathogenicity than JFH1 and demonstrate both the capacity of a nonfit virus to persist for weeks in the liver in the absence of detectable viremia as well as strong selective pressure against cell culture-adaptive mutations in vivo.

Original languageEnglish (US)
Pages (from-to)3678-3694
Number of pages17
JournalJournal of virology
Issue number7
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology


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