In vivo adaptation of hepatitis C virus in chimpanzees for efficient virus production and evasion of apoptosis

Mohsan Saeed, Masaaki Shiina, Tomoko Date, Daisuke Akazawa, Noriyuki Watanabe, Asako Murayama, Tetsuro Suzuki, Haruo Watanabe, Nobuhiko Hiraga, Michio Imamura, Kazuaki Chayama, Youkyung Choi, Krzysztof Krawczynski, T. Jake Liang, Takaji Wakita, Takanobu Kato

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Hepatitis C virus (HCV) employs various strategies to establish persistent infection that can cause chronic liver disease. Our previous study showed that both the original patient serum from which the HCV JFH-1 strain was isolated and the cell culture-generated JFH-1 virus (JFH-1cc) established infection in chimpanzees, and that infected JFH-1 strains accumulated mutations after passage through chimpanzees. The aim of this study was to compare the in vitro characteristics of JFH-1 strains emerged in each chimpanzee at early and late stages of infection, as it could provide an insight into the phenomenon of viral persistence. We generated full-genome JFH-1 constructs with the mutations detected in patient serum-infected (JFH-1/S1 and S2) and JFH-1cc-infected (JFH-1/C) chimpanzees, and assessed their effect on replication, infectious virus production, and regulation of apoptosis in cell culture. The extracellular HCV core antigen secreted from JFH-1/S1-, S2-, and C-transfected HuH-7 cells was 2.5, 8.9, and 2.1 times higher than that from JFH-1 wild-type (JFH-1/wt) transfected cells, respectively. Single cycle virus production assay with a CD81-negative cell line revealed that the strain JFH-1/S2, isolated from the patient serum-infected chimpanzee at a later time point of infection, showed lower replication and higher capacity to assemble infectious virus particles. This strain also showed productive infection in human hepatocyte-transplanted mice. Furthermore, the cells harboring this strain displayed lower susceptibility to the apoptosis induced by tumor necrosis factor α or Fas ligand compared with the cells replicating JFH-1/wt. Conclusion: The ability of lower replication, higher virus production, and less susceptibility to cytokine-induced apoptosis may be important for prolonged infection in vivo. Such control of viral functions by specific mutations may be a key strategy for establishing persistent infection.

Original languageEnglish (US)
Pages (from-to)425-433
Number of pages9
Issue number2
StatePublished - Aug 2011
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology


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