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In vivo adaptation of hepatitis C virus in chimpanzees for efficient virus production and evasion of apoptosis
Author(s) -
Saeed Mohsan,
Shiina Masaaki,
Date Tomoko,
Akazawa Daisuke,
Watanabe Noriyuki,
Murayama Asako,
Suzuki Tetsuro,
Watanabe Haruo,
Hiraga Nobuhiko,
Imamura Michio,
Chayama Kazuaki,
Choi Youkyung,
Krawczynski Krzysztof,
Liang T. Jake,
Wakita Takaji,
Kato Takanobu
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24399
Subject(s) - hepatitis c virus , virology , virus , cell culture , flaviviridae , viral replication , medicine , apoptosis , ns2 3 protease , hepacivirus , in vivo , biology , immunology , genetics
Abstract 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. (H EPATOLOGY 2011;)