Research Papers: Immunology:

Interferon sensitivity-determining region of hepatitis C virus influences virus production and interferon signaling

Ryuichi Sugiyama, Asako Murayama, Sayuri Nitta, Norie Yamada, Megumi Tasaka-Fujita, Takahiro Masaki, Hussein Hassan Aly, Masaaki Shiina, Akihide Ryo, Koji Ishii, Takaji Wakita and Takanobu Kato _

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Oncotarget. 2018; 9:5627-5640. https://doi.org/10.18632/oncotarget.23562

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Ryuichi Sugiyama1, Asako Murayama1, Sayuri Nitta1,2,3, Norie Yamada1, Megumi Tasaka-Fujita1,2, Takahiro Masaki1,6, Hussein Hassan Aly1, Masaaki Shiina1,4, Akihide Ryo5, Koji Ishii1, Takaji Wakita1 and Takanobu Kato1

1Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

2Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan

3Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

4Department of Gastroenterology and Hepatology, Shin-Yurigaoka General Hospital, Kawasaki, Japan

5Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan

6Present address: Department of Laboratory Medicine, The Jikei University School of Medicine, Nishi-shinbashi, Minato-ku, Tokyo, Japan

Correspondence to:

Takanobu Kato, email: [email protected]

Keywords: HCV; IFN; innate immunity; cell culture; drug resistance; Immunology

Received: March 29, 2017     Accepted: October 27, 2017     Published: December 21, 2017


The number of amino acid substitutions in the interferon (IFN) sensitivity-determining region (ISDR) of hepatitis C virus (HCV) NS5A is a strong predictor for the outcome of IFN-based treatment. To assess the involvement of ISDR in the HCV life cycle and to clarify the molecular mechanisms influencing IFN susceptibility, we used recombinant JFH-1 viruses with NS5A of the genotype 1b Con1 strain (JFH1/5ACon1) and with NS5A ISDR containing 7 amino acid substitutions (JFH1/5ACon1/i-7mut), and compared the virus propagation and the induction of interferon-stimulated genes (ISGs). By transfecting RNAs of these strains into HuH-7-derived cells, we found that the efficiency of infectious virus production of JFH1/5ACon1/i-7mut was attenuated compared with JFH1/5ACon1. After transfecting full-length HCV RNA into HepaRG cells, the mRNA expression of ISGs was sufficiently induced by IFN treatment in JFH1/5ACon1/i-7mut-transfected but not in JFH1/5ACon1-transfected cells. These data suggested that the NS5A-mediated inhibition of ISG induction was deteriorated by amino acid substitutions in the ISDR. In conclusion, using recombinant JFH-1 viruses, we demonstrated that HCV NS5A is associated with infectious virus production and the inhibition of IFN signaling, and amino acid substitutions in the NS5A ISDR deteriorate these functions. These observations explain the strain-specific evasion of IFN signaling by HCV.

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