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Oncotarget. 2017 Dec 21;9(5):5627-5640. doi: 10.18632/oncotarget.23562. eCollection 2018 Jan 19.

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

Author information

1
Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
2
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
3
Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
4
Present address: Department of Laboratory Medicine, The Jikei University School of Medicine, Nishi-shinbashi, Minato-ku, Tokyo, Japan.
5
Department of Gastroenterology and Hepatology, Shin-Yurigaoka General Hospital, Kawasaki, Japan.
6
Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.

Abstract

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.

KEYWORDS:

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

Conflict of interest statement

CONFLICTS OF INTEREST Megumi Tasaka-Fujita is currently an employee of Janssen Pharmaceutical K.K. The other authors have declared that no conflicts of interest exists.

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