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Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response

Megumi Tasaka^1,

Naoya Sakamoto^1,2,

¹ Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
² Department for Hepatitis Control, Tokyo Medical and Dental University, Tokyo, Japan
³ First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan
⁴ Laboratory of Molecular Genetics, Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto, Japan
⁵ Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan

Correspondence
Naoya Sakamoto
nsakamoto.gast{at}tmd.ac.jp

Viral infections activate cellular expression of type I interferons (IFNs). These responses are partly triggered by RIG-I and mediated by Cardif, TBK1, IKK and IRF-3. This study analysed the mechanisms of dsRNA-induced IFN responses in various cell lines that supported subgenomic hepatitis C virus (HCV) replication. Transfection of dsRNA into Huh7, HeLa and HEK293 cells induced an IFN expression response as shown by IRF-3 dimerization, whilst these responses were abolished in corresponding cell lines that expressed HCV replicons. Similarly, RIG-I-dependent activation of the IFN-stimulated response element (ISRE) was significantly suppressed by cells expressing the HCV replicon and restored in replicon-eliminated cells. Overexpression analyses of individual HCV non-structural proteins revealed that NS4B, as well as NS34A, significantly inhibited RIG-I-triggered ISRE activation. Taken together, HCV replication and protein expression substantially blocked the dsRNA-triggered, RIG-I-mediated IFN expression response and this blockade was partly mediated by HCV NS4B, as well as NS34A. These mechanisms may contribute to the clinical persistence of HCV infection and could constitute a novel antiviral therapeutic target.

These authors contributed equally to this work.

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