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Antiviral effects of the interferon‐induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein
Author(s) -
Itsui Yasuhiro,
Sakamoto Naoya,
Kakinuma Sei,
Nakagawa Mina,
SekineOsajima Yuko,
TasakaFujita Megumi,
NishimuraSakurai Yuki,
Suda Gouki,
Karakama Yuko,
Mishima Kako,
Yamamoto Machi,
Watanabe Takako,
Ueyama Mayumi,
Funaoka Yusuke,
Azuma Seishin,
Watanabe Mamoru
Publication year - 2009
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.23195
Subject(s) - ns5b , biology , hepatitis c virus , virology , interferon , viral replication , alpha interferon , virus , hepacivirus
Interferons (IFNs) and the interferon‐stimulated genes (ISGs) play a central role in antiviral responses against hepatitis C virus (HCV) infection. We have reported previously that ISGs, including guanylate binding protein 1 (GBP‐1), interferon alpha inducible protein (IFI)‐6‐16, and IFI‐27, inhibit HCV subgenomic replication. In this study we investigated the effects of these ISGs against HCV in cell culture and their direct molecular interaction with viral proteins. HCV replication and virus production were suppressed significantly by overexpression of GBP‐1, IFI‐6‐16, or IFI‐27. Knockdown of the individual ISGs enhanced HCV RNA replication markedly. A two‐hybrid panel of molecular interaction of the ISGs with HCV proteins showed that GBP‐1 bound HCV‐NS5B directly. A protein truncation assay showed that the guanine binding domain of GBP‐1 and the finger domain of NS5B were involved in the interaction. Binding of NS5B with GBP‐1 inhibited its guanosine triphosphatase GTPase activity, which is essential for its antiviral effect. Taken together, interferon‐induced GBP‐1 showed antiviral activity against HCV replication. Conclusion: Binding of the HCV‐NS5B protein to GBP‐1 countered the antiviral effect by inhibition of its GTPase activity. These mechanisms may contribute to resistance to innate, IFN‐mediated antiviral defense and to the clinical persistence of HCV infection. (H EPATOLOGY 2009.)