UNLABELLED: 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.
UNLABELLED: 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.
Authors: Elisabeth Kravets; Daniel Degrandi; Stefanie Weidtkamp-Peters; Britta Ries; Carolin Konermann; Suren Felekyan; Julia M Dargazanli; Gerrit J K Praefcke; Claus A M Seidel; Lutz Schmitt; Sander H J Smits; Klaus Pfeffer Journal: J Biol Chem Date: 2012-06-22 Impact factor: 5.157
Authors: Daniel B Nichols; Guy Fournet; K R Gurukumar; Amartya Basu; Jin-Ching Lee; Naoya Sakamoto; Frank Kozielski; Ira Musmuca; Benoît Joseph; Rino Ragno; Neerja Kaushik-Basu Journal: Eur J Med Chem Date: 2012-01-12 Impact factor: 6.514
Authors: Hangfei Qi; Virginia Chu; Nicholas C Wu; Zugen Chen; Shawna Truong; Gurpreet Brar; Sheng-Yao Su; Yushen Du; Vaithilingaraja Arumugaswami; C Anders Olson; Shu-Hua Chen; Chung-Yen Lin; Ting-Ting Wu; Ren Sun Journal: Proc Natl Acad Sci U S A Date: 2017-02-03 Impact factor: 11.205
Authors: Nathalie Britzen-Laurent; Michael Bauer; Valeria Berton; Nicole Fischer; Adrian Syguda; Simone Reipschläger; Elisabeth Naschberger; Christian Herrmann; Michael Stürzl Journal: PLoS One Date: 2010-12-07 Impact factor: 3.240
Authors: Carolyn Z Grimes; Lu-Yu Hwang; Peng Wei; Dimpy P Shah; Kelly A Volcik; Eric L Brown Journal: J Gen Virol Date: 2012-11-14 Impact factor: 3.891