These authors contributed equally.
Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection
Article first published online: 13 AUG 2014
Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
Volume 60, Issue 4, pages 1160–1169, October 2014
How to Cite
Werner, J. M., Serti, E., Chepa-Lotrea, X., Stoltzfus, J., Ahlenstiel, G., Noureddin, M., Feld, J. J., Liang, T. J., Rotman, Y. and Rehermann, B. (2014), Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection. Hepatology, 60: 1160–1169. doi: 10.1002/hep.27092
Potential conflict of interest: Nothing to report.
Supported by the NIDDK, NIH intramural research program. J.M.W. was supported by grant We-4675/1-1 from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany.
See Editorial on Page 1126
- Issue published online: 22 SEP 2014
- Article first published online: 13 AUG 2014
- Accepted manuscript online: 23 FEB 2014 03:18AM EST
- Manuscript Accepted: 20 FEB 2014
- Manuscript Received: 1 OCT 2013
Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-α/β receptor signaling, as NK cell cytotoxicity and IFN-γ production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-γ production decreases in response to endogenous, virus-induced IFN-α and during IFN-α-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-γ response of NK cells in the presence of IFN-α, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56dim NK cells with cytotoxic effector functions and the frequency of CD56bright NK cells with the capacity to produce IFN-γ decreased (P = 0.049 and P = 0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P < 0.01) but not pSTAT1 response of NK cells to subsequent stimulation with IFN-α. This was associated with an increase in IFN-γ production but not cytotoxicity of NK cells during subsequent IFN-α-based therapy. The frequency of IFN-γ-producing NK cells was greater in fast second-phase virological responders than in slow responders. Conclusion: RBV enhances the pSTAT4 and IFN-γ response of NK cells to IFN-α-stimulation. (Hepatology 2014;60:1160–1169)