Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection

Jens M. Werner, Elisavet Serti, Xenia Chepa-Lotrea, Jonathan Stoltzfus, Golo Ahlenstiel, Mazen Noureddin, Jordan J. Feld, T. Jake Liang, Yaron Rotman, Barbara Rehermann

Research output: Contribution to journalArticlepeer-review

Abstract

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

Original languageEnglish (US)
Pages (from-to)1160-1169
Number of pages10
JournalHepatology
Volume60
Issue number4
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

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