Ribavirin Pretreatment Improves the IFN-γ Response of Natural Killer Cells to IFN-based Therapy of Hepatitis C Virus Infection

Ribavirin is an important component of interferon-based and direct antiviral treatment regimens of hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host interferon response, has been proposed as a 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 STAT1- and STAT4-phosphorylation, respectively. Upon continued exposure to IFN-α, an increase in STAT1 levels limits STAT4 access at the IFN-α/β receptor and results in decreased IFN-γ production. Accordingly, NK cell IFN-γ production decreases during IFN-α-based therapy. To assess whether ribavirin improves the IFN-γ response of NK cells in the presence of IFN-α, NK cells were studied prospectively in 22 HCV patients with and 32 patients without 4 weeks of ribavirin monotherapy, and during subsequent PegIFN/ribavirin therapy. During ribavirin monotherapy, the frequency of IFN-γ producing NK cells decreased (p = 0.001) in correlation with a decrease in their ex vivo pSTAT4 levels ((Rho = 0.58, p = 0.019). However, in vitro or in vivo exposure of NK cells to ribavirin improved their pSTAT4 response to subsequent stimulation with IFN-α (P < 0.01). Furthermore, HCV patients who had received ribavirin-pretreatment showed a greater frequency of IFN-γ-producing NK cells during subsequent PegIFN/ribavirin therapy than those who had not been pretreated (P < 0.05). Finally, the frequency of IFN-γ-producing NK cells was greater in fast second-phase virological responders than in slow responders. Conclusions: Ribavirin improved the pSTAT4 and IFN-γ response of NK cells to IFN-α-treatment, which may contribute to an improved second-phase virological response.