Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients

Abstract

Natural killer (NK) cells exhibit a polarized phenotype with increased cytotoxicity and decreased IFN- γ production in chronic hepatitis C virus (HCV) infection. Here we asked whether this is due to type I interferon (IFN)-induced expression and phosphorylation levels of signal transducer and activator of transcription (STAT) molecules in NK cells and whether it affects the response and refractoriness of NK cells to IFN-α-based therapy of hepatitis C. STAT1 levels in NK cells were significantly higher in patients with chronic HCV infection than in uninfected controls. STAT1 levels and induction of phosphorylated STAT1 (pSTAT1) increased further during IFN-α-based therapy with preferential STAT1 over STAT4 phosphorylation. Induction of pSTAT1 correlated with increased NK cytotoxicity (TRAIL expression and degranulation) and decreased IFN-γ production. NK cells from patients with a greater than 2 log10 first phase HCV RNA decline to IFN-α-based therapy (>99% IFN effectiveness) displayed strong pSTAT1 induction in vivo and were refractory to further stimulation in vitro. In contrast, NK cells from patients with a less than 2 log10 first phase HCV RNA decline exhibited lower pSTAT1 induction in vivo (p=0.024) but retained greater IFN-α responsiveness in vitro (p=0.024). NK cells of all patients became refractory to in vivo and in vitro stimulation by IFN-α during the second phase virological response. Conclusion These data show that IFN-α-induced modulation of STAT1/4 phosphorylation underlies the polarization of NK cells towards increased cytotoxicity and decreased IFN-γ production in HCV infection, and that NK cell responsiveness and refractoriness correlate to the antiviral effectiveness of IFN-α-based therapy.

Impaired Toll-Like Receptor 3-Mediated Immune Responses from Macrophages of Patients Chronically Infected with Hepatitis C Virus

“…Taken together, these findings indicate that STAT1 induction is impaired in chronically infected VLϩ hepatitis C subjects and suggest a critical role for STAT1 in clearance of HCV. This is consistent with observations of monocytes and NK cells from chronically infected hepatitis C patients, in which levels of phosphorylated STAT1 correlated inversely with levels of programmed cell death 1 (PD-1) expression and better response to IFN therapy, respectively (28,29).…”

Therapeutic Depletion of Natural Killer Cells Controls Persistent Infection

“…Progression of HIV infection has also been linked to both type I IFN (12) and expression of particular NK cell receptors (13). Similarly, the activation state of NK cells and type I IFN have been linked to both chronicity of HCV infection and refractoriness to antiviral therapy (14,15). Recently, two groups demonstrated that blockade of type I IFN signaling during persistent LCMV infection in mice could facilitate viral clearance (16,17).…”

Emerging concepts in immunity to hepatitis C virus infection

“…HCV also enhances the susceptibility of primary human hepatocytes to TRAIL-mediated killing via increased expression of the death receptors DR4 and DR5 (81). The ex vivo expression of TRAIL and CD107a on NK cells increases as early as hours following the initiation of antiviral therapy (82,83), correlates with the induction of phosphorylated STAT1 levels (84), and is associated with early virologic response. Thus, on aggregate, these data identify NK cell markers associated with protection from early infection and predictors of response to IFN-based therapy.…”