Immunomodulatory Activities of IFN-γ1b in Combination with Type I IFN: Implications for the Use of IFN-γ1b in the Treatment of Chronic HCV Infections

The standard of care for chronic hepatitis C, pegylated interferon-α (IFN-α) and ribavirin (RBV), causes a sustained virologic response (SVR) in approximately 50% of patients. SVR is correlated with innate and adaptive immune system responses, such as natural killer (NK) cell activation, production of IFN-α from immature plasmocytoid dendritic cells (pDC), and polarization of CD4⁺ cells to a T helper 1 (Th1) cell phenotype. To examine how these immunologic responses vary with currently available regimens for chronic hepatitis C, cell populations purified from human peripheral blood mononuclear cells (PBMC) were treated with the clinically available combinations of pegylated IFN-α2b (PEG-IFN-α2b) + RBV, IFN-αcon1 + RBV, or IFN-αcon1 + IFN-γ1b, and activation of cellular immune system components was monitored. The magnitude of NK cell activation depended on regimen, with IFN-αcon1 + IFN-γ1b > IFN-αcon1 + RBV > PEG-IFN-αa2b + RBV. The maximum human serum concentrations of IFN-αcon1 + IFN-γ1b saturated NK cell activation, whereas the maximum human serum concentrations of IFN-αcon1 + RBV or PEG-IFN-α2b + RBV did not. IFN-γ1b also enhanced the production of IFN-α from immature pDCs, which are the dominant source of IFN-α upon viral infection. The rank order for induction of Th1 cell phenotype and repression of Th2 cell phenotype by the cocktails described was identical to that observed for NK cell activation. Additionally, IFN-γ1b suppressed the ability of the hepatitis C virus (HCV) NS4 protein to enhance monocyte secretion of interleukin- 10 (IL-10), a cytokine whose expression level is correlated with viral persistence. These results suggest that addition of IFN-γ1b to HCV treatment regimens may provide unique benefits.