IL-15 and IFN-γ signal through the ERK pathway to inhibit HCV replication, independent of type I IFN signaling

[Display omitted] •IFN-γ and IL-15 inhibit HCV replication in Huh7.5 cells.•IL-15 and IFN-γ do not induce anti-HCV effects via the type I IFN signaling pathway.•IL-15 and IFN-γ do not induce anti-HCV effects via nitric oxide production.•IL-15 and IFN-γ may provide protection against HCV via the ERK pathway.•Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti HCV effects of IL-15 and IFN-γ. Despite effective new treatments for Hepatitis C virus (HCV) infection, development of drug resistance, safety concerns and cost are remaining challenges. More importantly, there is no vaccine available against hepatitis C infection. Recent data suggest that there is a strong correlation between spontaneous HCV clearance and human NK cell function, particularly IFN-γ production. Further, IL-15 has innate antiviral activity and is also one of the main factors that activates NK cells to produce IFN-γ. To examine whether IL-15 and IFN-γ have direct antiviral activity against HCV, Huh7.5 cells were treated with either IFN-γ or IL-15 prior to HCV infection. Our data demonstrate that IFN-γ and IL-15 block HCV replication in vitro. Additionally, we show that IL-15 and IFN-γ do not induce anti-HCV effects through the type I interferon signaling pathway or nitric oxide (NO) production. Instead, IL-15 and IFN-γ provide protection against HCV via the ERK pathway. Treatment of Huh7.5 cells with a MEK/ERK inhibitor abrogated the anti-HCV effects of IL-15 and IFN-γ and overexpression of ERK1 prevented HCV replication compared to control transfection. Our in vitro data support the hypothesis that early production of IL-15 and activation of NK cells in the liver lead to control of HCV replication.