Monocytes sense hepatitis C virus-replicating cells and induce natural killer cell antiviral activity in an IL-18-mediated manner (INC8P.437)

Natural killer (NK) cells are important effectors in the innate immune defense against many viruses. However, NK cell IFN-γ production is attenuated in chronic hepatitis C virus (HCV) infection. Here, we asked whether this is due to an NK cell-intrinsic or extrinsic mechanism. Hepatoma cells expressing luciferase-tagged subgenomic HCV-replicons (Huh7/HCV-replicons) or their HCV-negative counterparts were co-cultured with NK cells in the presence or absence of other PBMC subpopulations. RESULTS: The IFN-γ-mediated antiviral effect of NK cells was reduced when isolated NK cells rather than PBMC were co-cultured with Huh7/HCV-replicons suggesting that other subpopulations contributed to NK cell activation. Increased monokines levels implicated a role of activated monocytes. Indeed, depletion of CD14+ monocytes, siRNA knockdown of the monocyte NALP3 inflammasome and neutralization of the inflammasome product IL-18 decreased the IFN-γ-mediated antiviral activity of NK cells. Interestingly, monocytes from chronic HCV patients were less effective than monocytes from healthy controls in inducing NK cell IFN-γ production. Vice versa, monocytes from healthy controls improved antiviral function and IFN-γ production of NK cells from chronic HCV patients. CONCLUSION: Monocytes sense HCV-replicating cells and induce, via inflammasome-mediated IL-18 production, an NK-cell mediated decrease in HCV replication. Impaired monocyte function in HCV infection attenuates the NK cell IFN-γ response.