Natural killer cells: multifaceted players with key roles in hepatitis C immunity

Natural killer cells (NKs) are involved in every stage of hepatitis C viral (HCV) infection, from protection against HCV acquisition and resolution in the acute phase to treatment-induced clearance. In addition to their direct antiviral actions, NKs are involved in the induction and priming of appropriate downstream T-cell responses. In the setting of chronic HCV, overall NK cell levels are decreased, subset distribution is altered, and changes in NK receptor (NKR) expression have been demonstrated, although the contribution of individual NKRs to viral clearance or persistence remains to be clarified. Enhanced NK cell cytotoxicity accompanied by insufficient interferon-γ production may promote liver damage in the setting of chronic infection. Treatment-induced clearance is associated with activation of NK cells, and it will be of interest to monitor NK cell responses to triple therapy. Activated NK cells also have anti-fibrotic properties, and the same hepatic NK cell populations that are actively involved in control of HCV may also be involved in control of HCV-associated liver damage. We still have much to learn, in particular: how do liver-derived NKs influence the outcome of HCV infection? Do NK receptors recognize HCV-specific components? And, are HCV-specific memory NK populations generated?