Antigen-Specific Natural Killer Cell Responses in Chronic Hepatitis C Virus Infection

Chronic hepatitis C virus (HCV) infection results in an inflammatory liver disease leading to fibrosis and cirrhosis. The progression of liver disease is thought to be immune-mediated because HCV itself is non-cytopathic. Given that HCV-specific T cells are diminished in number and functionally exhausted in chronic HCV infection, it remains unclear which cell population drives disease pathogenesis. Here, we investigated the function of natural killer (NK) cells, the major innate immune cell population in the liver. The NK cell population increases further in the setting of chronic hepatitis C infection and have multiple mechanisms of cytotoxicity. We investigated whether NK cells could respond to HCV in an antigen-specific manner. PBMCs from 39 patients with chronic HCV infection (gt 1) not recently on medication (>2 years) were stimulated for 8 hours in a whole blood activation assay with pools of overlapping 18-mer peptides comprising HCV structural (E1, E2) and nonstructural (NS3) proteins. Cytokine production by NK cells and T cells was assessed by multicolor flow cytometry. The frequency of IFN-γ+ NK cells was 5 fold greater than the frequency of IFN-γ+ T cells. A minority of IFN-γ+ NK cells co-produced TNF-α. NK cell responses to HCV peptides varied between subjects, but did not correlate with T cell responses or viremia. This study demonstrates that NK cells are activated in an antigen-specific manner in chronic HCV infection and respond to both structural and nonstructural HCV proteins. Natural killer cell cytokine and cytotoxic responses were larger than corresponding T cell responses. The mechanism of antigen-specific NK cell activation is currently under investigation.