Natural Cytotoxicity Receptor-Dependent Natural Killer Cytolytic Activity Directed at Hepatitis C Virus (HCV) Is Associated With Liver Inflammation, African American Race, IL28B Genotype, and Response to Pegylated Interferon/Ribavirin Therapy in Chronic HCV Infection

Background. Natural killer (NK) cells are implicated in the pathogenesis of hepatitis C virus (HCV) infection and outcome of interferon (IFN)-alpha based therapy, although mechanisms remain unclear. Methods. To evaluate NK ability to control HCV infection, we analyzed healthy donor and HCV-infected donor NK-cell cytolytic activity directed at HCV-infected target cells. Results. HCV-infected subjects' natural cytotoxicity receptor (NCR)-dependent NK-cell cytolytic activity directed at HCV-infected and uninfected Huh7.5 target cells was greater than that of cells from healthy donors, and this localized to the African American subset. However, IFN-alpha-enhanced NK cytolytic function was lower in HCV-infected subjects, again localized mainly to the African American subset. Additionally, whereas HCV-infected Huh7.5 cells were more readily targeted than uninfected cells, the selectivity of cytolytic activity for infected targets was lower during HCV infection and after IFN-alpha stimulation, and lower selectivity was in part attributable to greater NKp46 expression. Furthermore, cytolytic activity was associated with higher serum aspartate aminotransferase, rs12979860 IL28B genotype, and in vivo response to pegylated IFN/ribavirin therapy. Conclusions. These data indicate that during chronic HCV infection, race-associated increase in NCR expression and IL28B-associated cytolytic activity may participate in host response to IFN-a-containing HCV therapy.