During chronic HCV infection NCR dependent NK cytolytic activity directed at HCV is associated with liver inflammation, African American Race, IL28B genotype and response to PegIFN/RBV therapy.

Abstract

Background. Natural killer (NK)-cells are implicated in the pathogenesis of hepatitis C virus (HCV) infection and outcome of IFN-α based therapy, though 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 subject natural cytotoxicity receptor (NCR) dependent NK-cell cytolytic activity directed at HCV-infected and uninfected HUH 7.5 target cells was greater than that of cells from healthy donors, and this localized to the African American subset. However, IFN-α-enhanced NK cytolytic function was lower in HCV-infected subjects, again localized mainly to the African American subset. Additionally, while HCV-infected HUH 7.5 cells were more readily targeted than uninfected cells, the selectivity of cytolytic activity for infected targets was lower during HCV infection and after IFN-α stimulation, and lower selectivity was in part attributable to greater NKp46 expression. Furthermore, cytolytic activity was associated with higher serum AST, rs12979860 IL28B genotype, and in vivo response to PegIFN/RBV 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-α containing HCV therapy.