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

Factors associated with response to pegylated interferon-α/ribavirin (peg-IFN/RBV) include hepatitis C virus (HCV) genotype, age, race, human immunodeficiency virus (HIV) coinfection, baseline HCV level, and IL28B gene locus polymorphism [1–7]. The combination of natural killer (NK) KIR2DL3 and its ligand (HLA-C1) are associated with resolution of acute infection and response to peg-IFN/RBV therapy [8, 9], and KIR2DS3 and KIR3DS1 expression are associated with elevated serum alanine aminotransferase (ALT) and cirrhosis, indicating that greater NK activation potential is associated with self-resolution of infection, response to HCV therapy, and liver damage [10]. Although data on NK receptor expression have been consistently shown to be altered during chronic HCV infection, data are conflicting on whether specific receptors are up- or downregulated. Reasons for discrepancy have been proposed to be the result of differences in race, sex, and stage of HCV infection, as well as analysis of fresh vs frozen samples comparing different studies. There appears, however, to be a consensus that during chronic HCV infection, NK cells have increased expression of some activating receptors (NCRs; NKG2C and DNAM-1), greater cytotoxic activity (in part mediated by NKp30 and NKp46) directed at K562 or P815-targets, yet decreased production of IFN-γ in response to K562 targets or cytokines [11–19]. At the same time, greater P815-target cell–dependent NK-cell degranulation, and expression of NKp30 and DNAM-1, negatively predict response to peg-IFN/RBV therapy [15], whereas IFN-α–enhanced NKp30, pSTAT1, TRAIL, and K562 dependent degranulation positively predict therapy response [15, 16, 20, 21]. These data together suggest that altered NCR expression and NK-cell IFN-α responsiveness are associated with therapeutic outcome. In the HCV culture system, NK cells exhibit IFN-γ secretion and TRAIL-dependent cytolysis of HCV-infected targets [21–24]. Here we examined NK NCR expression and IFN-induced cytolytic activity directed at HCV-infected targets in relation to race, IL28B genotype, and in vivo response to peg-IFN/RBV therapy.