Genetically Associated CD161562 Natural Killer Cell Interferon (IFN)–aR Expression Regulates Signaling and Is Implicated in IFN-a–Induced Hepatitis C Virus Decline

Background. Natural killer (NK) cells likely contribute to outcome of acute hepatitis C virus (HCV) infection and interferon (IFN)–induced control of chronic HCV infection. We previously observed IFN-aR and NKp30 expression associated with IFN-a–dependent NK cell activity. Methods. Here, we examined CD161562, CD161561, and CD162561 NK cell subset IFN-aR and NKp30 expression in relation to magnitude of HCV genotype 1 decrease during pegylated IFN-a plus ribavirin therapy. Results. We observed greater baseline IFN-aR and NKp30 expression on CD161561 and CD162561 NK subsets in HCV-infected patients than in healthy control subjects. Baseline CD161562 NK IFN-aR expression was associated with IFN-a–induced pSTAT1, and both were associated with magnitude of HCV decrease during pegylated IFN-a plus ribavirin therapy. Baseline CD161562 NK IFN-aR expression was associated with race and interleukin 28B genotype, negatively associated with aspartate aminotransferase-to platelet ratio index, and positively associated with increase in NKp30 expression after in vivo IFN-a exposure. Finally, in vitro IFN-a2a–activated NK cytolysis of HCV-infected target cells was in part dependent on NKp30, and CD161562 NK cell IFN-aR expression correlated with cytolytic activity. Conclusions. IFN-aR expression on CD161562 NK cells during chronic HCV infection may in part be genetically determined, and level of expression regulates IFN-a signaling, which in turn may contribute to contro