Genetically associated CD16(+)56(-) natural killer cell interferon (IFN)-αR expression regulates signaling and is implicated in IFN-α-induced hepatitis C virus decline.

Abstract

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-αR and NKp30 expression associated with IFN-α-dependent NK cell activity. Here, we examined CD16(+)56(-), CD16(+)56(+), and CD16(-)56(+) NK cell subset IFN-αR and NKp30 expression in relation to magnitude of HCV genotype 1 decrease during pegylated IFN-α plus ribavirin therapy. We observed greater baseline IFN-αR and NKp30 expression on CD16(+)56(+) and CD16(-)56(+) NK subsets in HCV-infected patients than in healthy control subjects. Baseline CD16(+)56(-) NK IFN-αR expression was associated with IFN-α-induced pSTAT1, and both were associated with magnitude of HCV decrease during pegylated IFN-α plus ribavirin therapy. Baseline CD16(+)56(-) NK IFN-αR 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-α exposure. Finally, in vitro IFN-α2a-activated NK cytolysis of HCV-infected target cells was in part dependent on NKp30, and CD16(+)56(-) NK cell IFN-αR expression correlated with cytolytic activity. IFN-αR expression on CD16(+)56(-) NK cells during chronic HCV infection may in part be genetically determined, and level of expression regulates IFN-α signaling, which in turn may contribute to control of HCV infection.