Interferon-α-Induced Changes to Natural Killer Cells Are Associated with the Treatment Outcomes in Patients with HCV Infections

Shinji Shimoda,Hideyuki Nomura,Hironori Tanimoto,Satomi Hisamoto,Kazufumi Dohmen,Kosuke Sumida,Akira Kawano,Norihiro Furusyo,Koichi Akashi,Eiichi Ogawa,Jun Hayashi,Kazuhiro Takahashi,Sho Iwasaka

doi:10.1155/2013/374196

Abstract

Aim. We analyzed the pretreatment natural killer (NK) cell functions with the aim of predicting the sustained virological response (SVR) or the interleukin (IL) 28B polymorphism that is strongly associated with the treatment response. Methods. The peripheral NK cells from chronic hepatitis patients with HCV genotype 1 and high virus titers were activated using a Toll-like receptor (TLR) 4 ligand and IFN-α. The cell surface markers were evaluated using a flow cytometric analysis, and IFN-γ production was evaluated using an enzyme-linked immunosorbent assay (ELISA). The genotyping of the polymorphisms in the IL28B gene region (rs8099917) on chromosome 19 was performed on the DNA collected from each patient. Results. The production of IFN-γ was significantly higher in the SVR patients compared with the no-response (NR) patients, whereas the cell surface markers were similar between the SVR and the NR patients. There were no significant differences found in the IL28B genotype distribution associated with the production of IFN-γ. Conclusion. Differences in the NK cell functions were observed between the SVR patients and the NR patients, suggesting that NK cells play a potential role in the treatment response independent of the IL28B genotype.

Highlights

The hepatitis C virus (HCV) is the major cause of chronic liver disease, with an estimated global prevalence of 2.5%, that is, 170 million people infected worldwide [1], and is a leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation [2]
The HCV genotype, viral load, age, and fibrosis stage are well known as pretreatment variables [3,4,5,6]; single nucleotide polymorphisms (SNPs) located in the region of the interleukin (IL) 28B gene have been strongly associated with an sustained virologic response (SVR) [7, 8]
Because the natural killer (NK) cell cytotoxity and the presence of cell surface markers correlate with the virological response, NK cells can serve as biomarkers of a patient’s IFN-α responsiveness [14, 15]

Summary

Introduction

The hepatitis C virus (HCV) is the major cause of chronic liver disease, with an estimated global prevalence of 2.5%, that is, 170 million people infected worldwide [1], and is a leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation [2]. Antiviral treatment, which is based on the combination of pegylated interferon- (IFN-) α and the nucleoside analog ribavirin (RBV), is associated with a sustained virologic response (SVR), that is, serum HCV RNA negatively for 6 months after the cessation of the antiviral therapy. The HCV genotype, viral load, age, and fibrosis stage are well known as pretreatment variables [3,4,5,6]; single nucleotide polymorphisms (SNPs) located in the region of the interleukin (IL) 28B gene have been strongly associated with an SVR [7, 8]. The natural killer (NK) cells involved in innate immunity play central roles of defense against viral infections through a direct cytotoxic effect in the destruction of the virus-infected target cells and the production of inflammatory cytokines [9].

Methods

Results

Conclusion