Influence of genes suppressing interferon effects in peripheral blood mononuclear cells during triple antiviral therapy for chronic hepatitis C.

Sayuki Iijima,Takashi Fujita,Atsunori Kusakabe,Mio Endo,Kei Fujiwara,Tomokatsu Miyaki,Takashi Joh,Koji Onomoto,Etsuko Iio,Kyoko Ito,Shunsuke Nojiri,Tsunamasa Watanabe,Noboru Shinkai,Kentaro Matsuura,Yasuhito Tanaka,Ming-Lung Yu

doi:10.1371/journal.pone.0118000

Abstract

The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (IL28B) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-λs) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-λs were evaluated by real-time PCR. All 31 patients with a favorable IL28B genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for A20, SOCS1, and SOCS3, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as IRF1 were significantly higher at 8 h in patients with an unfavorable IL28B genotype than in those with a favorable one (P = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of IRF1 at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable IL28B genotype (P = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to IL28B genotypes, paralleling treatment efficacy.

Highlights

Chronic hepatitis C virus (HCV) infection is a significant risk factor for progressive liver fibrosis and hepatocellular carcinoma (HCC)
We determined that mRNAs for A20, suppressor of cytokine signaling 1 (SOCS1) and SOCS3, known to be genes suppressing antiviral activity via the IFN signaling pathway, as well as interferon regulatory transcription factor 1 (IRF1) were highly expressed in peripheral blood mononuclear cells (PBMCs) early after the initial administration of pegylated interferon (PEG-IFN)/RBV/protease inhibitor (PI) in patients with an unfavorable IL28B genotype, especially the non-sustained virological responses (SVR) group
The correlations of mRNA expression levels of these genes, ISG15, and IL28B suggest that the expression levels of these suppressive genes show similar dynamics independently with the genes promoting the antiviral state in the interferon signaling pathway

Summary

Introduction

Chronic hepatitis C virus (HCV) infection is a significant risk factor for progressive liver fibrosis and hepatocellular carcinoma (HCC). Recent genome-wide association studies (GWAS), including our own study on HCV infection [6], have identified a single nucleotide polymorphism (SNP) near the interleukin-28B (IL28B) gene encoding type III IFN-λ3 that was strongly associated with the response to PEGIFN/RBV therapy for chronic HCV genotype 1 infection [6,7,8,9]. A recent metaanalysis showed that the IL28B genotype was associated with efficacy of PEG-IFN/RBV plus NS3/4A protease inhibitor (PI) treatment, including telaprevir or boceprevir [10]. It is not known how the IL28B gene influences the elimination of HCV

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Conclusion