Distinct and Overlapping Genomic Profiles and Antiviral Effects of Interferon-λ and -α on HCV-infected and Noninfected Hepatoma Cells

A. Kohli; X. Zhang; J. Yang; R. S. Russell; R. P. Donnelly; F. Sheikh; A. Sherman; H. Young; T. Imamichi; R. A. Lempicki; H. Masur; S. Kottilil

Disclosures

J Viral Hepat. 2012;19(12):843-853. 

In This Article

Abstract and Introduction

Abstract

Recently, several SNPs in the region of the IL28B (IFN-λ) gene have been associated with spontaneous clearance of hepatitis C virus (HCV) and enhanced cure rates for IFN-alfa-based therapies, suggesting a potential correlation between IFN-λ and the ability to clear HCV. To understand the mechanism of IFN-λ's as compared to IFN-α's antiviral activity, we performed a comprehensive analysis of their anti-HCV effects, whole genome transcriptome profiling with validation, and signalling of IFN-α and IFN-λ using J6/JFH-1 and Huh7.5 cells in vitro. IFN-λ and IFN-α exhibited comparable anti-HCV activity and gene expression profiles in Huh7.5 cells. While the majority of genes induced by IFN-α and IFN-λ were similar, IFN-λ exhibits profound, but delayed kinetics of IFN-stimulated genes (ISG) induction, while IFN-α induced more rapid induction of ISGs. Furthermore, the increased induction of ISG expression by IFN-λ correlated with up-regulation of IFN-λ receptor (IL-28RA) expression and more prolonged activation of the Jak-STAT signalling pathway. The findings from our comparative analysis of IFN-α and IFN-λ in HCV-infected and noninfected cells support the clinical use of IFN-λ as a potential alternative to IFN-α in the treatment of chronic hepatitis C.

Introduction

Chronic hepatitis C affects approximately 160 million people worldwide.[1] Current standard treatment for chronic hepatitis C includes pegylated interferon (IFN) alfa, a Type 1 IFN, in combination with ribavirin. While effective in curing about 46–76% of patients[2] depending on hepatitis C virus (HCV) genotype, this treatment often is associated with numerous serious adverse events.

Recently, several SNPs in the region of interferon-lambda-3 gene (IFN-λ), also referred to as IL-28B, have been associated with spontaneous clearance of HCV and enhanced cure rates for IFN-alfa (IFN-α)-based therapy.[3–6] The exact mechanism associated with this effect is presently unknown; however, great interest has been generated by these findings, likely due to the fact that IFN-λ encodes for a Type 3 IFN, which shares similar biological properties with IFN-α, a Type 1 IFN. IFN-λ utilizes a heterodimeric receptor consisting of IFN-λR1 and IL-10R2, while IFN-α, uses the IFN-α/β receptor complex formed by two subchains, IFN-αR1 and IFN-αR2. However, both IFN-α and IFN-λ signal via the Jak-STAT pathway, leading to the phosphorylation of STAT1 and STAT2, formation of the ISGF3 transcription factor complexes and subsequent binding to IFN-stimulated response elements (ISRE) in the promoters of many IFN-stimulated genes (ISG).[7,8] Additionally, previous studies using in vitro HCV culture systems have shown that both IFN-α and IFN-λ inhibit HCV viral replication.[9,10] Presently, clinical trials are being performed to evaluate the safety, tolerability and antiviral efficacy of recombinant human IFN-λ in chronic hepatitis C patients.

Although IFN-α and IFN-λ share a number of biological properties, they are also quite distinct in many other characteristics. In this regard, as compared to IFN-α receptors, which are widely distributed, IFN-λ receptor distribution is limited to hepatocytes in the liver, B cells in the peripheral blood, and epithelial cells.[10,11] This limited receptor distribution might be the reason that early clinical trials of IFN-λ in humans have reported fewer adverse events and hematologic effects as compared to IFN-α-treated patients.[12,13] Despite the improved side effect profile and potential clinical utility, the role of IFN-λ in the control of HCV infection has not yet been well defined. The mechanisms of IFN-λ in the control and pathogenesis of chronic hepatitis C is presently unknown.

In this study, we compared the antiviral activity of IFN-α and IFN-λ in HCV-infected hepatoma cells. We also compared the ability of IFN-α and IFN-λ to regulate ISG expression in HCV-infected and noninfected hepatoma cells. In this regard, we compared the antiviral effect, gene expression profiles and signalling induced by IFN-α and IFN-λ in HCV-infected and noninfected Huh7.5 cells.

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