Insights into the role of interferon lambda in hepatitis C virus infection

Abstract

Infection with hepatitis C virus (HCV) is characterized by two different outcomes. Approximately 30% of HCV-infected patients spontaneously resolve HCV infection while the others fail to control the infection. Once chronic HCV infection is established, antiviral therapy based on pegylated interferon alpha (PEG-IFNa) and ribavirin achieves viral clearance in only 30–50% of cases [6]. Genome-wide association studies (GWAS) indicated that host genetic variation plays a key determinant in natural and treatment-induced control of HCV infection. Independent GWAS studies consistently identified variants within the IL28B gene region that are strongly associated with spontaneous HCV clearance and hepatitis C treatment-induced viral clearance [4,10,13,18– 20]. However, the mechanism by which IL28B variants influence viral clearance remains undetermined. The IL28B gene forms a cytokine gene cluster with IL28A and IL29 on human chromosome 19. IL29, IL28A, and IL28B are also known as IFNk1, IFNk2, and IFNk3, respectively. They are type III IFNs with antiviral activity. IL28B is highly homologous to IL28A (96%) and shows 81% homology with IL29. Type III IFNs have biological activities that are similar to those of type I IFNs (IFNa/b), although they share very little sequence homology. Type III IFN expression depends on the same stimuli (viral infection, Toll-like receptor ligands) and signal transduction pathways as those involved in type I IFN expression, which leads to the induction of several hundred interferon-stimulated genes (ISGs), such as Mx1, OAS or IFIT [7,16] (Fig. 1). In the current issue of the Journal of Hepatology, Langhans et al. performed a cross-sectional analysis of IFNk serum levels in HCV-infected patients with different outcomes and stratified their results with the single nucleotide polymorphism (SNP) rs12979860 that is located 3 kb upstream of the IL28B gene. GWAS studies carried out by Ge et al. [4] and McCarthy et al. [10] found a striking correlation between carriers with the rs12979860 CC genotype and sustained virological response (SVR) rates. The protective rs12979860 CC genotype was not only associated with significantly higher SVR rates in patients with chronic HCV infection but also predicted spontaneous HCV clearance [20]. The study by Langhans et al. included 60 treatment-naive patients with chronic HCV infection, 19 patients with