Interestingly, this region included a novel SNP (ss469415590[δG]), resulting in a frame shift mutation leading to the production of five transcripts, although one of these is likely eliminated by nonsense-mediated mRNA decay (Fig.
1). Genetic analysis of this region in patients from several independent clinical cohorts of hepatitis C studies revealed an association of the ss469415590[δG] allele with reduced response rates to IFN-β treatment (Virahep-C, HALT-C) and reduced association with spontaneous HCV clearance (UHS, ALIVE). The association pattern of ss469415590 to IFN-β treatment response and viral clearance was similar to rs12979860 in participants of the HALT-C and UHS trials but slightly more pronounced for ss469415590 in AA participants. Furthermore, the team Pritelivir concentration demonstrated
that ss469415590 is in high linkage disequilibrium with rs12979860 in the IFNL3 gene, suggesting that SNPs at these PF-02341066 in vitro positions are genetically linked in all populations studied. Using functional studies with expression plasmids and recombinant IFN-β and IFNL3 proteins in liver-derived cell lines, the authors found evidence that the largest gene product, p179, appears to activate STAT signaling and induces the expression of ISGs.18 Furthermore, transient expression of p179 in hepatoma cells carrying an HCV replicon inhibited viral replication, indicating an antiviral role of p179. Taken together, these findings led the authors to conclude that the identified gene products may have a functional role in the innate immune response to RNA viruses. Furthermore, p179 shares 40.8% amino acid sequence similarity with IFNL3 and was designated as a new member of the interferon lambda family, called IFNL4.18 The results of this study have several implications: First, the study identifies a new
starting point to better understand the role of IFNL in viral evasion. The correlation between the presence of a functional IFNL4 gene (i.e., ss469415590[δG]) acetylcholine and impaired clearance of HCV reported by Prokunina-Olsson et al. may suggest that IFNL4 is too weak to clear CHC. Furthermore, the authors conclude from this that weakly induced IFNL4 signals may reduce responsiveness of cells to IFN-β, thereby inhibiting efficient HCV clearance.18 Interestingly, the authors found that IFNL4 caused preactivation of interferon signaling which prevented further activation by IFN-β and IFNL3.18 This indicates that IFNL4 may cause refractoriness to IFN signaling, although it has been demonstrated that unlike IFN-β, hepatic IFNL signaling is resistant to refractoriness.17 IFNL4 appears to display different receptor binding sites compared to IFNL3 in regions required for the association with the second chain receptor of the IFNL receptor complex (IL10R2).18 This evidence led the authors to speculate that IFNL4 may engage a different receptor complex or act as a decoy cytokine competing with the classical IFNLs.