However, it seems that after induction by viral RNA mimics IFNL4 is merely enriched in the cytosol and it remains to be determined whether the protein is secreted to interact with cell surface receptors. Although intracellular overexpression of the IFNL4 protein appears to induce ISG expression, cells treated with recombinant Y-27632 protein failed to do so at significant levels. These findings indicate that further studies are needed to characterize the functional properties of the identified gene products, their mechanism of action, and their functional relevance in antiviral defense mechanisms. Second, the study may provide

insights into the understanding of the genetic evolution of innate immune responses. The authors found that the ss469415590[δG] frameshift variant encoding the putative IFNL4 is more common in AA patients and correlates with reduced HCV response in large clinical cohorts.18 The authors discussed the possibility that the beneficial allele ss469415590[TT] abrogating IFNL4 may have been selected during geographically

distinct Panobinostat purchase human evolution.18 It is tempting to speculate that the original purpose of the putative IFNL4 may have been important for the innate immune defense against other pathogens. It is conceivable that in an evolutionary context the “loss” of IFNL4 in humans occurred predominantly in geographic regions where the selective pressure from those pathogens eased. Moreover, since predominantly HCV-infected patients with genotype 1 were studied by the authors, a comprehensive multifactorial analysis of ss469415590 involving additional click here HCV genotypes, ethnic background, and geographic prevalence of different HCV genotypes may provide interesting insight into HCV evolution. For example, it will be interesting to determine whether more difficult-to-treat genotype 1 viruses co-evolved together with the selection of the ss469415590[TT].

Finally, the findings of the study may have clinical relevance for the management of patients with CHC. The recent groundbreaking discovery that SNPs in the region of IFNL3 are predictors for treatment outcome of CHC had revealed a new perspective for customized IFN-based therapies.8–16 In this context, potential algorithms have been proposed to utilize IFNL3 genotyping in the initial treatment decision making for CHC infections.19 Prokunina-Olsson et al. now extend these findings by revealing that ss469415590[δG] is more strongly associated with HCV clearance in AAs than the previously described SNPs, although it provides comparable information in patients with European and Asian ancestry.18 Including the upstream ss469415590 in the IFNL3 genotyping in the treatment decision algorithm may increase the reliability of prediction of IFN-based treatment outcome, especially in patients with African ancestry.