10 In patients who respond to therapy, after ≈24-48 hours, the viral decline enters a second phase of relatively slow exponential decay, which represents elimination of infected cells. Patients who are not responsive to therapy have a plateau or even a rebound in viral load during this second phase. After initiation of PEG-IFN and RBV therapy, patients with the C/C genotype at rs12979860 have a greater HCV RNA decline from days 0-28 than patients with the C/T or T/T genotype.8 Further studies show that the

difference can be detected in the first 48 hours of treatment (Fig. 2).11, 12 Among patients Selleck Midostaurin with the C/C genotype, Caucasians but not African Americans have greater HCV RNA declines than the other genotypes during the second phase (days 7-28). The specific mechanisms of how variations in IL28B SNPs affect HCV suppression remain unknown. However, IL28A, IL28B, and IL29, also called type 3 or lambda IFNs, are induced by viral infection and have antiviral activity.13 All three interact with a heterodimeric class II cytokine receptor that consists of IL10Rβ and IL28Rα (IFNλR1)14, 15 (Fig. 3). Lambda IFNs inhibit HCV replication in vitro16, 17 and may protect against other RNA-containing

viruses in vivo.13, 18 Lambda IFNs are thought to produce intracellular responses similar to those of IFN-α but are more specific in their tissue targets because of restricted receptor expression. This has led some to hypothesize that lambda IFNs have similar antiviral activity as IFN-α, but with fewer adverse effects. Supporting this hypothesis are results from an open-label study of PEG-IFN-λ1 Selleck MS-275 (IL29) in patients with genotype 1 HCV, in which weekly dosing had antiviral activity and was well tolerated.19 However, larger, blinded studies are needed to further evaluate the safety and efficacy of lambda IFNs. As for type 1 IFNs, expression of lambda IFNs

occurs predominantly in antigen-presenting cells such as macrophages and dendritic cells.13, 20 Within the liver, the receptor for lambda IFNs is predominantly expressed in hepatocytes.21 The kinetics of signal transduction appear to differ between type 1 NADPH-cytochrome-c2 reductase and type 3 IFNs, with type 3 IFN showing slower activation onset and prolonged duration of activity compared with type 1.16 However, type 1 and type 3 stimulate similar pathways, with receptor binding resulting in phosphorylation of the kinases JAK1 and Tyk2, activation of the transcription factor complex containing STAT1, STAT2, and IFN regulatory factor 9, and up-regulation of a similar set of interferon-stimulated genes (ISGs).16, 18 Improved viral clearance could result from alterations in IL28B expression, messenger RNA splicing, half-life, or cytokine-receptor affinity or specificity. The responder haplotype of rs8099917 has been weakly associated with higher expression levels of IL28A and IL28B in peripheral blood mononuclear cells.