Role of IL28B for Chronic Hepatitis C Treatment Toward Personalized Medicine

Kentaro Matsuura; Tsunamasa Watanabe; Yasuhito Tanaka


J Gastroenterol Hepatol. 2014;29(2):241-249. 

In This Article

Association Between IFN-λ and HCV Infection

IL28B encodes IFN-λ3, which belongs to the type III IFN-λ family consisting of IL29/IFN-λ1, IL28A/IFN-λ2, and IL28B. Signaling by IFN-λ is initiated through a membrane receptor distinct from receptors for type I IFNs composed of heterodimers of an IL28RA/IFN-λR subunit and an IL10R2 subunit.[78,79] Type I and III IFNs induce transcription of IFN-stimulated genes (ISGs) by activating the Janus kinase-signal transducer and activator of transcription pathway through different cell surface receptors[78,79] in order to mediate their potent antiviral effects. There have been several reports about the profile of ISG expression in liver or peripheral blood mononuclear cells (PBMCs) so far. It has been reported that high-level expression of intrahepatic ISGs affected poor response to PEG-IFN/RBV therapy.[80,81] Moreover, recent studies have revealed an association between IL28B genotype and expression levels of intrahepatic ISGs.[82,83] In addition, the innate immune system: Toll-like receptor 3 and retinoic acid-inducible gene I signaling pathways of IFN-β induction has an essential role in host antiviral defense against HCV infection. Asahina et al. showed that the intrahepatic genes expressions involving innate immunity were strongly associated with IL28B genotype and response to PEG-IFN/RBV.[84,85] With regard to IL28 expression in PBMCs, Suppiah et al. and we have shown to be higher in patients with a favorable IL28B genotype.[6,8] Asahina et al. showed that the induction of several ISGs in PBMCs after the initial administration of PEG-IFN/RBV tended to be stronger in SVR than in NVR group, but the difference was not statistically significant.[84] Similarly, most of other investigators have indicated less marked association between the expression of ISGs in PBMCs and treatment outcomes, or IL28B genotype in comparison with in liver of the same patients.[80,86] Thus, although there are several reports about the association between ISGs in liver or PBMCs and IL28B genotype or response to IFN therapy, the biological pathways linking IL28B genetic variants to spontaneous and/or treatment-induced HCV clearance remain unknown. However, recent reports suggest some possible scenarios. Using primary human hepatocytes or chimpanzee, Thomas et al. found that type III but not type I IFNs are primarily induced after HCV infection and that their degree of induction is closely correlated with the levels of ISGs.[87] These results strongly suggest that hepatic IFN-λ production may have important roles and could be a principal driver of ISG induction in response to HCV infection. On the other hand, in chronically HCV-infected chimeric mouse model that have the characteristic of immunodeficiency, larger amounts of IFN-λs on HCV-infected human hepatocytes were produced in liver with a favorable IL28B genotype on treatment with IFN-α.[88] However, no significant differences in HCV-RNA reduction related to IL28B variants were observed because of the lack of intrinsic immune cells in the model. In contrast, Zhang et al. and Yoshio et al. reported that a certain subset of dendritic cells (DCs) within human PBMCs could recognize HCV and produce large amounts of IFN-λs.[89,90] The ability of production of IFN-λ3 was superior in subjects with a favorable IL28B genotype.[90] Moreover, IFN-α directly affected DC function and significantly increased IFN-λ production.[89] Based on these findings, it is tempting to speculate that exogenous IFN-α would increase IFN-λ production by DCs and/or HCV-infected hepatocytes during IFN-α therapy, and this could provide a potential explanation as to why IL28B genetic variants predict the outcome of IFN-α therapy (Fig. 1).

Figure 1.

Potential role of interleukin-28B (IL28B) single nucleotide polymorphism (SNP) in the response to interferon (IFN)-α therapy. IFN-α upregulates hepatic IFN-stimulated genes (ISGs). According to in vivo models of chronic hepatitis C virus (HCV) infection,[88] exogenous IFN-α would increase IFN-λ production by HCV-infected hepatocytes during IFN-α therapy. The amounts of IFN-λs produced on HCV-infected human hepatocytes were larger in liver with a favorable IL28B genotype. Dendritic cells (DCs) also produce large amounts of IFN-λ, following an immune response against HCV infection in the liver environment. The ability of IFN-λ3 production by DCs was superior in subjects with a favorable IL28B genotype.[90]

Recently, Olsson et al. performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. They discovered that a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG) was strongly associated with HCV clearance. The ss469415590 polymorphism is located upstream of IL28B and is in high-linkage disequilibrium with rs12979860. The ss469415590 ΔG allele is a frameshift variant that creates a novel gene, designated IFNL4, encoding the type III IFN-λ4 protein, which is fairly similar to IFN-λ3. Interestingly, compared with rs12979860, ss469415590 is more strongly associated with spontaneous and treatment-induced HCV clearance in individuals of African ancestry, whereas it did not improve prediction among Caucasians and Asians. This can be explained by a lower level of linkage disequilibrium between the two polymorphisms in African Americans (r2 = 0.71) compared with Caucasians (r2 = 0.92) and Asians (r2 = 1.00).[91] Bibert et al. also noted that this polymorphism improved prediction of treatment-induced HCV clearance in patients infected with HCV genotype 1/4 or 2/3. In addition, they determined that induction of IL28B and IFN-γ-inducible protein 10 messenger RNA relies on ss469415590 but not rs12979860 in PBMCs.[92] Their findings provide new insights into the genetic regulation of HCV clearance and have implications for its clinical management.