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Numerous studies have confirmed and extended the striking results of independent genome-wide association studies showing that single nucleotide polymorphisms (SNPs) near the IL28B gene (encoding interferon-λ3 (IFN-λ3)) are strongly associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection (reviewed in1). Most importantly, these studies have shown that good-response IL28B SNPs (eg, rs12979860 CC vs CT/TT) increase sustained virological response rates in HCV genotype 1 and 4 patients after classical treatment with pegylated interferon-α (pegIFN-α) and ribavirin by approximately twofold.1 With respect to the strength of this association, the identification of IL28B as a genetic determinant of treatment outcome and spontaneous clearance from HCV infection constitutes a remarkable exception among numerous published genome-wide association studies, which generally yielded susceptibility loci that only had a moderate impact on the investigated phenotype (see http://www.genome.gov/26525384 for a listing). However, the outstanding findings regarding IL28B and HCV infection, initially made in cohorts treated with classical pegIFN-α/ribavirin therapy, coincide with a likewise stunning progress in therapeutic opportunities to manage HCV infection. Recently approved telaprevir and boceprevir-based triple therapies, as well as numerous other directly acting antiviral agents (DAAs) currently being in advanced clinical evaluation in both pegIFN-α-based and IFN-free treatment regimens, result in a dramatically improved therapeutic repertoire to treat chronic hepatitis C.2 Consequently, the clinical value of IL28B genotyping is currently under re-evaluation.
In this regard, recent data have clearly shown that IL28B genotype is predictive for treatment outcome of many pegIFN-α-based triple therapies as well, though its impact is strongly attenuated compared with pegIFN-α/ribavirin therapy.2 Perhaps more surprisingly, IL28B genotype also appears to have a moderate impact on virological response to IFN-free, all-oral regimens.3 Regarding the completely different mode of operation of immune-modulating IFN-α-based therapy in contrast to IFN-free DAA regimens, which directly tackle HCV, these observations are not self-evident. A nearby explanation of these findings might be that an appropriate endogenous immune response against HCV is still important for the definite clearance of residual, possibly drug-resistant virus escaping DAA combinations. Hence, IL28B genotype may remain a relevant parameter for clinical decision making even in the upcoming era of all-oral therapies for HCV infection, for example, for the choice of appropriate treatment regimens in selected cases. Furthermore, from a more global point of view, it might be important to define whether IL28B genetic variants play a role in other diseases than hepatitis C. The substantially different distribution of IL28B alleles across populations of different ancestries can be considered as a strong argument for an impact of this locus on diseases beyond HCV infection. While for example the ‘favourable’ IL28B rs12979860 C allele is relatively rare in individuals of African descent (approximately 20%–30%), 90%–100% of individuals originating from large parts of East Asia carry at least one rs12979860 C allele.4 This heterogeneity across populations is significantly higher than for most other known SNPs, suggesting that the IL28B locus has been under selection pressure particularly in Asia, for example, driven by ancient viral diseases. As in humans expression of the IFN-λ receptor complex (IL28-Rα/IL-10R2) is restricted to hepatocytes, epithelial cells and plasmacytoid dendritic cells, the IL28B gene might be especially relevant for infectious liver diseases other than hepatitis C, but also for lung or gastrointestinal diseases.1 Hence, accordant to HCV infection, some reports have shown an association between IL28B genotype and response to pegIFN-α-based treatment of chronic hepatitis B.5 Furthermore, an impact of IL28B genetic variants and IFN-λ-signalling has been suggested for the pathogenesis of asthma and other allergic and viral lung diseases.6 ,7
In parallel to these clinical considerations, the discovery of IL28B genotype as a strong determinant of spontaneous and treatment-induced clearance from HCV infection has also inspired basic researches to investigate possible mechanisms how the identified SNPs may exert their biological effects, as well as to further elucidate thus far poorly investigated IFN-λ signalling in general. In view of the above mentioned data on various diseases, these intentions appear highly relevant. The IL28B gene encodes for IFN-λ3, which constitutes the IFN-λ family (also called type III interferons), together with IFN-λ1 (encoded by IL29) and IFN-λ2 (encoded by IL28A).1 However, it is important to keep in mind that most thus far described IL28B variations associated with spontaneous and treatment-induced clearance are not located within coding regions, but only in close proximity of the IL28B gene. Consequently, the highly suggestive link between IL28B variations and IFN-λ3 expression/signalling has not yet been definitely proven. Moreover, data on blood and tissue levels of INF-λ3 in HCV patients with different IL28B genotypes remain conflicting.1
With respect to a better functional understanding of IL28B genetic variants, the study published by Watanabe and colleagues in this issue of Gut represents an important piece of work.8 While one part of their study describes known associations between IL28B genotype and virological response patterns in chronic hepatitis C patients, a second innovative part of the study by Watanabe et al assesses HCV viral kinetics upon pegIFN-α treatment in a chimeric mouse model with (partially) humanised livers of different IL28B genetic backgrounds. Importantly, these chimeric uPA/SCID mice show a phenotype of severe immunodeficiency, which, after repopulation with human hepatocytes, allows infection with HCV isolates. This model is suitable to assess the antiviral efficacy of IFN-α and other antiviral agents, and—as done by Watanabe et al in the present study—an analysis of the impact of different IL28B genetic variants present exclusively in the humanised liver but not in cells, for example, of the immune system. Importantly, in this model, Watanabe et al did not observe any differences in first or second phase HCV RNA decline upon treatment with pegIFN-α in mice with a poor-response versus a good-response hepatocellular IL28B genotype. In addition, pegIFN-α treatment led to a strong increase of interferon-stimulated gene (ISG) expression, which again was similar in mice with a poor-response versus a good-response liver IL28B genotype. These results are in sharp contrast to studies in HCV infected patients, which found strong associations between IL28B genotype and early viral kinetics as well as expression levels of ISGs in liver specimens.1 Hence, the data by Watanabe et al suggest that the presence of a specific IL28B genetic variant in the liver alone is not sufficient to impact on IFN-α-induced HCV kinetics and ISG expression, at least in the absence of an intact immune system. Nevertheless, Watanabe et al have observed higher levels of intrahepatic IFN-λ gene expression in uPA/SCID mice with a good-response versus a poor-response liver IL28B genetic background after administration of pegIFN-α treatment (IFN-λs are known to be induced by IFN-α). As this increased expression of IFN-λ did not translate into more pronounced viral load decline, the authors speculate that IFN-λ synthesised by hepatocytes impacts on HCV-replication via stimulating immune cells. Indeed, studies in humans have shown that a poor-response IL28B genotype is associated with insufficient innate and adaptive immune responses against HCV.1 Conversely, HCV-infected individuals with a good-response IL28B genotype display more severe necro-inflammation in liver biopsies than individuals with a poor-response IL28B genotype, as well as higher alanin and aspartate aminotransferase serum levels.1 Hence, the assumptions of Watanabe et al can be considered as plausible, though the artificial nature of their animal model should not be neglected. In summary, the study by Watanabe et al provides solid arguments that SNPs near IL28B indeed impact on hepatocellular IFN-λ gene expression (by a mechanism which is still unclear), but that an intact immune system is necessary to translate this effect in effective suppression of HCV replication.
In conclusion, innovative research as that reported by Watanabe et al is highly important for a better understanding of functional implications of IL28B genetic variants and of IFN-λ signalling in general. Together with additional recent studies showing, for example, that IL28B SNPs may affect IFN-λ expression via altering DNA methylation and transcription factor binding sites,9 or that the presence of a poor-response IL28B genotype even may result in expression of a novel protein of unknown function called interferon-analogue protein,10 these topical data represent important steps to solve the miracle how IL28B genotype impacts on the natural course and treatment of HCV infection. Certainly, it can be assumed that these studies will inspire researches in the field, but also beyond the field of hepatitis C.
Contributors CML alone wrote the manuscript.
Funding CML is supported by the Deutsche Forschungsgemeinschaft (LA 2806/2-1), as well as by grants of the Johann Wolfgang Goethe University Hospital (Förderung Nachwuchsforscher, LOEWE OSF). Furthermore, CML is the recipient of a stipend of the Deutsche Leberstiftung (S163/10087/2012).
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
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