IL28B and the control of hepatitis C virus infection

Abstract

Treatment-induced control and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-λ3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFN-λ3 up-regulates interferon-stimulated genes, similar to IFN-α and IFN-β but via a different receptor. There is also evidence that IFN-λ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated IFN-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFN-λ3, the clinical implications of the genetic association, and areas of future research.

Fig. 1. SNPs in IFNγ Gene Cluster Associated with HCV Control

The IFNγ gene cluster is shown in the top panel indicating its position on Chromosome 19. In the second panel the positions of the relevant SNPs corresponding to the text and published data are indicated in relation to the IFNγ gene cluster.^{, –} IL28B is upstream and in reverse orientation compared with IL28A. The third panel depicts the genomic structure of IL28B, including its 5 exons, intervening introns, and flanking putative regulatory regions. Vertical lines denote the position of individual SNPs that are associated with HCV treatment response; these are connected by hashed lines to the adjoining table. The only SNP that is in a coding region encodes K70R; it causes an A > G polymorphism on the negative, coding strand and a T > C polymorphism on the positive, non-coding strand. The bottom panel shows which SNPs were associated with response to treatment in each of the indicated studies, including those that were found by genetic mapping studies. As indicated in the legend, symbols are used to indicate if a given SNP was associated with SVR in each of 4 GWAS and genetic mapping studies. ● SNP was associated with SVR; ● SNP was not associated with SVR; −/● SNP was not found to be associated with SVR in the overall analysis, however ≥1 GWAS platform did not have probes to test for this SNP.

Fig. 2. Manhattan Plot of Genome-Wide Significant Associations of SNPs with Response to Treatment for HCV Infection

Using an Illumina Human610-quad BeadChip, Ge et al. performed a GWAS using DNA from 1671 HCV-infected persons who were treated with PEG-IFNα-2a or -2b and ribavirin for 48 weeks to find genetic determinants of treatment response. Chromosome number and relative position are indicated on the x-axis above the plot, and −log₁₀(P value) is in the y-axis. The top 6 SNPs were found in or near the IFNγ gene cluster. (Adapted by permission from Macmillan Publishers Ltd: Nature 461, 399–401 (16 August 2009)).

Fig. 3. Predicted Natural and Treatment History of HCV Infection based on Haplotype

Based on both GWAS and genetic mapping data several SNPs with alleles that are in strong linkage disequilibrium have been identified in or near the IL28B gene locus. These SNPs collectively delineate haplotypes associated with HCV clearance (green) or persistence (red). After acute HCV infection, a greater proportion of persons with specific haplotypes spontaneously clear HCV, compared to patients with other haplotypes. Of the persons who develop persistent HCV infections, intrahepatic expression of ISGs is lower in the group with the HCV clearance haplotype, compared with the persistence haplotype. Patients with the haplotype associated with HCV clearance are more likely to achieve SVRs when they receive treatment with PEG-IFN-α/RBV than patients with other haplotypes.

Fig. 4. Allele frequencies of the SNP rs12979860 among Different Ethnic Populations

Thomas et al. genotyped the rs12979860 SNP in 2371 person from 51 distinct populations. The frequency map shows the proportional prevalence of the C (associated with HCV clearance) and T (associated with persistence) alleles. People in East and Southeast Asia have the lowest frequency of the alleles associated with HCV persistence; people in Europe have intermediate incidence, and the highest frequencies are found in sub-Saharan Africa. (Adapted by permission from Macmillan Publishers Ltd: Nature 461, 798–801 (16 September 2009)).

Fig. 5. IFNγ, IFNα, and IFNβ Signaling in Response to HCV

HCV RNA is sensed by pattern recognition receptors such as RIG-I and TLR3, which signal using IRF3 and 7 and activate the transcription factor NF-κB to induce expression of IFNγ (plasmacytoid Dendritic Cells), IFNα, and IFNβ (pDCs and hepatocytes). When these factors bind their receptors, IFNγR (a heterodimer of IL28Rα and IL10Rβ), IFNAR1 and IFNAr2, respectively, they induce Jak–STAT signaling, which results in the formation of ISGF3, the transcription factor that upregulates hundreds of ISGs. Exogenously administered IFNs also bind and signal through their cognate receptors; in persistent HCV infection that does not respond to therapy, a steady-state environment exists that is characterized by increased expression of ISGs. (Figure adapted from Thio and Thomas et al., Gastroenterology, 2010).