Association of Gene Expression Involving Innate Immunity and Genetic Variation in Interleukin 28B With Antiviral Response

Abstract

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon a (PEG-IFNa) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNa-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNk). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (%3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P 5 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (%2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. Conclusion: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNa/ RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR. (HEPATOLOGY 2012;55:20-29)

Interaction of TLR–IFN and HLA polymorphisms on susceptibility of chronic HBV infection in Southwest Han Chinese

“…Unlike the IL28B SNP, rs12979860, which is associated with HCV clearance, there are few studies focusing on the mechanisms by which HLA gene variations may influence the development of HBV infection. Furthermore, studies investigating the mechanism between IL28B variation and HCV clearance have shown that IL28B variation is associated with other immune factors (19,21,29,30). Therefore, we attempted to define the association between genes of the innate immunity and HLA variation.…”

“…Although IL28B rs12979860 is a good predictor for HCV clearance (16), the level of IFN lambda 3, coded for by the IL28B gene, does not crucially influence the outcome in HCV infection (16,17). However, abnormal innate immune responses such as high levels of IL-10 and low IL-12p40 were found in patients with the poor-response genotype (18)(19)(20)(21).…”

Recent Advances in Management of the HIV/HCV Coinfected Patient

“…Two major polymorphisms, rs12979860 (C>T) [76,77] and rs8099917 (T>G) [72,73], in strong linkage disequilibrium are associated with responses to PEG-IFN and RBV [71,78]. The mechanism might be related to the regulation of innate immune responses by the IL28B gene product, IFN-λ3 [79]. The association appears relatively weaker between IL28B genotype and simeprevir with PEG-IFN and RBV.…”

PharmGKB summary

“…One explanation for this is that patients with the unfavorable genotype exhibit continual, ineffectual intrahepatic expression of ISGs. At the same time, IFN-signaling inhibitors such as SOC3 and protein inhibitor of activated STAT 1 are also upregulated; this preactivated ISG response may be insufficient to clear the virus, but it may cause reduced sensitivity to PEG-IFN-α therapy through negative regulation of JAK-STAT signaling by IFN-signaling inhibitors [104,106]. Thus, even when PEG-IFN-α is administered, the cell may fail to induce strong enough ISG expression and be unable to clear the virus [106].…”