Abstract
Background and AimsIL-28B gene polymorphisms predict better therapeutic response and spontaneous clearance of HCV. Moreover, higher expression of IFN-lambda has been reported in patients with the rs12979860 CC favourable genotype. The study aim was to establish possible relationships between IL-28B rs12979860 genotypes and expression of IFN-alpha receptor-1 (IFNAR-1) in naïve HCV patients, and to explore the possible role of IFN-lambda.MethodsIFNAR-1 mRNA levels were measured in PBMC from naïve patients with chronic hepatitis C with different IL-28 genotypes. The ability of IFN-lambda to up-regulate the expression of IFNAR-1 was established in PBMC from healthy donors carrying different IL-28B genotypes.ResultsLower IFNAR-1 mRNA levels were observed in PBMC from HCV-infected naïve patients as compared to healthy donors. In healthy donors, IFNAR-1 mRNA levels were independent from IL-28B genotype, while in HCV patients, an increasing gradient was observed in TT vs CT vs CC carriers. In the latter group, a direct correlation between IFNAR-1 and endogenous IL-28B expression was observed. Moreover, IFN-lambda up-regulated IFNAR-1 expression in normal PBMC in a time-and dose-dependent manner, with a more effective response in CC vs TT carriers.ConclusionEndogenous levels of IFN-lambda may be responsible for partial restoration of IFNAR-1 expression in HCV patients with favourable IL-28 genotype. This, in turn, may confer to CC carriers a response advantage to either endogenous or exogenous IFN-alpha, representing the biological basis for the observed association between CC genotype and favourable outcome of either natural infection (clearance vs chronicization) or IFN therapy.
Highlights
Hepatitis C virus (HCV) is the leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in developed countries [1]
Patients peripheral blood mononuclear cells (PBMC) and plasma samples from 40 treatment-naive patients, chronically infected with HCV, collected at the National Institute for Infectious Diseases and stored in the Institutional Biorepository, for whom IL-28B genotype at locus rs12979860 was known, were retrospectively selected, in order to include a sufficient number of patients harboring the CC genotype to perform a comparative analysis
To assess the relationships between the expression of IFN-alpha receptor-1 (IFNAR-1) mRNA and the IL-28B rs12979860 genotypes, mRNA levels of IFNAR-1 were tested at baseline and after 3 h of exposure to either control medium or IFN-alpha (103 IU/ml) in PBMC obtained from naive HCV-infected patients carrying different IL28B rs12979860 genotypes
Summary
Hepatitis C virus (HCV) is the leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in developed countries [1]. The standard of care (SOC) for chronic HCV infection consists of pegylated IFN (peg-IFN)-2a or -2b and ribavirin (RBV). This treatment produces sustained virologic response (SVR) in only 40–50% of patients with HCV genotype 1 and approximately 60% in those infected with genotype 4, whereas over 80% of patients with genotype 2 or 3 achieve SVR [3,4]. Several studies showed a correlation between pretreatment expression levels of IFN stimulated genes (ISGs) and response to treatment, using either liver tissues or serum or peripheral blood mononuclear cells (PBMC) [5,6]. The study aim was to establish possible relationships between IL-28B rs12979860 genotypes and expression of IFN-alpha receptor-1 (IFNAR-1) in naıve HCV patients, and to explore the possible role of IFN-lambda
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