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IFN-? receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-?3 genotype and with nonresponsiveness to IFN-? therapies.

ABSTRACT: The molecular mechanisms that link IFN-?3 genotypes to differential induction of interferon (IFN)-stimulated genes (ISGs) in the liver of patients with chronic hepatitis C (CHC) are not known. We measured the expression of IFN-? and of the specific IFN-? receptor chain (IFN-?R1) in 122 liver biopsies of patients with CHC and 53 control samples. The IFN-?3 genotype was not associated with differential expression of IFN-?, but rather IFN-?R1. In a series of 30 primary human hepatocyte (PHH) samples, IFN-?R1 expression was low but could be induced with IFN-?. IFN-?-induced IFN-?R1 expression was significantly stronger in PHHs carrying the minor IFN-?3 allele. The analysis of liver biopsies of patients with CHC revealed a strong association of high IFN-?R1 expression with elevated ISG expression, with IFN-?3 minor alleles, and with nonresponse to pegylated IFN-? and ribavirin. The findings provide a missing link between the IFN-?3 genotype and the associated phenotype of treatment nonresponse.

SUBMITTER: Duong FH

PROVIDER: S-EPMC4010915 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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IFN-λ receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-λ3 genotype and with nonresponsiveness to IFN-α therapies.

Duong Francois H T FH Trincucci Gaia G Boldanova Tujana T Calabrese Diego D Campana Benedetta B Krol Ilona I Durand Sarah C SC Heydmann Laura L Zeisel Mirjam B MB Baumert Thomas F TF Heim Markus H MH

The Journal of experimental medicine 20140421 5

The molecular mechanisms that link IFN-λ3 genotypes to differential induction of interferon (IFN)-stimulated genes (ISGs) in the liver of patients with chronic hepatitis C (CHC) are not known. We measured the expression of IFN-λ and of the specific IFN-λ receptor chain (IFN-λR1) in 122 liver biopsies of patients with CHC and 53 control samples. The IFN-λ3 genotype was not associated with differential expression of IFN-λ, but rather IFN-λR1. In a series of 30 primary human hepatocyte (PHH) sample ...[more]

PMID: 24752298

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Project description:To date, several on-treatment-level virological and serological indices that may predict the response to interferon alpha (IFN-α) have been reported. However, no effective predictors, such as drug-response genes, that can be detected before administration of anti-hepatitis B virus (HBV) therapy with IFN-α, have been found. In the diverse range of chronic viral infection, genes that affect human immunity play important roles in understanding host and viral co-evolution. Killer-cell immunoglobulin-like receptors (KIRs), which are highly polymorphic at the allele and haplotype levels, participate in the antiviral function of natural killer (NK) cells via fine-tuning inhibition and activation of NK-cell responses that occur when the NK cells interact with human leukocyte antigen (HLA) class I molecules on target cells. For each individual, the pairing of KIR and HLA ligand is genetically determined. To investigate whether a particular KIR and HLA repertoire influences the risk of HBV infection and response to IFN-α treatment for chronic hepatitis B (CHB), we genotyped the KIRs and HLA ligands of 119 hepatitis B e antigen (HBeAg)-positive CHB patients. These patients included 43 patients who achieved sustained response (SR) induced by IFN-α treatment for 48 weeks, 76 patients who achieved no response (NR), and 96 healthy subjects as controls. SR was defined as HBeAg loss with HBV DNA < 2,000 IU/ml and alanine aminotransferase normalization at 24 weeks posttreatment (week 72). In this study, we showed that activating KIR genes were less prevalent in Han Chinese, especially in Han Chinese with CHB, than in Caucasians. Furthermore, the KIR3DS1 gene, in combination with HLA-B Bw4-80Ile, strongly influenced the therapeutic outcomes for CHB patients who were treated with IFN-α. The frequency of the combination of genes encoding KIR3DS1 and HLA-B Bw4-80Ile was higher in patients who had a sustained treatment response than in patients who had NR [35.3 versus 1.3%; odds ratio (OR) = 19.85; P = 0.0008]. Activating KIR3DS1 and HLA-B Bw4-80Ile synergistically predicted SR to IFN-α for HBeAg-positive CHB patients. Genotyping for the KIR3DS1 gene and the HLA-B Bw4-80Ile allele might help physicians choose the optimal candidates for anti-HBV treatment with IFN-α.

Dataset Information

IFN-? receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-?3 genotype and with nonresponsiveness to IFN-? therapies.

Publications

IFN-λ receptor 1 expression is induced in chronic hepatitis C and correlates with the IFN-λ3 genotype and with nonresponsiveness to IFN-α therapies.

Similar Datasets

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