Affiliation:
1. Clinical Microbiology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
2. Gastroenterohepatology Research Center, Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Fars, Iran
Abstract
Background:
The cellular antiviral responses induced by interferons require some cellular
protein kinase for its activation. Evidence indicated that a number of Hepatitis C Virus (HCV) proteins
can repress double-stranded (ds) RNA-dependent Protein Kinase (PKR) function and help HCV to escape.
However, the reports are controversial, some researchers have suggested that a region in Nonstructural
5A (NS5A) gene called Protein Kinase R-Binding Domain (PKR-BD) is associated with HCV sensitivity
to the antiviral effects of Interferon (IFN). In addition, the other factor that might be associated
with response to PEGylated-IFNα (Peg-IFNα) and Ribavirin (RBV) combination therapy, is IFNL4
genotypes.
Objective:
The aim of this study was to investigate the association between amino acid (aa) substitutions
in the NS5A region and the IFNL4 genotypes in two Single Nucleotide Polymorphism (SNP)
(rs8099917. rs12979860) in patients with HCV genotypes 1a and 3a. We also examined their response
to combination therapy and the effect of these mutations on the function and structure of PKR-BD.
Methods:
Eighty-six patients with hepatitis C were recruited and follow-up for 6 months. Several tests,
including alanine aminotransferase (ALT), aspartate aminotransferase (AST), viral load, IFNL4 genotyping,
and PKR-BD sequencing were performed. Using several well-known and trustworthy bioinformatics
tools, sequences were analyzed to define physio-chemical properties, structural features, immune
epitopes and protein-protein interaction.
Results:
Of the 86 patients, 65.1% had high viral load at baseline, 64% had CT genotype for rs12979860
and 57% had GT genotype for rs8099917. Several aa residues changes were found in the PKR-BD region.
We could not find any link between mutations in the PKR-BD region and different genotypes of IFNL4
in response to antiviral therapy. Regardless of pI, PKR-BD 1a and 3a showed similar physio-chemical
properties, and 2 phosphorylation sites and one glycosylation site were estimated for both PKR-BD 1a
and 3a. Trustworthy software were employed in order to predict B-cell epitopes, 3 regions (6-17, 26-32,
34-41) were found for both proteins, indicating a huge potential of PKR-BD protein to induce humoral
immune system. Docking analysis determined non-responder sequences in both 1a and 3a genotypes
to have higher energy value and are more compatible with PKR.
Conclusion:
To sum up, our results could not determine any significant relationship between mutations
of PKR-BD and genotypes of IFNL4 with other factors; ALT, AST, viral load. However, docking results
showed strengthened interaction between PKR-BD and PKR in non-responders that could have a
momentous impact on the illness severity.
Funder
Shiraz University of Medical Sciences
Publisher
Bentham Science Publishers Ltd.
Subject
Molecular Biology,Biochemistry
Cited by
7 articles.
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