Genotypic Regulation of Type I Interferon Induction Pathways by Frameshift (F) Proteins of Hepatitis C Virus
Journal
Journal of Virology
Journal Volume
94
Journal Issue
15
Date Issued
2020
Author(s)
Abstract
Hepatitis C virus (HCV) has evolved mechanisms to evade innate immunity that are leading to chronic infections. The immunological function of the HCV frameshift (F) protein, which is a frameshift product of core coding sequences, has not been well characterized. The HCV F protein is produced during natural HCV infections and is found most commonly in genotype 1 HCV. In this study, we investigated whether the F protein plays a role in type I interferon (IFN) induction pathways. We engineered F expression constructs from core coding sequences of 4 genotypes (1a, 2a, 3a, and 4a) of HCV as well as the sequences which would only be able to produce core proteins. The peptide lengths and amino acids sequences of F proteins are highly variable. We hypothesized that F proteins from different genotypes might control the type I IFN production and response differently. We found that both IFN-beta (IFN-β) promoter activities are significantly higher in genotype 1a F protein (F1a)-expressing cells. Conversely, the IFN-β promoter activities are lower in genotype 2a F (F2a) protein-expressing cells. We also used real-time PCR to confirm IFN-β mRNA expression levels. By generating chimera F proteins, we discovered that the effects of F proteins were determined by the amino acid sequence 40 to 57 of genotype 1a. The regulation of type I IFN induction pathway is related but not limited to the activity of F1a to interact with proteasome subunits and to disturb the proteasome activity. Further molecular mechanisms of how F proteins from different genotypes of HCV control these pathways differently remain to be investigated.IMPORTANCE Although naturally present in HCV infection patient serum, the virological or immunological functions of the HCV F protein, which is a frameshift product of core coding sequences, remain unclear. Here, we report the effects of the HCV F protein between genotypes and discuss a potential explanation for the differential responses to type I IFN-based therapy among patients infected with different genotypes of HCV. Our study provides one step forward to understanding the host response during HCV infection and new insights for the prediction of the outcome of IFN-based therapy in HCV patients.
Subjects
frameshift protein; hepatitis C virus; interferons; proteasome; type I interferon
Frameshift protein; Hepatitis C virus; Interferons; Proteasome; Type I interferon
SDGs
Other Subjects
beta interferon; frameshift protein; interferon; proteasome; unclassified drug; viral protein; beta interferon; core protein; hepatitis C protein F, Hepatitis C virus; amino acid sequence; Article; cytokine production; cytokine response; gene expression; genetic regulation; genotypic regulation; Hepatitis C virus; Hepatitis C virus genotype 2; Hepatitis C virus genotype 2a; Hepatitis C virus genotype 3; Hepatitis C virus genotype 3a; Hepatitis C virus genotype 4; Hepatitis C virus genotype 4a; Hepatitis C virus subtype 1a; IFN beta gene; nonhuman; phenotype; priority journal; protein expression; protein function; protein interaction; real time polymerase chain reaction; signal transduction; biosynthesis; genetics; genotype; Hepacivirus; hepatitis C; human; metabolism; tumor cell line; Cell Line, Tumor; Genotype; Hepacivirus; Hepatitis C; Humans; Interferon-beta; Signal Transduction; Viral Core Proteins
Publisher
American Society for Microbiology