Genotypic Regulation of Type I Interferon Induction Pathways by Frameshift (F) Proteins of Hepatitis C Virus

Abstract

HCV has evolved mechanisms to evade innate immunity leading in chronic infections. The immunological function of HCV F protein, which is a frameshift product of core coding sequence, has not been well-characterized. HCV F protein is produced during natural HCV infections and found most commonly in genotype 1 HCV. In this study, we investigated whether F protein plays a role in type I 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 protein. The peptide lengths and amino acids sequences of F proteins are highly variable. We hypothesized that the F protein from different genotypes might control the type I IFN production and response differently. We found that both IFNβ promoter activities are significantly higher in genotype 1a F protein (F1a) expressing cells. Conversely, the IFNβ promoter activities are lower in genotype 2a F (F2a) protein expressing cells. We also used real-time PCR to confirm IFNβ mRNA expressing levels. By generating chimera F proteins, we discovered that the effects of F proteins were determined by the amino acid sequence 40-57 of the 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 mechanism how F proteins from different genotypes of HCV control these pathways differently remained to be investigated. IMPORTANCE Although naturally present in HCV-infection patient serum, the virological or immunogical functions of HCV F protein, which is a frameshift product of core coding sequence, remain unclear. Here we report the effects of 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 understand the host response during HCV infection and the new insights for the prediction to the outcome of IFN-based therapy in HCV patients.