Naturally Occurring Mutations in the Nonstructural Region 5B of Hepatitis C Virus (HCV) from Treatment-Naïve Korean Patients Chronically Infected with HCV Genotype 1b

Dong-Won Kim,Bum-Joon Kim,You-Sub Won,Hong Kim,Seoung-Ae Lee

doi:10.1371/journal.pone.0087773

Abstract

The nonstructural 5B (NS5B) protein of the hepatitis C virus (HCV) with RNA-dependent RNA polymerase (RdRp) activity plays a pivotal role in viral replication. Therefore, monitoring of its naturally occurring mutations is very important for the development of antiviral therapies and vaccines. In the present study, mutations in the partial NS5B gene (492 bp) from 166 quasispecies of 15 genotype-1b (GT) treatment-naïve Korean chronic patients were determined and mutation patterns and frequencies mainly focusing on the T cell epitope regions were evaluated. The mutation frequency within the CD8+ T cell epitopes was significantly higher than those outside the CD8+ T cell epitopes. Of note, the mutation frequency within predicted CD4+ T cell epitopes, a particular mutational hotspot in Korean patients was significantly higher than it was in patients from other areas, suggesting distinctive CD4+ T cell-mediated immune pressure against HCV infection in the Korean population. The mutation frequency in the NS5B region was positively correlated with patients with carrier-stage rather than progressive liver disease (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma). Furthermore, the mutation frequency in four codons (Q309, A333, V338 and Q355) known to be related to the sustained virological response (SVR) and end-of treatment response (ETR) was also significantly higher in Korean patients than in patients from other areas. In conclusion, a high degree of mutation frequency in the HCV GT-1b NS5B region, particularly in the predicted CD4+ T cell epitopes, was found in Korean patients, suggesting the presence of distinctive CD4+ T cell pressure in the Korean population. This provides a likely explanation of why relatively high levels of SVR after a combined therapy of pegylated interferon (PEG-IFN) and ribavirin (RBV) in Korean chronic patients with GT-1b infections are observed.

Highlights

According to the WHO, 3% of the global population is infected with the hepatitis C virus (HCV), with 3–4 million people newly infected each year [1,2,3,4]
Prior investigations can partly explain the high sustained virological response (SVR) rates in Korean patients, other mechanisms may contribute to this effect. To address this issue, we investigated via quasispecies analysis the mutation frequencies and patterns in the partial nonstructural 5B (NS5B) from Korean patients infected with HCV GT-1b, as these are known to be related to the SVR rates, Methods
The aim of the present study is to investigate the background mutation frequency and patterns of HCV NS5B, reportedly related to a high SVR, from

Summary

Introduction

According to the WHO, 3% of the global population is infected with the hepatitis C virus (HCV), with 3–4 million people newly infected each year [1,2,3,4]. The HCV RNA-dependent RNA polymerase (RdRp) is an essential enzyme that lacks proofreading activity, leading to a population of distinctive but closely related viral variants, termed viral quasispecies, within an infected individual [12,13,14]. Variations in the nonstructural 5B (NS5B) protein, in specific codons, were reported to be positively related to a sustained virological response (SVR) and end-of treatment response (ETR) of patients infected with GT-1b [15,16]

Objectives

Results

Conclusion