Comparative Analysis of Within-Host Mutation Patterns and Diversity of Hepatitis C Virus Subtypes 1a, 1b, and 3a

Abstract

Understanding within-host evolution is critical for predicting viral evolutionary outcomes, yet such studies are currently lacking due to difficulty involving human subjects. Hepatitis C virus (HCV) is an RNA virus with high mutation rates. Its complex evolutionary dynamics and extensive genetic diversity are demonstrated in over 67 known subtypes. In this study, we analyzed within-host mutation frequency patterns of three HCV subtypes, using a large number of samples obtained from treatment-naïve participants by next-generation sequencing. We report that overall mutation frequency patterns are similar among subtypes, yet subtype 3a consistently had lower mutation frequencies and nucleotide diversity, while subtype 1a had the highest. We found that about 50% of genomic sites are highly conserved across subtypes, which are likely under strong purifying selection. We also compared within-host and between-host selective pressures, which revealed that Hyper Variable Region 1 within hosts was under positive selection, but was under slightly negative selection between hosts, which indicates that many mutations created within hosts are removed during the transmission bottleneck. Examining the natural prevalence of known resistance-associated variants showed their consistent existence in the treatment-naïve participants. These results provide insights into the differences and similarities among HCV subtypes that may be used to develop and improve HCV therapies.

Assessing in vivo mutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

“…RNA viruses are considered to replicate at a mutagenesis level close to the lethal threshold, at which the error rates exceed the tolerance limit of genetic information preservation [ 38 ]. A delicate balance between this threshold and host selective pressures is likely responsible for shaping the observed in vivo mutation patterns; approximately 50% of sites were highly conserved while the remaining variable sites contribute to continuous generation of variation [ 39 ]. From a clinical perspective, one of the most challenging aspects of the treatment and management of pathogenic RNA viruses is their high genetic diversity.…”

Rapid detection of φx-174 virus based on synchronous fluorescence of Tryptophan

“…[19] A big advantage of sequencing the whole viral genome derives from the ability to identify unexpected mutations and being able to follow evolutionary evolvement. [20] Nevertheless, whole genome sequencing is still relatively expensive for a large-scale usage.…”

“…Another identification method that is very precise is the next generation sequencing (NGS) that can sequence the whole genome of the virus in a relatively short time 19 . A big advantage of sequencing the entire viral genome derives from the ability to identify unexpected mutations and being able to follow evolutionary evolvement 20 . Nevertheless, whole genome sequencing is still relatively expensive for large-scale applications.…”