Abstract
Genetic variability plays a key role in the biology and medical treatment of RNA viruses. As an RNA virus, Hepatitis C virus (HCV) replicate as complex distributions of closely related genomes termed viral quasispecies. The behavior of the evolving HCV quasispecies population is influenced by the ensemble of mutants that compose the viral population. One such influence is the presence of minority subpopulations, termed memory genomes, in the mutant spectra. Biologically relevant mutants have been previously observed to be present as memory genomes in RNA viral populations. For that reason, an in-depth analysis of HCV quasispecies populations is crucial for our understanding viral evolution, drug resistance and therapy outcome. Recently developed next-generation sequencing (NGS) platforms make it possible to investigate viral quasispecies at much greater detail. In order to gain insight into these matters, we have performed a Bayesian coalescent analysis of hypervariable region 1 (HVR1) sequences of a HCV quasispecies population circulating in a chronic patient, recently obtained by ultra-deep sequencing. The results of these studies revealed a mean rate of evolution of HCV HVR1 of the intra-host quasispecies population of 4.80 × 10-2 amino acid substitutions/site/year. A sharp and rapid diversification of the HCV quasispecies isolated from the patient in three different sub-populations was observed. The most abundant sequence in the quasispecies population was not found to be the center of a tight and complex network around this sequence, suggesting that the quasispecies population as a whole efficiently explore a wide sequence space. Co-evolution of relevant amino acid sites had been identified in the HVR1. This speaks of the possible roll of these residues in HVR1 to allow the virus to shift between combinations of residues to escape the immune system while retaining its structure and functions. The results of these studies highlight the importance of minority genomes in HCV population history and evolution, the mutant clouds as reservoirs of phenotypic and genetic variants for virus adaptability, as well as the roll of the mutant spectra to overcome selective constraints.
Highlights
Hepatitis C virus (HCV) is a positive-polarity, single-stranded RNA virus that belongs to the genus Hepacivirus in the family Flaviviridae [1]
In order to gain insight into these matters, we have performed a Bayesian coalescent analysis of hypervariable region 1 (HVR1) sequences of a HCV quasispecies population circulating in a chronic patient infected with HCV genotype 1b recently obtained by ultra-deep sequencing [22]
In order to gain insight into the mode of evolution of an HCV HVR1 quasispecies population, we used a Bayesian Markov Chain Markov Chain Monte Carlo (MCMC) approach to analyze 100 HCV HVR1 amino acid sequences from a quasispecies population circulating in a HCV 1b genotype patient [22]
Summary
Hepatitis C virus (HCV) is a positive-polarity, single-stranded RNA virus that belongs to the genus Hepacivirus in the family Flaviviridae [1]. The HCV population in each patient consists of closely related but nonidentical genomes, referred to as viral quasispecies [6] [7]. This high degree of genetic variability allows rapid evolution that favors escape from immune and antiviral drug pressures [8] [9], allowing the virus to evolve and optimize its fitness in each host [10]. The behavior of the evolving quasispecies and its response to selective pressure are influenced by the ensemble of mutants that compose the viral population [11]. One such influence is the presence of minority subpopulations in the mutant spectra of viral quasispecies, termed memory genomes [12]
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