title: Characterization and evolution of NS5A quasispecies of hepatitis C virus genotype 1b in patients with different stages of liver disease.
abstract: The quasispecies nature of hepatitis C virus (HCV) is thought to play a central role in modulating viral functions. Recent work has linked NS5A protein with viral replication, resistance to interferon (IFN), and control of cellular growth, probably through the interaction of its protein kinase R (double stranded RNA-activated protein kinase, PKR) binding domain (PKR-bd) with cellular PKR, but knowledge of how PKR-bd viral population evolves during disease progression is limited. Since we have previously described an association between amino acid composition of the PKR-bd and the presence of HCC, in this report we further investigated the dynamic behavior of viral population parameters by sequencing an average of 20 clones per sample in 27 samples from 19 untreated patients with different degrees of liver disease, 8 of whom were followed over time. Viral population parameters varied widely from patient to patient, but no differences were observed in the complexity, diversity, types of nucleotide changes, or evolutionary pattern of the quasispecies according to the stage of liver disease. In five samples, we detected "quasispecies-tails"; that is, clones whose minimum genetic distance to the remaining clones of their own quasispecies were higher than the maximum genetic distance found between any other two clones of the same sample. In summary, independent of the degree of liver disease, or the mutations detected within the consensus sequence of the PKR-bd, the NS5A of HCV presents a flexible and variable quasispecies structure that remains largely stable during the natural course of an HCV infection, highlighting the central role of NS5A protein in viral life cycle.
authors.affiliation: Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d' Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Franco
authors.forename: Mireia
authors.initials: M
authors.lastname: Giménez-Barcons
authors.forename: Francesc
authors.initials: F
authors.lastname: Puig-Basagoiti
authors.forename: Ivana
authors.initials: I
authors.lastname: Furcic
authors.forename: José-María
authors.initials: JM
authors.lastname: Sánchez-Tapias
authors.forename: Juan
authors.initials: J
authors.lastname: Rodés
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Sáiz
mesh_terms: D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology* / Q000821:virology; D018450:Disease Progression; D019143:Evolution, Molecular; D016174:Hepacivirus / Q000145:classification / Q000235:genetics / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000503:physiopathology* / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000503:physiopathology* / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase