title: Network Analysis of the Chronic Hepatitis C Virome Defines Hypervariable Region 1 Evolutionary Phenotypes in the Context of Humoral Immune Responses.
abstract: Hypervariable region 1 (HVR1) of hepatitis C virus (HCV) comprises the first 27 N-terminal amino acid residues of E2. It is classically seen as the most heterogeneous region of the HCV genome. In this study, we assessed HVR1 evolution by using ultradeep pyrosequencing for a cohort of treatment-naive, chronically infected patients over a short, 16-week period. Organization of the sequence set into connected components that represented single nucleotide substitution events revealed a network dominated by highly connected, centrally positioned master sequences. HVR1 phenotypes were observed to be under strong purifying (stationary) and strong positive (antigenic drift) selection pressures, which were coincident with advancing patient age and cirrhosis of the liver. It followed that stationary viromes were dominated by a single HVR1 variant surrounded by minor variants comprised from conservative single amino acid substitution events. We present evidence to suggest that neutralization antibody efficacy was diminished for stationary-virome HVR1 variants. Our results identify the HVR1 network structure during chronic infection as the preferential dominance of a single variant within a narrow sequence space.
  
  
  OBJECTIVE
  HCV infection is often asymptomatic, and chronic infection is generally well established in advance of initial diagnosis and subsequent treatment. HVR1 can undergo rapid sequence evolution during acute infection, and the variant pool is typically seen to diverge away from ancestral sequences as infection progresses from the acute to the chronic phase. In this report, we describe HVR1 viromes in chronically infected patients that are defined by a dominant epitope located centrally within a narrow variant pool. Our findings suggest that weakened humoral immune activity, as a consequence of persistent chronic infection, allows for the acquisition and maintenance of host-specific adaptive mutations at HVR1 that reflect virus fitness.
authors.affiliation: Molecular Virology Diagnostic & Research Laboratory, Department of Medicine, University College Cork, Cork, Ireland.
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Palmer
authors.affiliation: Molecular Virology Diagnostic & Research Laboratory, Department of Medicine, University College Cork, Cork, Ireland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Schmidt-Martin
authors.affiliation: Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Dimitrova
authors.affiliation: Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Skums
authors.affiliation: Department of Hepatology, Cork University Hospital, Cork, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Crosbie
authors.affiliation: Department of Hepatology, Cork University Hospital, Cork, Ireland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kenny-Walsh
authors.affiliation: Molecular Virology Diagnostic & Research Laboratory, Department of Medicine, University College Cork, Cork, Ireland l.fanning@ucc.ie.
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Fanning
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001483:Base Sequence; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000821:virology*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017423:Sequence Analysis, RNA; D014759:Viral Envelope Proteins / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; C087035:E1 protein, Hepatitis C virus; C400562:HVR1 protein, Hepatitis C virus; D018937:Hepatitis C Antibodies; D007074:Immunoglobulin G; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C091015:glycoprotein E2, Hepatitis C virus