title: Humoral immune system targets clonotypic antibody-associated hepatitis C virus.
abstract: Hypervariable region 1 (HVR1) is one of the potential neutralization domains in the E2 glycoprotein of hepatitis C virus (HCV). Point mutations of the HVR1 can lead to humoral immune escape in HCV-infected patients. In this study, we segregated the chronically infected viraemic sera from HCV-infected patients into populations of antibody-free virus and antibody-associated virus (AAV) and mapped potential epitopes within the E1E2 gene junction of AAV sequences (residues 364-430). Furthermore, we generated HCV pseudoparticles (HCVpp) derived from AAV sequences to assess their infectivity. We studied the neutralization potential of virus-free Fab obtained from antibody-virus complexes, in the HCVpp system. We observed selective targeting of clonotypic HCV variants from the quasispecies pool. Moreover, we identified potential neutralizing epitopes within the HVR1 and an additional epitope that overlapped with a broadly neutralizing AP33 epitope (amino acid 412-423 in E2). We observed a marked difference in the infectivity of HCVpp generated using E1E2 sequences isolated from AAV. We document reduction in the infectivity of HCVpp-H77 and HCVpp derived from AAV sequences when challenged with virus-free Fab. Our results provide novel insights into the complexities of engagement between HCV and the humoral immune system.
authors.affiliation: 1​Department of Medicine, Clinical Sciences Building, University College Cork, Cork, Ireland.
authors.forename: Amruta S
authors.initials: AS
authors.lastname: Naik
authors.affiliation: 1​Department of Medicine, Clinical Sciences Building, University College Cork, Cork, Ireland.
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Palmer
authors.affiliation: 2​Department of Hepatology, Cork University Hospital, Cork, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Crosbie
authors.affiliation: 2​Department of Hepatology, Cork University Hospital, Cork, Ireland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kenny-Walsh
authors.affiliation: 1​Department of Medicine, Clinical Sciences Building, University College Cork, Cork, Ireland.
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Fanning
mesh_terms: D000595:Amino Acid Sequence; D019286:Endopeptidase K / Q000737:chemistry; D018604:Epitope Mapping; 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; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology; D009500:Neutralization Tests; D044967:Serum / Q000737:chemistry / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D014766:Viremia / Q000276:immunology
chemical_list: C087035:E1 protein, Hepatitis C virus; C400562:HVR1 protein, Hepatitis C virus; D018937:Hepatitis C Antibodies; D007140:Immunoglobulin Fab Fragments; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C091015:glycoprotein E2, Hepatitis C virus; D019286:Endopeptidase K