title: Determination of the human antibody response to the epitope defined by the hepatitis C virus-neutralizing monoclonal antibody AP33.
abstract: Hepatitis C virus (HCV) is a major cause of liver disease worldwide and there is a pressing need for the development of a preventative vaccine as well as new treatments. It was recently demonstrated that the mouse monoclonal antibody (mAb) AP33 potently neutralizes infectivity of HCV pseudoparticles (HCVpp) carrying E1E2 envelopes representative of all of the major genotypes of HCV. This study determined the prevalence of human serum antibodies reactive to the region of HCV E2 recognized by AP33. Antibodies recognizing this region were present in less than 2.5 % of sera obtained from individuals with chronic HCV infection. A similar prevalence was found in a smaller cohort of individuals who had experienced an acute infection, suggesting that AP33-like antibodies do not play a major role in natural clearance of HCV infection. Sera exhibited different patterns of reactivity to a panel of peptides representing circulating variants, highlighting the presence of distinct epitopes in this region. Only two sera contained antibodies that could recognize a specific AP33-reactive peptide mimotope. AP33-like antibodies made a measurable contribution to the ability of these sera to inhibit E2-CD81 interaction, but not to the overall neutralization of cell entry. Together, these data show that antibodies to the AP33 epitope are not commonly generated during natural infection and that generation of such antibodies via vaccination may require modified immunogens to focus the generation of specific antibodies. Importantly, individuals harbouring AP33-like antibodies are an important potential source of human mAbs for future therapeutic development.
authors.affiliation: The Institute of Infection, Immunity and Inflammation and Division of Microbiology, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Tarr
authors.affiliation: MRC Virology Unit, Institute of Virology, University of Glasgow, Church Street, Glasgow G11 5JR, UK.
authors.forename: Ania M
authors.initials: AM
authors.lastname: Owsianka
authors.affiliation: The Institute of Infection, Immunity and Inflammation and Division of Microbiology, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Jayaraj
authors.affiliation: The Institute of Infection, Immunity and Inflammation and Division of Microbiology, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Richard J P
authors.initials: RJP
authors.lastname: Brown
authors.affiliation: The Institute of Infection, Immunity and Inflammation and Division of Microbiology, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hickling
authors.affiliation: The Institute of Infection, Immunity and Inflammation and Division of Microbiology, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: William L
authors.initials: WL
authors.lastname: Irving
authors.affiliation: MRC Virology Unit, Institute of Virology, University of Glasgow, Church Street, Glasgow G11 5JR, UK.
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.affiliation: The Institute of Infection, Immunity and Inflammation and Division of Microbiology, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Ball
mesh_terms: D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000097:blood*; D006801:Humans; D011485:Protein Binding; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C554798:CD81 protein, human; C554799:Cd81 protein, mouse; D000939:Epitopes; D018937:Hepatitis C Antibodies; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus