title: Hepatitis C virus epitope-specific neutralizing antibodies in Igs prepared from human plasma.
abstract: Neutralizing antibodies directed against hepatitis C virus (HCV) are present in Igs made from anti-HCV-positive plasma. However, these HCV-specific Igs are largely ineffective in vivo. The mechanism for the poor effectiveness is currently unknown. We hypothesize that the presence of nonneutralizing antibodies in HCV-specific Igs interferes with the function of neutralizing antibodies, resulting in the reduction or blockage of their effect. In the present study, we identified at least two epitopes at amino acid residues 412-419 (epitope I) and 434-446 (epitope II), located downstream of the hypervariable region I within the HCV E2 protein. We demonstrated that epitope I, but not epitope II, was implicated in HCV neutralization and that binding of a nonneutralizing antibody to epitope II completely disrupted virus neutralization mediated by antibody binding at epitope I. The dynamic interaction between nonneutralizing and neutralizing antibodies may thus play a key role in determining the outcomes of HCV infection. Further exploration of this interplay should lead to a better understanding of the mechanisms of neutralization and immune escape and may indicate pathways for the manufacture of an effective HCV-specific Ig product for immune prophylaxis of HCV infection.
authors.affiliation: Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Bethesda, MD 20892, USA. pei.zhang@fda.hhs.gov
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.forename: Charles G
authors.initials: CG
authors.lastname: Wu
authors.forename: Kathleen
authors.initials: K
authors.lastname: Mihalik
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Virata
authors.forename: Mei-Ying W
authors.initials: MY
authors.lastname: Yu
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Alter
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Feinstone
mesh_terms: D000595:Amino Acid Sequence; D000918:Antibody Specificity / Q000276:immunology*; D002460:Cell Line; D004252:DNA Mutational Analysis; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000276:immunology*; D018936:Hepatitis C Antigens / Q000737:chemistry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010455:Peptides / Q000737:chemistry
chemical_list: D000939:Epitopes; D018937:Hepatitis C Antibodies; D018936:Hepatitis C Antigens; D007074:Immunoglobulin G; D010455:Peptides