title: Amino acid residue-specific neutralization and nonneutralization of hepatitis C virus by monoclonal antibodies to the E2 protein.
abstract: Antibodies to epitopes in the E2 protein of hepatitis C virus (HCV) reduce the viral infectivity in vivo and in vitro. However, the virus can persist in patients in the presence of neutralizing antibodies. In this study, we generated a panel of monoclonal antibodies that bound specifically to the region between residues 427 and 446 of the E2 protein of HCV genotype 1a, and we examined their capacity to neutralize HCV in a cell culture system. Of the four monoclonal antibodies described here, two were able to neutralize the virus in a genotype 1a-specific manner. The other two failed to neutralize the virus. Moreover, one of the nonneutralizing antibodies could interfere with the neutralizing activity of a chimpanzee polyclonal antibody at E2 residues 412 to 426, as it did with an HCV-specific immune globulin preparation, which was derived from the pooled plasma of chronic hepatitis C patients. Mapping the epitope-paratope contact interfaces revealed that these functionally distinct antibodies shared binding specificity for key amino acid residues, including W(437), L(438), L(441), and F(442), within the same epitope of the E2 protein. These data suggest that the effectiveness of antibody-mediated neutralization of HCV could be deduced from the interplay between an antibody and a specific set of amino acid residues. Further understanding of the molecular mechanisms of antibody-mediated neutralization and nonneutralization should provide insights for designing a vaccine to control HCV infection in vivo.
authors.affiliation: Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.
authors.forename: Hongying
authors.initials: H
authors.lastname: Duan
authors.forename: Alla
authors.initials: A
authors.lastname: Kachko
authors.forename: Lilin
authors.initials: L
authors.lastname: Zhong
authors.forename: Evi
authors.initials: E
authors.lastname: Struble
authors.forename: Shivani
authors.initials: S
authors.lastname: Pandey
authors.forename: Hailing
authors.initials: H
authors.lastname: Yan
authors.forename: Christine
authors.initials: C
authors.lastname: Harman
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Virata-Theimer
authors.forename: Lu
authors.initials: L
authors.lastname: Deng
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhao
authors.forename: Marian
authors.initials: M
authors.lastname: Major
authors.forename: Stephen
authors.initials: S
authors.lastname: Feinstone
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000235:genetics; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D002679:Pan troglodytes; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000939:Epitopes; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus