title: Antibodies Targeting Novel Neutralizing Epitopes of Hepatitis C Virus Glycoprotein Preclude Genotype 2 Virus Infection.
abstract: Currently, there is no effective vaccine to prevent hepatitis C virus (HCV) infection, partly due to our insufficient understanding of the virus glycoprotein immunology. Most neutralizing antibodies (nAbs) were identified using glycoprotein immunogens, such as recombinant E1E2, HCV pseudoparticles or cell culture derived HCV. However, the fact that in the HCV acute infection phase, only a small proportion of patients are self-resolved accompanied with the emergence of nAbs, indicates the limited immunogenicity of glycoprotein itself to induce effective antibodies against a highly evolved virus. Secondly, in previous reports, the immunogen sequence was mostly the genotype of the 1a H77 strain. Rarely, other genotypes/subtypes have been studied, although theoretically one genotype/subtype immunogen is able to induce cross-genotype neutralizing antibodies. To overcome these drawbacks and find potential novel neutralizing epitopes, 57 overlapping peptides encompassing the full-length glycoprotein E1E2 of subtype 1b were synthesized to immunize BALB/c mice, and the neutralizing reactive of the induced antisera against HCVpp genotypes 1-6 was determined. We defined a domain comprising amino acids (aa) 192-221, 232-251, 262-281 and 292-331 of E1, and 421-543, 564-583, 594-618 and 634-673 of E2, as the neutralizing regions of HCV glycoprotein. Peptides PUHI26 (aa 444-463) and PUHI45 (aa 604-618)-induced antisera displayed the most potent broad neutralizing reactive. Two monoclonal antibodies recognizing the PUHI26 and PUHI45 epitopes efficiently precluded genotype 2 viral (HCVcc JFH and J6 strains) infection, but they did not neutralize other genotypes. Our study mapped a neutralizing epitope region of HCV glycoprotein using a novel immunization strategy, and identified two monoclonal antibodies effective in preventing genotype 2 virus infection.
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Deng
authors.affiliation: Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
authors.forename: Ruyu
authors.initials: R
authors.lastname: Liu
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Rao
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging infectious Diseases, Beijing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China.
authors.forename: Xingwang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood; D057134:Antibodies, Neutralizing / Q000097:blood; D002460:Cell Line; D000939:Epitopes / Q000008:administration & dosage* / Q000276:immunology; D057809:HEK293 Cells; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000097:blood / Q000517:prevention & control*; D018937:Hepatitis C Antibodies / Q000097:blood; D018936:Hepatitis C Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D019151:Peptide Library; D013045:Species Specificity; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C087035:E1 protein, Hepatitis C virus; D000939:Epitopes; D018937:Hepatitis C Antibodies; D018936:Hepatitis C Antigens; D019151:Peptide Library; D014759:Viral Envelope Proteins; D014761:Viral Hepatitis Vaccines; C091015:glycoprotein E2, Hepatitis C virus