title: Structural basis of hepatitis C virus neutralization by broadly neutralizing antibody HCV1.
abstract: Hepatitis C virus (HCV) infects more than 2% of the global population and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and end-stage liver diseases. Circulating HCV is genetically diverse, and therefore a broadly effective vaccine must target conserved T- and B-cell epitopes of the virus. Human mAb HCV1 has broad neutralizing activity against HCV isolates from at least four major genotypes and protects in the chimpanzee model from primary HCV challenge. The antibody targets a conserved antigenic site (residues 412-423) on the virus E2 envelope glycoprotein. Two crystal structures of HCV1 Fab in complex with an epitope peptide at 1.8-Å resolution reveal that the epitope is a β-hairpin displaying a hydrophilic face and a hydrophobic face on opposing sides of the hairpin. The antibody predominantly interacts with E2 residues Leu(413) and Trp(420) on the hydrophobic face of the epitope, thus providing an explanation for how HCV isolates bearing mutations at Asn(415) on the same binding face escape neutralization by this antibody. The results provide structural information for a neutralizing epitope on the HCV E2 glycoprotein and should help guide rational design of HCV immunogens to elicit similar broadly neutralizing antibodies through vaccination.
authors.affiliation: Departments of Molecular Biology, International AIDS Vaccine Initiative Neutralizing Antibody Center, and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Leopold
authors.initials: L
authors.lastname: Kong
authors.forename: Erick
authors.initials: E
authors.lastname: Giang
authors.forename: Justin B
authors.initials: JB
authors.lastname: Robbins
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Stanfield
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: Mansun
authors.initials: M
authors.lastname: Law
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D057131:Immune Evasion; D023421:Models, Animal; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D011487:Protein Conformation; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D014765:Viral Vaccines