title: Human monoclonal antibodies against West Nile virus induced by natural infection neutralize at a postattachment step.
abstract: West Nile virus (WNV) is a neurotropic flavivirus that is now a primary cause of epidemic encephalitis in North America. Studies of mice have demonstrated that the humoral immune response against WNV limits primary infection and protects against a secondary challenge. The most-potent neutralizing mouse monoclonal antibodies (MAbs) recognize an epitope on the lateral ridge of domain III (DIII-lr) of the envelope (E) protein. However, studies with serum from human patients show that antibodies against the DIII-lr epitope comprise, at best, a minor component of the human anti-WNV antibody response. Herein, we characterize in detail two WNV-specific human MAbs, CR4348 and CR4354, that were isolated from B-cell populations of convalescent patients. These MAbs strongly neutralize WNV infection of cultured cells, protect mice against lethal infection in vivo, and yet poorly recognize recombinant forms of the E protein. Instead, CR4348 and CR4354 bind determinants on intact WNV virions and subviral particles in a pH-sensitive manner, and neutralization is altered by mutations at the dimer interface in domain II and the hinge between domains I and II, respectively. CR4348 and CR4354 human MAbs neutralize infection at a postattachment step in the viral life cycle, likely by inhibiting acid-induced fusion within the endosome.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Vogt
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Moesker
authors.forename: Jaap
authors.initials: J
authors.lastname: Goudsmit
authors.forename: Mandy
authors.initials: M
authors.lastname: Jongeneelen
authors.forename: S Kyle
authors.initials: SK
authors.lastname: Austin
authors.forename: Theodore
authors.initials: T
authors.lastname: Oliphant
authors.forename: Steevenson
authors.initials: S
authors.lastname: Nelson
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Pierson
authors.forename: Jan
authors.initials: J
authors.lastname: Wilschut
authors.forename: Mark
authors.initials: M
authors.lastname: Throsby
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D018604:Epitope Mapping; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000276:immunology; D013379:Substrate Specificity; D014759:Viral Envelope Proteins / Q000276:immunology; D014901:West Nile Fever / Q000276:immunology / Q000517:prevention & control*; D014902:West Nile virus / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins