title: Fusion loop peptide of the West Nile virus envelope protein is essential for pathogenesis and is recognized by a therapeutic cross-reactive human monoclonal antibody.
abstract: West Nile virus is an emerging pathogen that can cause fatal neurological disease. A recombinant human mAb, mAb11, has been described as a candidate for the prevention and treatment of West Nile disease. Using a yeast surface display epitope mapping assay and neutralization escape mutant, we show that mAb11 recognizes the fusion loop, at the distal end of domain II of the West Nile virus envelope protein. Ab mAb11 cross-reacts with all four dengue viruses and provides protection against dengue (serotypes 2 and 4) viruses. In contrast to the parental West Nile virus, a neutralization escape variant failed to cause lethal encephalitis (at higher infectious doses) or induce the inflammatory responses associated with blood-brain barrier permeability in mice, suggesting an important role for the fusion loop in viral pathogenesis. Our data demonstrate that an intact West Nile virus fusion loop is critical for virulence, and that human mAb11 targeting this region is efficacious against West Nile virus infection. These experiments define the molecular determinant on the envelope protein recognized by mAb11 and demonstrate the importance of this region in causing West Nile encephalitis.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hameeda
authors.initials: H
authors.lastname: Sultana
authors.forename: Harald G
authors.initials: HG
authors.lastname: Foellmer
authors.forename: Girish
authors.initials: G
authors.lastname: Neelakanta
authors.forename: Theodore
authors.initials: T
authors.lastname: Oliphant
authors.forename: Michael
authors.initials: M
authors.lastname: Engle
authors.forename: Michel
authors.initials: M
authors.lastname: Ledizet
authors.forename: Manoj N
authors.initials: MN
authors.lastname: Krishnan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonafé
authors.forename: Karen G
authors.initials: KG
authors.lastname: Anthony
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
authors.forename: Paul
authors.initials: P
authors.lastname: Kaplan
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Koski
authors.forename: Erol
authors.initials: E
authors.lastname: Fikrig
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use; D001666:Binding Sites, Antibody; D002460:Cell Line; D003429:Cross Reactions; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism; D014760:Viral Fusion Proteins / Q000276:immunology* / Q000378:metabolism; D014901:West Nile Fever / Q000276:immunology* / Q000628:therapy / Q000821:virology; D014902:West Nile virus / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D000911:Antibodies, Monoclonal; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins