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.
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.
Sultana
Hameeda
H
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Foellmer
Harald G
HG
Neelakanta
Girish
G
Oliphant
Theodore
T
Engle
Michael
M
Ledizet
Michel
M
Krishnan
Manoj N
MN
Bonafé
Nathalie
N
Anthony
Karen G
KG
Marasco
Wayne A
WA
Kaplan
Paul
P
Montgomery
Ruth R
RR
Diamond
Michael S
MS
Koski
Raymond A
RA
Fikrig
Erol
E
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*
D000911:Antibodies, Monoclonal; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins