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Journal of Virology, December 2006, p. 12149-12159, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01732-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Antibody Recognition and Neutralization Determinants on Domains I and II of West Nile Virus Envelope Protein{triangledown} ,{dagger}

Theodore Oliphant,1 Grant E. Nybakken,2 Michael Engle,3 Qing Xu,4 Christopher A. Nelson,2 Soila Sukupolvi-Petty,3 Anantha Marri,3 Bat-El Lachmi,5 Udy Olshevsky,5 Daved H. Fremont,2 Theodore C. Pierson,4 and Michael S. Diamond1,2,3*

Departments of Molecular Microbiology,1 Pathology and Immunology,2 Medicine, Washington University School of Medicine, St. Louis, Missouri 63110,3 Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institutes of Health, Bethesda, Maryland 20892,4 Department of Infectious Diseases, Israel Institute for Biological Research, Ness-Ziona 70450, Israel5

Received 10 August 2006/ Accepted 25 September 2006

Previous studies have demonstrated that monoclonal antibodies (MAbs) against an epitope on the lateral surface of domain III (DIII) of the West Nile virus (WNV) envelope (E) strongly protect against infection in animals. Herein, we observed significantly less efficient neutralization by 89 MAbs that recognized domain I (DI) or II (DII) of WNV E protein. Moreover, in cells expressing Fc {gamma} receptors, many of the DI- and DII-specific MAbs enhanced infection over a broad range of concentrations. Using yeast surface display of E protein variants, we identified 25 E protein residues to be critical for recognition by DI- or DII-specific neutralizing MAbs. These residues cluster into six novel and one previously characterized epitope located on the lateral ridge of DI, the linker region between DI and DIII, the hinge interface between DI and DII, and the lateral ridge, central interface, dimer interface, and fusion loop of DII. Approximately 45% of DI-DII-specific MAbs showed reduced binding with mutations in the highly conserved fusion loop in DII: 85% of these (34 of 40) cross-reacted with the distantly related dengue virus (DENV). In contrast, MAbs that bound the other neutralizing epitopes in DI and DII showed no apparent cross-reactivity with DENV E protein. Surprisingly, several of the neutralizing epitopes were located in solvent-inaccessible positions in the context of the available pseudoatomic model of WNV. Nonetheless, DI and DII MAbs protect against WNV infection in mice, albeit with lower efficiency than DIII-specific neutralizing MAbs.

* Corresponding author. Mailing address: Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, Saint Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail: diamond{at}borcim.wustl.edu.

{triangledown} Published ahead of print on 11 October 2006.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, December 2006, p. 12149-12159, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.01732-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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