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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900093v1 183/1/650    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Sultana, H. Articles by Fikrig, E. PubMed PubMed Citation Articles by Sultana, H. Articles by Fikrig, E.

Fusion Loop Peptide of the West Nile Virus Envelope Protein Is Essential for Pathogenesis and Is Recognized by a Therapeutic Cross-Reactive Human Monoclonal Antibody¹

Hameeda Sultana^*, Harald G. Foellmer^*, Girish Neelakanta^*, Theodore Oliphant, Michael Engle^¶, Michel Ledizet, Manoj N. Krishnan^*, Nathalie Bonafé, Karen G. Anthony, Wayne A. Marasco^||, Paul Kaplan, Ruth R. Montgomery, Michael S. Diamond^,¶, Raymond A. Koski and Erol Fikrig^2,*,#

^* Section of Infectious Diseases and Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; L2 Diagnostics, New Haven, CT 06511; Department of Molecular Microbiology and Departments of ^¶ Medicine, Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63130; ^|| Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115; and ^# Howard Hughes Medical Institute, Chevy Chase, MD 20815

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These studies were supported in part by National Institutes of Health Grants AI 070343, AI 50031, and AI061373. E.F. is an investigator of the Howard Hughes Medical Institute. The funding agencies had no role in conducting the study and in preparing the manuscript.

² Address correspondence and reprint requests to Dr. Erol Fikrig, Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, S525A, 300 Cedar Street, New Haven, CT 06520-8022. E-mail address: erol.fikrig{at}yale.edu

³ The online version of this article contains supplemental material.

⁴ Abbreviations used in this paper: DENV, dengue virus; i.c., intracranial; qRT-PCR, quantitative RT-PCR; TBEV, tick-borne encephalitis virus.