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Journal of Virology, July 2009, p. 6494-6507, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00286-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Monoclonal Antibodies against West Nile Virus Induced by Natural Infection Neutralize at a Postattachment Step{triangledown}

Matthew R. Vogt,1 Bastiaan Moesker,4 Jaap Goudsmit,5 Mandy Jongeneelen,5 S. Kyle Austin,1 Theodore Oliphant,2 Steevenson Nelson,6 Theodore C. Pierson,6 Jan Wilschut,4 Mark Throsby,5 and Michael S. Diamond1,2,3*

Departments of Pathology and Immunology,1 Molecular Microbiology,2 Medicine, Washington University School of Medicine, St. Louis, Missouri 63110,3 Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands,4 Crucell Holland B.V., 2301 CA Leiden, The Netherlands,5 Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institutes of Health, Bethesda, Maryland 208926

Received 9 February 2009/ Accepted 16 April 2009

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.

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

{triangledown} Published ahead of print on 22 April 2009.

Journal of Virology, July 2009, p. 6494-6507, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00286-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nelson, S., Poddar, S., Lin, T.-Y., Pierson, T. C. (2009). Protonation of Individual Histidine Residues Is Not Required for the pH-Dependent Entry of West Nile Virus: Evaluation of the "Histidine Switch" Hypothesis. J. Virol. 83: 12631-12635 [Abstract] [Full Text]  


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