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Journal of Virology, June 2007, p. 6111-6116, Vol. 81, No. 11
0022-538X/07/$08.00+0     doi:10.1128/JVI.02387-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Combination of Naturally Occurring Mutations in North American West Nile Virus Nonstructural Protein Genes and in the 3' Untranslated Region Alters Virus Phenotype

C. Todd Davis,^1, Sareen E. Galbraith,¹ Shuliu Zhang,² Melissa C. Whiteman,¹ Li Li,¹ Richard M. Kinney,⁶ and Alan D. T. Barrett^1,3,4,5*

Department of Pathology,¹ Department of Microbiology and Immunology,² Center for Biodefense and Emerging Infectious Diseases,³ Sealy Center for Vaccine Development,⁴ Institute for Human Infections and Immunity, University of Texas Medical Branch, 301 University Blvd., Galveston, Texas 77555,⁵ Arboviral Diseases Branch, Division of Vector-Borne Infectious Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Fort Collins, Colorado⁶

Received 31 October 2006/ Accepted 5 March 2007

We previously reported mutations in North American West Nile viruses (WNVs) with a small-plaque (sp), temperature-sensitive (ts), and/or mouse-attenuated (att) phenotype. Using an infectious clone, site-directed mutations and 3' untranslated region (3'UTR) exchanges were introduced into the WNV NY99 genome. Characterization of mutants demonstrated that a combination of mutations involving the NS4B protein (E249G) together with either a mutation in the NS5 protein (A804V) or three mutations in the 3'UTR (A10596G, C10774U, A10799G) produced sp, ts, and/or att variants. These results suggested that the discovery of North American WNV-phenotypic variants is rare because of the apparent requirement of concurrent polygenic mutations.

Published ahead of print on 21 March 2007.

Present address: Molecular Virology and Vaccines Branch, Influenza Division, CDC, 1600 Clifton Road N.E., MS-G16, Atlanta, GA 30333.

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