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Journal of Virology, July 2005, p. 8339-8347, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8339-8347.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Envelope Protein Glycosylation Status Influences Mouse Neuroinvasion Phenotype of Genetic Lineage 1 West Nile Virus Strains

David W. C. Beasley,1* Melissa C. Whiteman,1 Shuliu Zhang,1 Claire Y.-H. Huang,2 Bradley S. Schneider,1 Darci R. Smith,1 Gregory D. Gromowski,1 Stephen Higgs,1 Richard M. Kinney,2 and Alan D. T. Barrett1

Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas,1 Arbovirus Diseases Branch, Division of Vector-Borne Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Fort Collins, Colorado2

Received 21 December 2004/ Accepted 3 March 2005

The introduction of West Nile virus (WNV) into North America has been associated with relatively high rates of neurological disease and death in humans, birds, horses, and some other animals. Previous studies identified strains in both genetic lineage 1 and genetic lineage 2, including North American isolates of lineage 1, that were highly virulent in a mouse neuroinvasion model, while other strains were avirulent or significantly attenuated (D. W. C. Beasley, L. Li, M. T. Suderman, and A. D. T. Barrett, Virology 296:17-23, 2002). To begin to elucidate the basis for these differences, we compared a highly virulent New York 1999 (NY99) isolate with a related Old World lineage 1 strain, An4766 (ETH76a), which is attenuated for mouse neuroinvasion. Genomic sequencing of ETH76a revealed a relatively small number of nucleotide (5.1%) and amino acid (0.6%) differences compared with NY99. These differences were located throughout the genome and included five amino acid differences in the envelope protein gene. Substitution of premembrane and envelope genes of ETH76a into a NY99 infectious clone backbone yielded a virus with altered in vitro growth characteristics and a mouse virulence phenotype comparable to ETH76a. Further site-specific mutagenesis studies revealed that the altered phenotype was primarily mediated via loss of envelope protein glycosylation and that this was associated with altered stability of the virion at mildly acidic pH. Therefore, the enhanced virulence of North American WNV strains compared with other Old World lineage 1 strains is at least partly mediated by envelope protein glycosylation.

* Corresponding author. Mailing address: Dept. of Pathology, UTMB, 301 University Blvd., Galveston, TX 77555-0609. Phone: (409) 772-2547. Fax: (409) 747-2415. E-mail: d.beasley{at}utmb.edu.

Journal of Virology, July 2005, p. 8339-8347, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8339-8347.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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