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Journal of Virology, August 2004, p. 8271-8280, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.8271-8280.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Common E Protein Determinants for Attenuation of Glycosaminoglycan-Binding Variants of Japanese Encephalitis and West Nile Viruses

Eva Lee,1* Roy A. Hall,2 and Mario Lobigs1

John Curtin School of Medical Research, Australian National University Canberra,1 Department of Microbiology and Parasitology, University of Queensland Brisbane Australia2

Received 19 January 2004/ Accepted 19 March 2004

Natural isolates and laboratory strains of West Nile virus (WNV) and Japanese encephalitis virus (JEV) were attenuated for neuroinvasiveness in mouse models for flavivirus encephalitis by serial passage in human adenocarcinoma (SW13) cells. The passage variants displayed a small-plaque phenotype, augmented affinity for heparin-Sepharose, and a marked increase in specific infectivity for SW13 cells relative to the respective parental viruses, while the specific infectivity for Vero cells was not altered. Therefore, host cell adaptation of passage variants was most likely a consequence of altered receptor usage for virus attachment-entry with the involvement of cell surface glycosaminoglycans (GAG) in this process. In vivo blood clearance kinetics of the passage variants was markedly faster and viremia was reduced relative to the parental viruses, suggesting that affinity for GAG (ubiquitously present on cell surfaces and extracellular matrices) is a key determinant for the neuroinvasiveness of encephalitic flaviviruses. A difference in pathogenesis between WNV and JEV, which was reflected in more efficient growth in the spleen and liver of the WNV parent and passage variants, accounted for a less pronounced loss of neuroinvasiveness of GAG binding variants of WNV than JEV. Single gain-of-net-positive-charge amino acid changes at E protein residue 49, 138, 306, or 389/390, putatively positioned in two clusters on the virion surface, define molecular determinants for GAG binding and concomitant virulence attenuation that are shared by the JEV serotype flaviviruses.

* Corresponding author. Mailing address: Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, P. O. Box 334, Canberra, ACT 2600, Australia. Phone: 61 2 61253526, Fax: 61 2 61252595. E-mail: Eva.Lee{at}anu.edu.au.

Journal of Virology, August 2004, p. 8271-8280, Vol. 78, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.15.8271-8280.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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