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Journal of Virology, June 2001, p. 5627-5637, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5627-5637.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Adaptation of Tick-Borne Encephalitis Virus to BHK-21 Cells Results in the Formation of Multiple Heparan Sulfate Binding Sites in the Envelope Protein and Attenuation In Vivo

Christian W. Mandl,* Helga Kroschewski, Steven L. Allison, Regina Kofler, Heidemarie Holzmann, Tamara Meixner, and Franz X. Heinz

Institute of Virology, University of Vienna, Vienna, Austria

Received 31 January 2001/Accepted 20 March 2001

Propagation of the flavivirus tick-borne encephalitis virus in BHK-21 cells selected for mutations within the large surface glycoprotein E that increased the net positive charge of the protein. In the course of 16 independent experiments, 12 different protein E mutation patterns were identified. These were located in all three of the structural domains and distributed over almost the entire upper and lateral surface of protein E. The mutations resulted in the formation of local patches of predominantly positive surface charge. Recombinant viruses carrying some of these mutations in a defined genetic backbone showed heparan sulfate (HS)-dependent phenotypes, resulting in an increased specific infectivity and binding affinity for BHK-21 cells, small plaque formation in porcine kidney cells, and significant attenuation of neuroinvasiveness in adult mice. Our results corroborate the notion that the selection of attenuated HS binding mutants is a common and frequent phenomenon during the propagation of viruses in cell culture and suggest a major role for HS dependence in flavivirus attenuation. Recognition of this principle may be of practical value for designing attenuated flavivirus strains in the future.

* Corresponding author. Mailing address: Institute of Virology, Kinderspitalgasse 15, A-1095 Vienna, Austria. Phone: 43-1-404 90, ext. 79502. Fax: 43-1-406 21 61. E-mail: christian.mandl{at}univie.ac.at.

Journal of Virology, June 2001, p. 5627-5637, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5627-5637.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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