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Journal of Virology, June 2008, p. 6024-6033, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02509-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

E Protein Domain III Determinants of Yellow Fever Virus 17D Vaccine Strain Enhance Binding to Glycosaminoglycans, Impede Virus Spread, and Attenuate Virulence{triangledown}

Eva Lee* and Mario Lobigs

Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2600, Australia

Received 22 November 2007/ Accepted 30 March 2008

The yellow fever virus (YFV) 17D strain is one of the most effective live vaccines for human use, but the in vivo mechanisms for virulence attenuation of the vaccine and the corresponding molecular determinants remain elusive. The vaccine differs phenotypically from wild-type YFV by the loss of viscerotropism, despite replicative fitness in cell culture, and genetically by 20 amino acid changes predominantly located in the envelope (E) protein. We show that three residues in E protein domain III inhibit spread of 17D in extraneural tissues and attenuate virulence in type I/II interferon-deficient mice. One of these residues (Arg380) is a dominant glycosaminoglycan-binding determinant, which mainly accounts for more rapid in vivo clearance of 17D from the bloodstream in comparison to 17D-derived variants with wild-type-like E protein. While other mutations will account for loss of neurotropism and phenotypic stability, the described impact of E protein domain III changes on virus dissemination and virulence is the first rational explanation for the safety of the 17D vaccine in humans.

* 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

{triangledown} Published ahead of print on 9 April 2008.

Journal of Virology, June 2008, p. 6024-6033, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02509-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Anez, G., Men, R., Eckels, K. H., Lai, C.-J. (2009). Passage of Dengue Virus Type 4 Vaccine Candidates in Fetal Rhesus Lung Cells Selects Heparin-Sensitive Variants That Result in Loss of Infectivity and Immunogenicity in Rhesus Macaques. J. Virol. 83: 10384-10394 [Abstract] [Full Text]  
  • Nickells, J., Cannella, M., Droll, D. A., Liang, Y., Wold, W. S. M., Chambers, T. J. (2008). Neuroadapted Yellow Fever Virus Strain 17D: a Charged Locus in Domain III of the E Protein Governs Heparin Binding Activity and Neuroinvasiveness in the SCID Mouse Model. J. Virol. 82: 12510-12519 [Abstract] [Full Text]  


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