Determinants of attenuation in the envelope protein of the flavivirus Alfuy

Prow, Natalie A., May, Fiona J., Westlake, Daniel J., Hurrelbrink, Robert J., Biron, Rebecca M., Leung, Jason Y., McMinn, Peter C., Clark, David C., Mackenzie, John S., Lobigs, Mario, Khromykh, Alexander A. and Hall, Roy A. (2011) Determinants of attenuation in the envelope protein of the flavivirus Alfuy. Journal of General Virology, 92 10: 2286-2296. doi:10.1099/vir.0.034793-0


Author Prow, Natalie A.
May, Fiona J.
Westlake, Daniel J.
Hurrelbrink, Robert J.
Biron, Rebecca M.
Leung, Jason Y.
McMinn, Peter C.
Clark, David C.
Mackenzie, John S.
Lobigs, Mario
Khromykh, Alexander A.
Hall, Roy A.
Title Determinants of attenuation in the envelope protein of the flavivirus Alfuy
Journal name Journal of General Virology   Check publisher's open access policy
ISSN 0022-1317
1465-2099
Publication date 2011-10
Sub-type Article (original research)
DOI 10.1099/vir.0.034793-0
Volume 92
Issue 10
Start page 2286
End page 2296
Total pages 11
Place of publication Reading, United Kingdom
Publisher Society for General Microbiology
Collection year 2012
Language eng
Formatted abstract
Murray Valley encephalitis virus (MVEV) is a mosquito-borne flavivirus endemic to Australia and Papua New Guinea. Most strains of MVEV cause potentially fatal cases of encephalitis in humans and horses, and have been shown to be highly neuroinvasive in weanling mice. In contrast, the naturally occurring subtype Alfuy virus (ALFV) has never been associated with human disease, nor is it neuroinvasive in weanling mice, even at high doses. To identify viral factors associated with ALFV attenuation, a chimeric infectious clone was constructed containing the structural genes premembrane (prM) and envelope (E) of ALFV swapped into the MVEV genome. The resulting virus (vMVEV/ALFVstr) was no longer neuroinvasive in mice, suggesting that motifs within prM–E of ALFV confer attenuation. To define these motifs further, mutants were constructed by targeting divergent sequences between the MVEV and ALFV E proteins that are known markers of virulence in other encephalitic flaviviruses. MVEV mutants containing a unique ALFV sequence in the flexible hinge region (residues 273–277) or lacking the conserved glycosylation site at position 154 were significantly less neuroinvasive in mice than wild-type MVEV, as determined by delayed time to death or increased LD50. Conversely, when the corresponding MVEV sequences were inserted into the vMVEV/ALFVstr chimera, the mutant containing the MVEV hinge sequence was more neuroinvasive than the parental chimera, though not to the same level as wild-type MVEV. These results identify the hinge region and E protein glycosylation as motifs that contribute to the attenuation of ALFV. 
Keyword Valley Encephalitis Virus
West Nile Virus
Arthropod Borne Viruses
Membrane Fusion
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
 
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