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Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design
CL. Gardner, J. Hritz, C. Sun, DL. Vanlandingham, TY. Song, E. Ghedin, S. Higgs, WB. Klimstra, KD. Ryman,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural
NLK
Directory of Open Access Journals
od 2007
Free Medical Journals
od 2007
Public Library of Science (PLoS)
od 2007
PubMed Central
od 2007
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od 2007
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od 2007-10-01
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od 2007-01-01
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od 2007-01-01
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od 2007-08-30
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od 2009-04-01
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- MeSH
- atenuované vakcíny genetika imunologie MeSH
- biologická adaptace účinky léků genetika MeSH
- cytokiny metabolismus MeSH
- heparitinsulfát farmakologie MeSH
- molekulární modely MeSH
- mutace genetika MeSH
- myši MeSH
- neutralizující protilátky imunologie MeSH
- proteiny virového obalu genetika MeSH
- statická elektřina MeSH
- substituce aminokyselin genetika MeSH
- virové vakcíny genetika imunologie MeSH
- virulence genetika MeSH
- virus chikungunya * účinky léků genetika imunologie patogenita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Mosquito-borne chikungunya virus (CHIKV) is a positive-sense, single-stranded RNA virus from the genus Alphavirus, family Togaviridae, which causes fever, rash and severe persistent polyarthralgia in humans. Since there are currently no FDA licensed vaccines or antiviral therapies for CHIKV, the development of vaccine candidates is of critical importance. Historically, live-attenuated vaccines (LAVs) for protection against arthropod-borne viruses have been created by blind cell culture passage leading to attenuation of disease, while maintaining immunogenicity. Attenuation may occur via multiple mechanisms. However, all examined arbovirus LAVs have in common the acquisition of positively charged amino acid substitutions in cell-surface attachment proteins that render virus infection partially dependent upon heparan sulfate (HS), a ubiquitously expressed sulfated polysaccharide, and appear to attenuate by retarding dissemination of virus particles in vivo. We previously reported that, like other wild-type Old World alphaviruses, CHIKV strain, La Réunion, (CHIKV-LR), does not depend upon HS for infectivity. To deliberately identify CHIKV attachment protein mutations that could be combined with other attenuating processes in a LAV candidate, we passaged CHIKV-LR on evolutionarily divergent cell-types. A panel of single amino acid substitutions was identified in the E2 glycoprotein of passaged virus populations that were predicted to increase electrostatic potential. Each of these substitutions was made in the CHIKV-LR cDNA clone and comparisons of the mutant viruses revealed surface exposure of the mutated residue on the spike and sensitivity to competition with the HS analog, heparin, to be primary correlates of attenuation in vivo. Furthermore, we have identified a mutation at E2 position 79 as a promising candidate for inclusion in a CHIKV LAV.
Citace poskytuje Crossref.org
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