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Virology. 2010 Mar 30;399(1):1-10. doi: 10.1016/j.virol.2009.12.031. Epub 2010 Jan 25.

Modulation of type I IFN induction by a virulence determinant within the alphavirus nsP1 protein.

Author information

1
Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
Department of Immunology, University of Washington, Seattle, WA 98195-76504, USA.
3
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology, The University of Colorado Denver, Aurora, CO 80045.
4
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: heisem@med.unc.edu.

Abstract

Alphaviruses are mosquito-borne viruses that cause serious human and animal diseases. Previous studies demonstrated that a determinant within the nsP1/nsP2 cleavage domain of the virulent Sindbis AR86 virus played a key role in regulating adult mouse virulence without adversely affecting viral replication. Additional characterization of this determinant demonstrated that a virus with the attenuating mutation induced more type I IFN production both in vivo and in vitro. Interestingly, this phenotype was not specific to the Sindbis AR86 virus, as a similar mutation in a distantly related alphavirus, Ross River Virus (RRV), also led to enhanced IFN induction. This effect was independent of virus-induced host shutoff, since IRF-3 phosphorylation, which occurs independently of de novo host transcription/translation, was induced more robustly in cells infected with the mutant viruses. Altogether, these results demonstrate that critical determinants within the nsP1/nsP2 cleavage domain play an important role in regulating alphavirus-induced IFN responses.

PMID:
20097400
PMCID:
PMC2830325
DOI:
10.1016/j.virol.2009.12.031
[Indexed for MEDLINE]
Free PMC Article

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