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Pathogenesis and Immunity

An Attenuating Mutation in nsP1 of the Sindbis-Group Virus S.A.AR86 Accelerates Nonstructural Protein Processing and Up-Regulates Viral 26S RNA Synthesis

Mark T. Heise, Laura J. White, Dennis A. Simpson, Christopher Leonard, Kristen A. Bernard, Rick B. Meeker, Robert E. Johnston
Mark T. Heise
1Department of Microbiology and Immunology
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  • For correspondence: heisem@med.unc.edu
Laura J. White
1Department of Microbiology and Immunology
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Dennis A. Simpson
1Department of Microbiology and Immunology
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Christopher Leonard
1Department of Microbiology and Immunology
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Kristen A. Bernard
1Department of Microbiology and Immunology
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Rick B. Meeker
2Department of Neurology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
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Robert E. Johnston
1Department of Microbiology and Immunology
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DOI: 10.1128/JVI.77.2.1149-1156.2003
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ABSTRACT

The Sindbis-group alphavirus S.A.AR86 encodes a threonine at nonstructural protein 1 (nsP1) 538 that is associated with neurovirulence in adult mice. Mutation of the nsP1 538 Thr to the consensus Ile found in nonneurovirulent Sindbis-group alphaviruses attenuates S.A.AR86 for adult mouse neurovirulence, while introduction of Thr at position 538 in a nonneurovirulent Sindbis virus background confers increased neurovirulence (M. T. Heise et al., J. Virol. 74:4207-4213, 2000). Since changes in the viral nonstructural region are likely to affect viral replication, studies were performed to evaluate the effect of Thr or Ile at nsP1 538 on viral growth, nonstructural protein processing, and RNA synthesis. Multistep growth curves in Neuro2A and BHK-21 cells revealed that the attenuated s51 (nsP1 538 Ile) virus had a slight, but reproducible growth advantage over the wild-type s55 (nsP1 538 Thr) virus. nsP1 538 lies within the cleavage recognition domain between nsP1 and nsP2, and the presence of the attenuating Ile at nsP1 538 accelerated the processing of S.A.AR86 nonstructural proteins both in vitro and in infected cells. Since nonstructural protein processing is known to regulate alphavirus RNA synthesis, experiments were performed to evaluate the effect of Ile or Thr at nsP1 538 on viral RNA synthesis. A combination of S.A.AR86-derived reporter assays and RNase protection assays determined that the presence of Ile at nsP1 538 led to earlier expression from the viral 26S promoter without affecting viral minus- or plus-strand synthesis. These results suggest that slower nonstructural protein processing and delayed 26S RNA synthesis in wild-type S.A.AR86 infections may contribute to the adult mouse neurovirulence phenotype of S.A.AR86.

  • Copyright © 2003 American Society for Microbiology
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An Attenuating Mutation in nsP1 of the Sindbis-Group Virus S.A.AR86 Accelerates Nonstructural Protein Processing and Up-Regulates Viral 26S RNA Synthesis
Mark T. Heise, Laura J. White, Dennis A. Simpson, Christopher Leonard, Kristen A. Bernard, Rick B. Meeker, Robert E. Johnston
Journal of Virology Jan 2003, 77 (2) 1149-1156; DOI: 10.1128/JVI.77.2.1149-1156.2003

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An Attenuating Mutation in nsP1 of the Sindbis-Group Virus S.A.AR86 Accelerates Nonstructural Protein Processing and Up-Regulates Viral 26S RNA Synthesis
Mark T. Heise, Laura J. White, Dennis A. Simpson, Christopher Leonard, Kristen A. Bernard, Rick B. Meeker, Robert E. Johnston
Journal of Virology Jan 2003, 77 (2) 1149-1156; DOI: 10.1128/JVI.77.2.1149-1156.2003
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KEYWORDS

mutation
Protein Processing, Post-Translational
RNA, Viral
Sindbis virus
Up-Regulation
viral nonstructural proteins

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