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Journal of Virology, April 2001, p. 3363-3370, Vol. 75, No. 7
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.7.3363-3370.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Single Amino Acid Substitution in the V Protein of Simian Virus 5 Differentiates Its Ability To Block Interferon Signaling in Human
and Murine Cells
D. F.
Young,1
N.
Chatziandreou,1
B.
He,2
S.
Goodbourn,3
R. A.
Lamb,2 and
R. E.
Randall1,*
School of Biomedical Sciences, University of St. Andrews,
Fife, Scotland KY16 9TS,1 and Department
of Biochemistry and Immunology, St. George's Hospital Medical School,
University of London, London SW17 ORE,3 United
Kingdom, and Howard Hughes Medical Institute and Department
of Biochemistry, Molecular Biology, and Cell Biology, Northwestern
University, Evanston, Illinois 60208-35002
Received 19 October 2000/Accepted 16 December 2000
Previous work has demonstrated that the V protein of simian virus 5 (SV5) targets STAT1 for proteasome-mediated degradation (thereby
blocking interferon [IFN] signaling) in human but not in murine
cells. In murine BF cells, SV5 establishes a low-grade persistent infection in which the virus fluxes between active and repressed states in response to local production of IFN. Upon passage of persistently infected BF cells, virus mutants were selected that were better able to replicate in murine cells than the
parental W3 strain of SV5 (wild type [wt]). Viruses with
mutations in the Pk region of the N-terminal domain of the V protein
came to predominate the population of viruses carried in the
persistently infected cell cultures. One of these mutant viruses,
termed SV5 mci-2, was isolated. Sequence analysis of the V/P gene
of SV5 mci-2 revealed two nucleotide differences compared to
wt SV5, only one of which resulted in an amino acid substitution
(asparagine [N], residue 100, to aspartic acid [D]) in V. Unlike
the protein of wt SV5, the V protein of SV5 mci-2 blocked IFN signaling
in murine cells. Since the SV5 mci-2 virus had additional mutations in
genes other than the V/P gene, a recombinant virus (termed rSV5-V/P N100D) was constructed that contained this
substitution alone within the wt SV5 backbone to evaluate what effect
the asparagine-to-aspartic-acid substitution in V had on the virus
phenotype. In contrast to wt SV5, rSV5-V/P N100D blocked
IFN signaling in murine cells. Furthermore, rSV5-V/P
N100D virus protein synthesis in BF cells continued
for significantly longer periods than that for wt SV5. However, even in
cells infected with rSV5-V/P N100D, there was a late, but
significant, inhibition in virus protein synthesis. Nevertheless, there
was an increase in virus yield from BF cells infected with rSV5-V/P N100D compared to wt SV5, demonstrating a clear selective
advantage to SV5 in being able to block IFN signaling in these cells.
*
Corresponding author. Mailing address: School of
Biomedical Sciences, Biomolecular Sciences Bldg., North Haugh,
University of St. Andrews, Fife, Scotland KY16 9TS, United Kingdom.
Phone: (44) 1334-463397. Fax: (44) 1334-462595. E-mail:
rer{at}st-and.ac.uk.
Journal of Virology, April 2001, p. 3363-3370, Vol. 75, No. 7
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.7.3363-3370.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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