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Journal of Virology, November 2000, p. 10304-10311, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Persistent Virus Infection despite Chronic Cytotoxic T-Lymphocyte
Activation in Gamma Interferon-Deficient Mice Infected with
Lymphocytic Choriomeningitis Virus
Christina
Bartholdy,1
Jan Pravsgaard
Christensen,2
Dominik
Wodarz,3 and
Allan Randrup
Thomsen1,*
Institute of Medical Microbiology and
Immunology, University of Copenhagen, Copenhagen,
Denmark1; Department of Immunology,
St. Jude Children's Research Hospital, Memphis,
Tennessee2; and Institute for
Advanced Study, Princeton, New Jersey3
Received 17 May 2000/Accepted 23 August 2000
The role of gamma interferon (IFN-
) in the permanent control of
infection with a noncytopathic virus was studied by comparing immune
responses in wild-type and IFN-
-deficient (IFN-
/
) mice
infected with a slowly invasive strain of lymphocytic choriomeningitis virus (LCMV Armstrong). While wild-type mice rapidly cleared the infection, IFN-
/
mice became chronically infected. Virus
persistence in the latter mice did not reflect failure to generate
cytotoxic T-lymphocyte (CTL) effectors, as an unimpaired primary CTL
response was observed. Furthermore, while ex vivo CTL activity
gradually declined in wild-type mice, long-standing cytolytic activity
was demonstrated in IFN-
/
mice. The prolonged effector phase in infected IFN-
/
mice was associated with elevated numbers of CD8+ T cells. Moreover, a higher proportion of these cells
retained an activated phenotype and was actively cycling. However,
despite the increased CD8+ T-cell turnover, which might
have resulted in depletion of the memory CTL precursor pool, no
evidence for exhaustion was observed. In fact, at 3 months
postinfection we detected higher numbers of LCMV-specific CTL
precursors in IFN-
/
mice than in wild-type mice. These findings
indicate that in the absence of IFN-
, CTLs cannot clear the
infection and are kept permanently activated by the continuous presence
of live virus, resulting in a delicate new balance between viral load
and immunity. This interpretation of our findings is supported by
mathematical modeling describing the effect of eliminating
IFN-
-mediated antiviral activity on the dynamics between virus
replication and CTL activity.
*
Corresponding author. Mailing address: Institute of
Medical Microbiology and Immunology, University of Copenhagen, The
Panum Institute, 3C Blegdamsvej, DK-2200 Copenhagen N, Denmark. Phone: 45 35 32 78 71. Fax: 45 35 32 78 74. E-mail:
a.r.thomsen{at}immi.ku.dk.
Journal of Virology, November 2000, p. 10304-10311, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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