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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-gamma ) in the permanent control of infection with a noncytopathic virus was studied by comparing immune responses in wild-type and IFN-gamma -deficient (IFN-gamma -/-) mice infected with a slowly invasive strain of lymphocytic choriomeningitis virus (LCMV Armstrong). While wild-type mice rapidly cleared the infection, IFN-gamma -/- 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-gamma -/- mice. The prolonged effector phase in infected IFN-gamma -/- 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-gamma -/- mice than in wild-type mice. These findings indicate that in the absence of IFN-gamma , 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-gamma -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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