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  • Title: Persistent virus infection despite chronic cytotoxic T-lymphocyte activation in gamma interferon-deficient mice infected with lymphocytic choriomeningitis virus.
    Author: Bartholdy C, Christensen JP, Wodarz D, Thomsen AR.
    Journal: J Virol; 2000 Nov; 74(22):10304-11. PubMed ID: 11044074.
    Abstract:
    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.
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