Persistent virus infection despite chronic cytotoxic T-lymphocyte activation in gamma interferon-deficient mice infected with lymphocytic choriomeningitis virus

The role of gamma interferon (IFN-gamma) in the permanent control of infect ion with a noncytopathic virus was studied by comparing immune responses in wild-type and IFN-gamma -deficient (IFN-gamma -/-) mice infected with a sl owly invasive strain of lymphocytic choriomeningitis virus (LCMV Armstrong) . While wild-type mice rapidly cleared the infection, IFN-gamma -/- mice be came chronically infected. Virus persistence in the latter mice did not ref lect failure to generate cytotoxic T-lymphocyte (CTL) effecters, as an unim paired primary CTL response was observed. Furthermore, while ex vivo CTL ac tivity gradually declined in wild-type mice, long-standing cytolytic activi ty 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 p recursor pool, no evidence for exhaustion was observed. In fact, at 3 month s 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 p ermanently activated by the continuous presence of live virus, resulting in a delicate new balance between viral load and immunity. This interpretatio n of our findings is supported by mathematical modeling describing the effe ct of eliminating IFN-gamma -mediated antiviral activity on the dynamics be tween virus replication and CTL activity.