INTERFERON-GAMMA REGULATES ACUTE AND LATENT MURINE CYTOMEGALOVIRUS-INFECTION AND CHRONIC DISEASE OF THE GREAT-VESSELS

To define immune mechanisms that regulate chronic and latent herpesvir us infection, we analyzed the role of interferon gamma (IFN-gamma) dur ing murine cytomegalovirus (MCMV) infection. Lethality studies demonst rated a net protective role for IFN-gamma, independent of IFN-alpha/be ta, during acute MCMV infection. Mice lacking the IFN-gamma receptor ( IFN-gamma R-/-) developed and maintained striking chronic aortic infla mmation. Arteritis was associated with inclusion bodies and MCMV antig en in the aortic media. To understand how lack of IFN-gamma responses could lead to chronic vascular disease, we evaluated the role of IFN-g amma in MCMV latency. MCMV-infected IFN-gamma R-/- mice shed preformed infectious MCMV in spleen, peritoneal exudate cells, and salivary gla nd for up to 6 mo after infection, whereas the majority of congenic co ntrol animals cleared chronic productive infection. However, the IFN-g amma R was not required for establishment of latency. Using an in vitr o el;plant reactivation model, we showed that IFN-gamma reversibly inh ibited MCMV reactivation from latency. This was at least partly explai ned by IFN-gamma-mediated blockade of growth of low levels of MCMV in tissue explants. These in vivo and in vitro data suggest that IFN-gamm a regulation of reactivation from latency contributes to control of ch ronic vascular disease caused by MCMV. These studies are the first to demonstrate that a component of the immune system (IFN-gamma) is neces sary to regulate MCMV-associated elastic arteritis and latency in vivo and reactivation of a herpesvirus from latency in vitro. This provide s a new model for analysis of the interrelationships among herpesvirus latency, the immune system, and chronic disease of the seat vessels.