To define immune mechanisms that regulate chronic and latent
herpesvirus infection, we analyzed the role of
interferon gamma (IFN-gamma) during murine cytomegalovirus (MCMV)
infection. Lethality studies demonstrated a net protective role for IFN-gamma, independent of IFN-alpha/beta, during acute MCMV
infection. Mice lacking the IFN-gamma receptor (
IFN-gammaR-/-) developed and maintained striking chronic aortic
inflammation.
Arteritis was associated with inclusion bodies and MCMV
antigen in the aortic media. To understand how lack of IFN-gamma responses could lead to chronic
vascular disease, we evaluated the role of IFN-gamma in MCMV latency. MCMV-infected
IFN-gammaR-/- mice shed preformed infectious MCMV in spleen, peritoneal exudate cells, and salivary gland for up to 6 mo after
infection, whereas the majority of congenic control animals cleared chronic productive
infection. However, the
IFN-gammaR was not required for establishment of latency. Using an in vitro explant reactivation model, we showed that IFN-gamma reversibly inhibited MCMV reactivation from latency. This was at least partly explained 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-gamma regulation of reactivation from latency contributes to control of chronic
vascular disease caused by MCMV. These studies are the first to demonstrate that a component of the immune system (IFN-gamma) is necessary to regulate MCMV-associated elastic
arteritis and latency in vivo and reactivation of a herpesvirus from latency in vitro. This provides a new model for analysis of the interrelationships among herpesvirus latency, the immune system, and
chronic disease of the great vessels.