Herpes viruses, in particular cytomegalovirus (CMV), have coevolved with humans in a host-specific fashion for millions of years. CMV causes overt encephalitis in immunosuppressed patients. We have found that mouse CMV (mCMV) transiently reprograms macrophages and microglia with respect to immunophenotype, transcriptome and proteome, leading to the acquisition of stem cell-like properties and a unique ameboid migratory behavior. The Wnt pathway is critical in mCMV-induced reprogramming. The complex transformation process allows for viral spread while minimizing clinical pathology in infection. In CMV encephalitis the virus spreads from periventricular regions and CNS interfaces, which are inhabited by distinct CNS macrophage subsets, to other regions of the brain. Here, we will explore models of mCMV encephalitis to interlink autonomous reprogramming of CNS macrophage subsets with antiviral activity, immunopathology and neurological damage. Thus, we will characterize the diversity of CNS macrophages involved in mCMV encephalitis. Particular foci will be the Wnt pathway and long-term changes, including epigenetic imprinting and neurodevelopmental alterations.