Our results indicate that the immune system keeps the ''hidden'' persistent viral CNS infection under permanent control. Manipulation of Tregs in the periphery had significant consequences for the fate of the viral infection in the brain, although only few infected neurons are present during the persistent phase of the infection. Expanding the number of Tregs by superagonistic CD28 antibody D665 led to an activation of virus replication and dramatic increase of the number of infected neurons, whereas transient depletion of Tregs by DT led to a significant reduction of the number of infected neurons. Interestingly, complete elimination of virus and clearance of the infection was not achieved by transient depletion of Tregs suggesting that additional means of an antiviral immune response are required for complete clearance.