Cytomegalovirus (HCMV) evolved several strategies to evade NK and cytotoxic T cells, including the specific down modulation of ligands of the activating receptors NKG2D and DNAM-1. Despite this, we believe that there is a window of opportunity to develop an adequate immune response, during which activating molecules can be expressed as a consequence of viral-induced stress response, and before immune-evasion events occurs. To this purpose we focused on MICA, ULBP3 (NKG2DL) and PVR (DNAM-1L) expression, and investigated the role of the DNA damage response (DDR) and its central mediator ATM, that is crucial in the regulation of NKG2DL and DNAM-1L expression. Human primary fibroblasts (HFF) infected with the AD169 strain significantly increased MICA, ULBP3 and PVR expression. However, if infected cells were treated with caffeine, an inhibitor of ATM/ATR kinases, ligand up-regulation was prevented, demonstrating that the DDR pathway was crucial in regulating these activating molecules also in the context of HCMV infection. Notably, DDR was necessary for HCMV productive replication as well, since little or no infectious virus was recovered from caffeine treated cells. Ligand up-regulation was however observed to be HCMV replication-independent, as demonstrated by using Foscarnet, an inhibitor of viral DNA elongation, and related to HCMV-mediated exit from G0/G1 phases of the cell cycle. We are currently addressing the involvement of early viral proteins in ligand up-regulation capable of modulating early events responsible for an effective immune response.