Description:
<jats:title>Significance</jats:title>
<jats:p>Depending on the host cell type and differentiation status, herpesviruses establish different modes of infection to either maintain or replicate their genomes. How viruses discriminate between individual host cell environments upon infection is poorly understood. Here we identify a viral sensor mechanism that restricts human cytomegalovirus (HCMV) replication to the G0/G1 phase of the cell division cycle and to differentiated cells. The mechanism is based on the HCMV tegument 150-kDa phosphoprotein which enters the cell as a constituent of the virus particle, interacts with cyclin A2, and blocks the onset of viral lytic gene expression when cyclin A2-dependent kinase activity is high. This suggests a scenario where specific tegument–host interactions enable herpesviruses to select sites of silent or productive infection.</jats:p>