Raf1 promotes successful Human Cytomegalovirus replication and is regulated by AMPK-mediated phosphorylation during infection.

Growth factor signaling plays a critical role in many aspects of viral infection. Here we show that a component of one of these pathways, Raf1, contributes to successful infection of Human Cytomegalovirus (HCMV). We find that AMP-activated protein kinase (AMPK), which is known to be important for HCMV infection, modulates Raf1 phosphorylation throughout infection, and contributes to Raf1 binding to its activating co-factor, 14-3-3. In addition, inhibition of Raf1 inhibits HCMV infection and viral spread. These results suggest a link between two cellular pathways that are important for HCMV replication, AMPK signaling and growth factor receptor signaling, that converge as an important aspect of HCMV infection. This could lead to the potential for new therapeutic targets in immunocompromised individuals afflicted by acute HCMV infection.