The Akt Forkhead Box O Transcription Factor Axis Regulates Human Cytomegalovirus Replication

Abstract

Evidence from diverse herpesvirus infection models suggests that the PI3K/Akt signaling pathway suppresses reactivation from latency and that inactivation of the pathway stimulates viral lytic replication. Here, we show that Akt accumulates in an inactive state during HCMV infection of lytically permissive cells while the presence of constitutive Akt activity causes substantial viral replication defects. Although Akt phosphorylates a diverse array of cellular substrates, we identify an important role for the Forkhead box class O transcription factors. Our findings show that when FoxO3a nuclear localization is decoupled from its negative regulation by Akt, the viral replication defects observed in the presence of constitutively active Akt are reversed. Collectively, our results reveal that HCMV inactivates Akt to promote the nuclear localization of FoxO transcription factors, which strongly implies that FoxOs play critical roles in transactivating cellular and/or viral genes during infection.