FOXO transcription factors activate alternative major immediate early promoters to induce human cytomegalovirus reactivation
Andrew Hale, Donna Collins-McMillen, Erik M. Lenarcic, Suzu Igarashi, Jeremy P. Kamil, Felicia Goodrum, Nathaniel J. Moorman
Abstract
Significance Human cytomegalovirus (HCMV) infection is lifelong and persistent. Periodic reactivation of cytomegalovirus poses serious disease risk for immune-compromised patients. A critical driver of reactivation is expression of viral genes from the major immediate early locus. Recent paradigm-shifting evidence shows that reactivation is driven from promoters distinct from those that drive replication in permissive cells. Understanding the contextual control of these promoters and how they specifically respond to cellular cues that drive reactivation is critical for establishing future therapies that prevent reactivation. Our findings mechanistically define a previously enigmatic relationship between differentiation and reactivation and provide potential targets for therapeutic intervention to prevent HCMV reactivation and disease.