Epstein–Barr virus and host cell methylation: regulation of latency, replication and virus reactivation

• EBV's life cycle consists of a prelatent, a latent, and a lytic phase.
• Each phase is characterized by a unique set of active and silenced viral genes.
• Cell-driven epigenetic modifications govern viral gene expression in all phases.
• EBV's transcription factor BZLF1 is the key to switch from latency to the lytic phase.
• BZLF1 binds to methylated viral promoters and reverts epigenetically repressed genes.

Epigenetic mechanisms govern the different life phases of Epstein–Barr virus (EBV). In the first prelatent phase the viral DNA acquires nucleosomes, histone marks are established, and 5′-methyl cytosine residues become detectable. In the latent phase repressive histone marks and extensive DNA methylation silence the majority of viral promoters sparing a few latent genes. DNA methylation is a prerequisite for the induction of EBV's lytic phase in order to escape from latency and give rise to viral progeny. All three phases rely on the different epigenetic states of viral DNA and the availability of viral and cellular factors. EBV exploits cellular mechanisms of epigenetic regulation for its different life phases and serves as a marvelous example of an intimate host–pathogen relationship.