Role of Epitranscriptomic and Epigenetic Modifications during the Lytic and Latent Phases of Herpesvirus Infections

Herpesviruses are double-stranded DNA viruses occurring at a high prevalence in the human population and are responsible for a wide array of clinical manifestations and diseases, from mild to severe. These viruses are classified in three subfamilies (Alpha-, Beta- and Gammaherpesvirinae), with eight members currently known to infect humans. Importantly, all herpesviruses can establish lifelong latent infections with symptomatic or asymptomatic lytic reactivations. Accumulating evidence suggest that chemical modifications of viral RNA and DNA during the lytic and latent phases of the infections caused by these viruses, are likely to play relevant roles in key aspects of the life cycle of these viruses by modulating and regulating their replication, establishment of latency and evasion of the host antiviral response. Here, we review and discuss current evidence regarding epitranscriptomic and epigenetic modifications of herpesviruses and how these can influence their life cycles. While epitranscriptomic modifications such as m⁶A are the most studied to date and relate to positive effects over the replication of herpesviruses, epigenetic modifications of the viral genome are generally associated with defense mechanisms of the host cells to suppress viral gene transcription. However, herpesviruses can modulate these modifications to their own benefit to persist in the host, undergo latency and sporadically reactivate.