Control of animal virus replication by RNA adenosine methylation

Methylation at the N⁶-position of either adenosine (m⁶A) or 2'-O-methyladenosine (m⁶Am) represents two of the most abundant internal modifications of coding and non-coding RNAs, influencing their maturation, stability and function. Additionally, although less abundant and less well-studied, monomethylation at the N¹-position (m¹A) can have profound effects on RNA folding. It has been known for several decades that RNAs produced by both DNA and RNA viruses can be m⁶A/m⁶Am modified and the list continues to broaden through advances in detection technologies and identification of the relevant methyltransferases. Recent studies have uncovered varied mechanisms used by viruses to manipulate the m⁶A pathway in particular, either to enhance virus replication or to antagonize host antiviral defenses. As such, RNA modifications represent an important frontier of exploration in the broader realm of virus-host interactions, and this new knowledge already suggests exciting opportunities for therapeutic intervention. In this review we summarize the principal mechanisms by which m⁶A/m⁶Am can promote or hinder viral replication, describe how the pathway is actively manipulated by biomedically important viruses, and highlight some remaining gaps in understanding how adenosine methylation of RNA controls viral replication and pathogenesis.