The most widely described RNA modification in mammalian viruses is mA, which was first identified in Influenza virus mRNAs, in 1976. The epitranscriptomic analysis of viral transcripts has revealed that mA levels in viral and cellular transcripts are similar. Nevertheless, in some viruses such as adenovirus-2, mA levels are higher in viral mRNAs. As with cellular RNAs, mA is predominantly added in the nucleus by METTL3, with the assistance of several cofactors such as METTL14, WTAP, KIAA1429 and RBM15/RMB15B. A recent study demonstrates the presence of mA in the small T antigen of Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma, a fatal skin cancer.
Studies of the viral mA mark have mostly been conducted with HIV. Despite the high mutagenic rate of this virus, mA sites have been evolutionarily conserved. This is due to the fact that mA is involved in regulating multiple stages in the HIV life-cycle. In addition to the normal functions mA has in pre-mRNA splicing, nuclear export, mRNA stability and translation; this mark also inhibits the recognition of viral transcripts by Toll-like receptors and RIG-1 receptors. As a result, mA positively influences viral replication. On the other hand, HIV also regulates the addition of the mA mark in a number of cellular mRNAs. For instance, 56 cellular transcripts that only contain mA during HIV infection have been identified. The effect this mark has on cellular transcripts during the course of the viral infection remains unknown.
Even if mA-marked viral transcripts are involved in regulating gene expression of a number of different viruses, the mechanisms by which this happens have not been identified. To date, three possible models have been proposed.
Although METTL3 and METTL14 are mostly localized in the nucleus, they can also be found in the cytoplasm, where they methylate the genomes and transcripts of cytoplasmic RNA viruses. As opposed to nuclear viruses, loss of mA on hepatitis C virus (HCV, a cytoplasmic RNA virus) increases the production of infectious HCV virions, which indicates that in this particular virus the mA mark has a negative effect on virus production. Nevertheless, in other cytoplasmic RNA viruses such as dengue virus and yellow fever virus, mA sites have been selected for during evolution, suggesting that the mA mark is beneficial for these viruses.
Since mA enhances viral replication, mA can be used as a target for antiviral therapy. The major challenge is to target this mark in viral transcripts without causing major effects to the host cells, as normally occurring cellular mA marks will also be depleted. The S-adenosylhomocysteine (SAC) hydrolase inhibitor 3-dezaadenosine (DAA) can be used as an antiviral drug, because it inhibits the addition of mA. However, it is yet to be determined whether this drug has any off-target effects.