An exciting new area of research is focused on modifications of individual bases on viral mRNAs that affect mRNA expression and/or function, referred to as epitranscriptomic gene regulation. The most common co-transcriptional modification of mRNAs is addition of a methyl group to the N6 position of adenosine to give an “m6A” residue. These are then bound in the cytoplasm by the m6A reader proteins YTHDF1, 2 and 3. We have precisely mapped sites of m6A addition on the HIV-1 genome and have shown that m6A substantially increases HIV-1 mRNA abundance and gene expression. As a result, inhibition of m6A addition, or blocking YTHDF protein binding to m6A, inhibits viral gene expression. We have recently extended this research to two other nuclear viruses, the orthomyxovirus influenza A virus (IAV) (in collaboration with Nick Heaton’s lab at Duke) and the polyomavirus SV40. In both cases, we have observed that m6A addition significantly increases viral gene expression and replication in culture and, in the case of IAV, we also observed that m6A addition increases viral pathogenicity in mice. We are continuing to work on the mechanisms underlying these observed effects and we are now extending our analysis to other mRNA modifications, such as the m5C and 2’0Me modifications, both of which are found on HIV-1 transcripts.
|