m6A RNA Modification Controls HTLV-1 Tax and Host Gene Expression.

Human T-cell Leukemia Virus Type 1 (HTLV-1) is a pathogenic human retrovirus that is responsible for intractable diseases such as adult T-cell leukemia-lymphoma (ATL), a malignancy with a poor patient prognosis. Although recent studies have delineated several genomic, epigenomic, and transcriptomic abnormalities associated with HTLV-1, to date the importance of epitranscriptomic modifications, particularly N6-methyladenosine (m6A), remains unclear. Here, we showed that the HTLV-1 RNA genome undergoes m6A modification, thereby suggesting that these modifications act as bidirectional regulators of both viral and host processes. Moreover, targeted depletion of m6A modification within the viral transactivator HTLV-1 Tax resulted in markedly destabilized Tax mRNA, attenuated Tax protein abundance, and suppression of downstream expression of host genes including IL2RA and TXN. Overall, these findings suggest that m6A methylation is an essential determinant of the HTLV-1 life cycle, and understanding it may offer mechanistic insight into viral latency and present novel avenues for therapeutic intervention and prophylaxis.