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

Abstract

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.