Requirement of the m6A reader protein YTHDF2 for HTLV-1 replication and persistence

N6-methyladenosine (m6A) as one of the important RNA modifications, has been implicated in viral infection. In this study, we identify a number of m6A modification sites within HTLV-1 RNAs, particularly in the mRNA of the Tax oncogene. We demonstrate that YTHDF2, a cytoplasmic m6A reader protein, is required for HTLV-1 replication in both de novo infected HeLa S3 cells and persistently infected T cell lines. Specifically, YTHDF2 interacts with and stabilizes Tax RNA, in an m6A-dependent manner. Furthermore, YTHDF2 dysregulates cellular pathways to promote the proliferation of HTLV-1 infected cells in vitro and in vivo, likely by functioning upstream of Tax. Our findings characterize YTHDF2 as a novel host factor required for HTLV-1 replication and persistence, and suggest its potential as a therapeutic target for viral eradication.