Abstract
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy, and its viral transactivator Tax is central to disrupting host transcriptional control. Although individual interactions between Tax and host factors have been investigated, their global network and functional impact remain unclear. In this study, we performed proteomic analyses of Tax-associated complexes in HTLV-1-infected T-cells and mapped interactions between host factors and Tax. In addition to known nuclear factor kappa B (NF-κB) regulators, we identified the transcription factor interferon regulatory factor 4 (IRF4) as a novel interactor. Co-immunoprecipitation experiments confirmed Tax-IRF4 binding, and chromatin profiling revealed that Tax reprograms genome-wide IRF4 occupancy. In infected T-cells, IRF4 was enriched in super-enhancer (SE) regions, where Tax, IRF4, and NF-κB factors colocalized at ATL-related loci, and this was accompanied by histone acetylation changes and transcriptional activation. Functionally, Tax and IRF4 co-expression cooperatively restructured chromatin accessibility and induced aberrant gene expression programs. Moreover, ATL-associated IRF4 mutants (K59R, L70V, and S114N) partially reproduced Tax-driven chromatin remodeling and transcriptional reprogramming, suggesting that convergent mechanisms drive leukemogenesis. Collectively, these findings demonstrate that Tax exploits IRF4 to establish a novel regulatory mechanism. This interaction drives widespread epigenomic reprogramming in HTLV-1-infected T-cells. Overall, our study underscores the central role of Tax in IRF4 exploitation to induce infection-specific epigenomic changes, which offers novel insights into ATL pathogenesis and therapeutic strategies.