HTLV-1 Persistence and Transcriptional Regulation as Molecular Drivers of Adult T-cell Leukemia/Lymphoma

Although decades of research have established human T-cell leukemia virus type 1 (HTLV-1) as the causative agent of adult T-cell leukemia/lymphoma (ATL), our understanding of the molecular mechanisms that enable HTLV-1 to persist for decades and develop into ATL is still incomplete. To address these gaps of knowledge, we combined structural, molecular, and genomic approaches to investigate HTLV-1 persistence and pathogenesis. Electron microscopy confirmed its type C retrovirus morphology, while hybridization assays demonstrated minimal homology with other retroviruses and little integration into normal human DNA or RNA. Plasma RNA measurements revealed low or undetectable viraemia compared to HIV-1, consistent with latency maintained through transcriptional regulation of the viral LTR, with RUNX1 acting as a repressor and ETS1 as an activator. In vivo studies in rabbits showed that the Hbz protein is essential for sustaining proviral load. Whole-genome and transcriptome sequencing identified frequently occurring IKZF2 mutations that produced truncated isoforms, disrupting T-cell regulation. Together, these findings support a development model in which HTLV-1 persistence and ATL pathogenesis arise from the interplay of viral latency, Hbz-driven maintenance, and host genomic instability.