Human T-cell Leukemia Virus type-1 (HTLV-1) is a blood-borne retrovirus infecting up to 20 million people globally. HTLV-1 infection causes Adult T-cell Leukemia (ATL) and systemic inflammation, leading to a high incidence of inflammatory conditions across multiple organs collectively termed HTLV-1 Associated Inflammatory Disease (HAID). These diseases are often severe and contribute to a 60% increase in all-cause mortality. Yet, the mechanisms underlying HTLV-1–associated disease development and progression remain poorly understood.
HTLV-1 integration into the human genome has profound consequences for the host T-lymphocyte genome. A notable feature of HTLV-1–associated disease is the emergence of flower cells—atypical lymphocytes with multilobate nuclei. To resolve how HTLV-1 integration rewires host nuclear architecture, we applied Oxford Nanopore long-read sequencing to map genetic and DNA methylation changes in infected T-lymphocytes within a humanised mouse model of HTLV-1c infection and disease. We profiled early and late time points post-infection, capturing both pre-disease and late-stage disease states, and integrated these data with chromatin conformation capture to model large-scale chromatin reorganisation following infection. Our analyses reveal widespread loss of DNA methylation concentrated at enhancers in CD8⁺ T cells, suggesting that ectopic enhancer activation within this infection reservoir may be a defining feature of HTLV-1 persistence and immune dysfunction. Together, these findings provide new insight into how viral integration reshapes host genome regulation, linking epigenetic reprogramming and 3D genome organisation to the establishment and progression of HTLV-1–associated disease.