Work

Clonal dynamics of HTLV-1–infected cells under immunosuppression stratify ATL risk and reveal restoration of Tax-specific immune surveillance

Year: 2026

Type: article

Abstract: The impact of immunosuppressive therapy on the risk of adult T-cell leukemia/lymphoma (ATL) in HTLV-1–infected individuals remains poorly defined. In particular, it is unclear whether and how the baseline clonal architecture of infected cells modulates this risk—a question of direct clinical relevance to neurologists managing patients with HTLV-1–associated myelopathy (HAM) who require long-term immunosuppression. We conducted a retrospective longitudinal study of 133 HTLV-1–positive patients (122 with HAM) receiving immunosuppressive therapy. The clonal architecture of HTLV-1–infected cells was quantified using the RAISING method—a proviral integration-site sequencing approach that yields a clonality value (Cv) reflecting the degree of clonal dominance—and patients were stratified into three ATL risk groups (low-, intermediate-, high-risk). In selected cases, single-cell RNA sequencing (scRNA-seq) combined with T-cell receptor repertoire analysis was performed to characterize clonal evolution and immune microenvironmental changes. ATL developed exclusively in the intermediate- and high-risk groups (overall incidence, 1.5%; intermediate-risk, 3.8%; high-risk, 25.0%), with a monotonic increase in cumulative incidence according to baseline Cv ( p = 0.001 by permutation-based log-rank test; p = 0.002 by trend test), while no cases occurred in the low-risk group. Clonal dynamics remained stable in most patients under immunosuppression; however, ATL progression was characterized by expansion of a dominant clone (from 52.6% to 90.7% of infected cells), transcriptional diversification into multiple cellular states, and marked immune microenvironmental remodeling. By contrast, patients maintaining a polyclonal architecture exhibited minimal immune perturbation. Importantly, discontinuation of immunosuppressive therapy led to contraction of the dominant clone and near-complete elimination of tax/rex -expressing infected cells, accompanied by acquisition of enhanced cytotoxic effector features at the single-cell level. ATL risk under immunosuppressive therapy is determined by the baseline clonal architecture of HTLV-1–infected cells and is modulated by host immune surveillance. Clonality-based risk stratification provides a clinically actionable framework for risk-adapted management of HTLV-1–infected patients requiring immunosuppression, and restoration of antigen-specific immunity represents a potential mechanism for reversing malignant trajectories.

Source: Retrovirology

DOI: 10.1186/s12977-026-00685-6