HTLV-1-Induced Neuroimmunome Correlates with Disease Progression and Severity

ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects approximately 5–10 million people worldwide. While most individuals remain asymptomatic, a significant subset develops debilitating neuroinflammatory or malignant disorders, including adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). To unravel the systemic molecular mechanisms underlying HTLV-1 pathogenesis, we employed a multi-dimensional systems biology approach, integrating bulk transcriptomic data from total PBMCs (n = 200) with single-cell RNA sequencing (scRNA-seq) from 233,093 peripheral blood mononuclear cells (PBMCs). Our analysis revealed a consistent and clinically relevant neuroimmune signature within leukocytes, termed the neuroimmunome, comprising a set of differentially expressed genes shared across the nervous and immune systems. Through dimensionality reduction and machine learning techniques, such as PCA, gradient boosting, and MANOVA with bootstrapping, we identified potential biomarkers predictive of HTLV-1-driven leukemogenesis, which were subsequently validated across ATL, HAM/TSP, and asymptomatic cohorts via flow cytometry. Notably, expression levels of proteins such as ATF4 and SKIL were strongly correlated with proviral load, suggesting that sustained neuroimmune dysregulation may contribute to disease progression. These findings highlight a previously underappreciated neuroimmunological layer, redefining HTLV-1-associated disease as a condition deeply rooted in neuroimmune network disruption within leukocytes and offering potential novel targets.