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

Abstract HTLV-1 infects 10–20 million people globally. While most remain asymptomatic, some develop severe neuroinflammatory or malignant diseases, such as adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Using a systems biology approach, we integrated bulk transcriptomics from PBMCs (n = 200) with single-cell RNA sequencing from 233,093 PBMCs. We identified a consistent neuroimmune signature (“neuroimmunome”) composed of differentially expressed genes mediating nervous–immune crosstalk. This signature was enriched in synapse-related pathways, including glutamatergic, noradrenergic, and neuregulin signaling, and linked to neuroinflammatory processes such as glial activation, motor neuron apoptosis, L-glutamate transport, and synaptic dysfunction. Through PCA, gradient boosting, and MANOVA with bootstrapping, we found potential biomarkers predictive of HTLV-1 leukemogenesis, validated via flow cytometry in ATL, HAM/TSP, and asymptomatic cohorts. Proteins such as ATF4 and SKIL correlated with proviral load, suggesting sustained neuroimmune dysregulation drives disease progression. These findings reveal a deeper pathophysiological complexity, framing HTLV-1 disease as rooted in neuroimmune network disruption.