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

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects approximately 10–20 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 underpinning 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 uncovered a consistent and clinically relevant neuroimmune signature within leukocytes, termed here the neuroimmunome, comprising a set of differentially expressed genes that mediate molecular crosstalk between the nervous and immune systems. This signature revealed significant enrichment in synapse-associated signaling pathways, including glutamatergic, noradrenergic, and neuregulin-mediated signaling, and was implicated in key neuroinflammatory processes such as glial activation, motor neuron apoptosis, L-glutamate transport, and synaptic dysfunction. 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 layer of pathophysiological complexity, redefining HTLV-1-associated disease as a condition deeply rooted in neuroimmune network disruption withing leukocytes and offering potential novel targets for diagnosis and therapeutic intervention. Information & Authors Information Version history Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 231views 147downloads Citations Download citation Fernando Y. N. do Vale, Carlota Miranda-Solé, Adriel Leal Nóbile, et al. HTLV-1-Induced Neuroimmunome Correlates with Disease Progression and Severity. Authorea. 05 August 2025. DOI: https://doi.org/10.22541/au.175436851.12475580/v1 DOI: https://doi.org/10.22541/au.175436851.12475580/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.