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Intracellular T-cell Metabolomics Reveals Distinct Signatures Across Human T-lymphotropic Virus Type 1 Clinical Phenotypes and Uninfected Controls

Year: 2026

Type: article

Abstract: Introduction Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with heterogeneous clinical outcomes, ranging from persistent asymptomatic infection to HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Aim This study investigated phenotype-associated intracellular metabolic differences in isolated CD4+ T cells across these clinical groups. Methodology The cross-sectional analytical cohort comprised 44 participants: 15 asymptomatic HTLV-1 carriers, 12 patients with HAM/TSP, 7 patients with ATLL, and 10 uninfected controls. CD4+ T cells were isolated from cryopreserved peripheral blood mononuclear cells by immunomagnetic negative selection. Intracellular metabolites were analyzed using high-resolution mass spectrometry. Analytical features were evaluated using Kruskal-Wallis screening followed by Dunn’s post hoc testing with contrast-specific Benjamini-Hochberg false-discovery rate correction. Results The largest curated differential feature set was observed between ATLL and asymptomatic carriers, comprising 348 putatively annotated MSI level 2 features, followed by HAM/TSP versus asymptomatic carriers with 190 features and ATLL versus uninfected controls with 163 features. Lipid-related features, particularly glycerophospholipids, sphingolipids, and oxidized glycerophospholipids, were prominently represented. A total of 155 features were shared between the ATLL-versus-asymptomatic-carrier and HAM/TSP-versus-asymptomatic-carrier comparisons, all with concordant directionality. Discussion Intracellular CD4+ T-cell metabolomics revealed both shared metabolic alterations and phenotype-specific signatures associated with distinct clinical outcomes of HTLV-1 infection. The predominant metabolic changes involved lipid remodeling, particularly glycerophospholipids and sphingolipids, suggesting a shared metabolic background across symptomatic HTLV-1 disease with superimposed mechanisms related to chronic inflammation in HAM/TSP and malignant transformation in ATLL. Conclusion These findings indicate that intracellular CD4+ T-cell metabolomic profiling captures biological heterogeneity across the clinical spectrum of HTLV-1 infection and provides a framework for future biomarker discovery and mechanistic studies. Validation in larger cohorts and functional investigations will be necessary to confirm these observations.

Source: Hematology Transfusion and Cell Therapy

DOI: 10.1016/j.htct.2026.106792