HTLV-1-associated myelopathy as a translational model of progressive neurodegeneration

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and progressive forms of multiple sclerosis are chronic CNS diseases characterized by persistent inflammation and progressive neurodegeneration. Although triggered by distinct upstream events [persistent HTLV-1 infection in HAM/TSP and autoimmune mechanisms in multiple sclerosis, with increasing evidence implicating Epstein-Barr virus (EBV) in multiple sclerosis initiation], both conditions converge on shared inflammatory and neurodegenerative cascades. In HAM/TSP, a hierarchical Tax-MAP3K8-MEK-ERK signalling axis emerges as a proximal disease-defining pathway that promotes Th1 polarization and sustained interferon-driven inflammation, with JAK/STAT functioning predominantly as a downstream amplification loop. Neurodegeneration in HAM/TSP appears largely secondary to chronic virus-driven immune activation, whereas in progressive multiple sclerosis the degenerative mechanisms may evolve alongside compartmentalized, smouldering inflammation within the CNS. Rather than representing strictly 'secondary' versus 'primary' paradigms, both diseases are better understood along a continuum in which inflammatory, metabolic and age-related mechanisms interact to sustain axonal loss. Advanced imaging techniques reveal convergent patterns of spinal cord atrophy and microstructural injury. Biomarkers, such as proviral load and CXCL10 in HAM/TSP and neurofilament light chain and glial fibrillary acidic protein in multiple sclerosis, provide complementary insights into inflammatory burden and neuroaxonal damage. Emerging therapies target immune and glial signalling pathways, including MAPK and JAK/STAT axes, yet disease progression remains controlled only in part. By integrating hierarchical molecular signalling, viral-immune interactions, imaging correlates and biomarker profiles, this review positions HAM/TSP as a reductionist human model of chronic inflammation-driven neurodegeneration, offering translational insights relevant to progressive multiple sclerosis and other neuroinflammatory disorders.