Abstract HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) and progressive forms of multiple sclerosis (MS) are chronic central nervous system 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 MS, with increasing evidence implicating Epstein–Barr virus (EBV) in MS initiation—both conditions converge on shared inflammatory and neurodegenerative cascades. In HAM/TSP, a hierarchical Tax–MAP3K8–MEK–ERK signaling 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 MS, 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 GFAP in MS, provide complementary insights into inflammatory burden and neuroaxonal damage. Emerging therapies target immune and glial signaling pathways, including MAPK and JAK/STAT axes, yet disease progression remains only partially controlled. By integrating hierarchical molecular signaling, 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 MS and other neuroinflammatory disorders.
Silva et al. (Thu,) studied this question.