Pathogenesis of human T‐lymphotropic virus type 1‐associated myelopathy/tropical spastic paraparesis

<jats:title>Abstract</jats:title><jats:p>Human T‐lymphotropic virus type 1 (<jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1) is a human retrovirus that preferentially infects <jats:styled-content style="fixed-case">CD</jats:styled-content>4+ lymphocytes <jats:italic>in vivo</jats:italic>. The virus causes a hematological malignancy known as adult T‐cell leukemia, and an inflammatory disease in the central nervous system (<jats:styled-content style="fixed-case">CNS</jats:styled-content>) called <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1‐associated myelopathy/tropical spastic paraparesis (<jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content>). Approximately 0.3% of <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1‐infected individuals develop <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content>. <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content> patients show spastic paraparesis and sphincter dysfunction, as well as sensory disturbance of the lower extremities, which corresponds to pathological lesions in the spinal cord. Although the majority of <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content> patients progress slowly, this disease progresses rapidly in some patients. An increased <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1 proviral load is more common in <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content> patients than in asymptomatic <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1 carriers, and is considered to be a strong risk factor for <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content> development. A prominent cellular immune response in <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content> patients is a significantly elevated number of <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1 Tax‐specific <jats:styled-content style="fixed-case">CD</jats:styled-content>8+ cytotoxic T lymphocytes (<jats:styled-content style="fixed-case">CTL</jats:styled-content>) in peripheral blood mononuclear cells compared with asymptomatic <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1 carriers. Additionally, <jats:styled-content style="fixed-case">CD</jats:styled-content>4+ and <jats:styled-content style="fixed-case">CD</jats:styled-content>8+ lymphocytes accumulate in the perivascular areas of spinal cords in <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content> patients. Viral <jats:styled-content style="fixed-case">DNA</jats:styled-content>,<jats:styled-content style="fixed-case"> mRNA</jats:styled-content> and proteins are detected only in infiltrating <jats:styled-content style="fixed-case">CD</jats:styled-content>4+ T cells, but not in neural cells. A high proportion of <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1‐specific <jats:styled-content style="fixed-case">CTL</jats:styled-content> infiltrates the CNS. Furthermore, some neural cells surrounding the <jats:styled-content style="fixed-case">CTL</jats:styled-content>, predominantly oligodendrocytes, undergo apoptosis. These findings suggest the pathogenesis that the <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1‐specific inflammation induced by the interaction of <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1‐infected <jats:styled-content style="fixed-case">CD</jats:styled-content>4+ T cells and <jats:styled-content style="fixed-case">HTLV</jats:styled-content>‐1‐specific <jats:styled-content style="fixed-case">CD</jats:styled-content>8+ <jats:styled-content style="fixed-case">CTL</jats:styled-content> causes bystander damage in the CNS. In the present review, a more exact pathogenesis of <jats:styled-content style="fixed-case">HAM</jats:styled-content>/<jats:styled-content style="fixed-case">TSP</jats:styled-content> is discussed based on virology, immunology and neuropathology.</jats:p>