Human T-cell leukemia virus type-1 (HTLV-1) is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL) and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic progressive myelopathy characterized by spastic paraparesis, sphincter dysfunction, and mild sensory disturbance in the lower extremities. Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence from host population genetics, viral genetics, DNA expression microarrays, and assays of lymphocyte function suggests that complex virus-host interactions and the host immune response play an important role in the pathogenesis of HAM/TSP. Especially, the efficiency of an individual's cytotoxic T-cell (CTL) response to HTLV-1 limits the HTLV-1 proviral load and the risk of HAM/TSP. This paper focuses on the recent advances in HAM/TSP research with the aim to identify the precise mechanisms of disease, in order to develop effective treatment and prevention. 1. Introduction Human T-cell leukemia virus type-1 (HTLV-1) is a human retrovirus etiologically associated with adult T-cell leukemia (ATL) [1–3] and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [4, 5]. HAM/TSP is a chronic progressive myelopathy characterized by spastic paraparesis, sphincter dysfunction, and mild sensory disturbance in the lower extremities [6]. Cases of HAM/TSP have been reported throughout the HTLV-1 endemic areas such as Southern Japan, the Caribbean, Central and South America, the Middle East, Melanesia, and equatorial regions of Africa [7]. Sporadic cases have also been described in nonendemic areas such as the United States and Europe, mainly in immigrants from an HTLV-1 endemic area. In contrast to HIV-1 infection, few with HTLV-1 develop disease: approximately 2%-3% of infected persons develop ATL [8] and other 0.25%–3.8% develop HAM/TSP [9–12], while the majority of infected individuals remain lifelong asymptomatic carriers (ACs). However, the ability to evaluate the individual risk of HTLV-1-associated diseases in each AC would make a significant clinical impact, especially in HTLV-1 endemic areas. During the last three decades since the discovery of HTLV-1 as the first pathogenic human retrovirus, advances in HTLV-1 research have helped us to understand the clinical features of HTLV-1 associated diseases, the
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