Human T-cell lymphotrophic virus type-I (HTLV-I) retrovirus and human disease
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Tropical spastic paraparesis
Seroprevalence
Deltaretrovirus
Tropical spastic paraparesis
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Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the precise mechanisms leading to HTLV-1 chronic infection and the onset of the diseases have remained unclear, and effective vaccines for inhibiting the infection and the progression of pathogenesis have therefore not been developed. The use of a nonhuman primate (NHP) model is thought to be important for revealing the mechanisms of the progressive status and for the development of prevention procedures. In this study, we developed a cynomolgus macaque (CM) model of HTLV-1 infection by direct intravenous inoculation of HTLV-1-producing cells derived from ATL patients. The cell line used for infection, ATL-040, was selected as the most infectious one in our cell line library. CMs inoculated intravenously with 1 × 108 ATL-040 cells per animal became persistently infected with HTLV-1, as shown by the HTLV-1 provirus load (PVL) in peripheral blood mononuclear cells and HTLV-1-specific antibodies (2/2 animals). One CM inoculated intravenously with 1 × 107 ATL-040 cells did not have detectable PVLs despite the fact that anti-HTLV-1 antibodies were maintained for more than 2 years. Furthermore, immunological approaches, including CD8+ T cell depletion prior to infection (3/3 animals) and intrathecal inoculation (3/3 animals), led to increased proviral loads in the cynomolgus monkeys. The present method and the cynomolgus monkey model of HTLV-1 infection will be beneficial for immunological and virological studies on HTLV-1 aiming at the development of anti-HTLV-1 prophylactic vaccines and therapy drugs. IMPORTANCE HTLV-1 was discovered in the 1980s as the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. However, the precise mechanisms leading to HTLV-1 chronic infection and the onset of the diseases still remain unidentified. Thus, no effective vaccines to inhibit the infection and the progressive of pathogenesis have been developed. The use of appropriate animal models is essential for understanding HTLV-1 infection and pathogenesis. In order to establish a new nonhuman primate model for studies on HTLV-1 infection, cynomolgus monkeys were infected with HTLV-1 under a variety of experimental conditions. Our method, using a cell line generated from an ATL patient as a source of HTLV-1, was able to establish HTLV-1 infection in monkeys with a 100% success rate. This cynomolgus macaque model of HTLV-1 infection will contribute to the elucidation of HTLV-1 infection and its associated disease development.
Tropical spastic paraparesis
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Human T-cell leukemia virus type 1 (HTLV-1) belongs to the delta type retroviruses, which also include bovine leukemia virus (BLV), human T-cell leukemia virus type 2 (HTLV-2), and simian T-cell leukemia virus (STLV) [1]. HTLV-1 is the first retrovirus that was identified as a causative agent of several human diseases, including adult T-cell leukemia (ATL), HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis (TSP), and HTLV-1 associated uveitis [2, 3]. ATL is a neoplastic disease of CD4-positive T lymphocytes, which is characterized by pleomorphic tumor cells with hypersegmented nuclei, called "flower cells." HTLV-1 encodes in its pX regaion a potent oncoprotein, Tax. Tax is a transcriptional activator protein that has been reported to activate and inactivate the transcription of many cellular genes. Ectopic over expression of the HTLV-1 Tax has been found to transforms rodent cells and immortalizes human cells ex vivo [4, 5, 6, 7, 8]. Moreover, transgenic mice engineered to express Tax also form tumors readily [9, 10, 11, 12]. Taken together, these findings strongly support a physiological role for Tax in ATL leukemogenesis. Nevertheless, there are reports that tax transcripts are detected in only ∼40% of transformed ATL cells and that only a small proportion of HTLV-1 carriers (6.6% for males and 2.1% for females in Japan) develop ATL after a long latency period (about 60 years in Japan, and 40 years in Jamaica) from the initial infection [1]. These observations argue that besides Tax, other factors such as additional viral genes, host cell, and immune factors may also contribute to the development of ATL. Compatible with the above thinking, it was recently discovered that the HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is ubiquitously expressed in all ATL cells and possesses cell proliferative function in T cells [13]. HBZ may also contribute to leukemogenesis.
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ABSTRACT. Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus endemic in many areas around the world. HTLV-1 can induce the development of adult T-cell leukemia (ATL) or myelopathy/tropical spastic paraparesis (HAM/TSP). We report a patient who presented to our outpatient clinic with massive splenomegaly, weight loss, urinary retention, and lower extremity weakness for the previous 3 years. The patient was found to have positive HTLV-1 by ELISA and Western blot from peripheral blood. Evaluation of the spleen demonstrated T-cell large granular lymphocyte leukemia consistent with ATL. In addition to progressive lower extremity weakness, hyperreflexia and clonus, cerebral spinal fluid was positive for HTLV-1 by ELISA and had a reversed CD4-to-CD8 ratio consistent with HAM/TSP. These findings suggest HTLV-1 induced ATL and HAM/TSP presenting simultaneously in the same patient.
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Human T-cell leukemia virus type I (HTLV-1) causes T-cell leukemia and tropical spastic paraparesis (TSP) in a minority of infected people, whereas the majority remain healthy. No association between a particular HTLV-I sequence and disease manifestation has been found in previous studies. We studied here the sequence variability of the gene for the HTLV-I Tax protein, which is the dominant target antigen of the very strong cytotoxic T-lymphocyte response to the virus. In HTLV-I infection, the intraisolate nucleotide variability is much greater than the variability between isolates. The predicted protein sequence of Tax was significantly more variable in the healthy seropositive individuals' provirus than in those of the patients with TSP. Thus, tax sequence heterogeneity, rather than the presence of particular sequences, distinguishes healthy HTLV-I-seropositive individuals from patients with TSP.
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Human T-cell leukemia virus (HTLV) is a human type-C RNA tumor virus (retrovirus) previously identified in and isolated from several patients with T-cell leukemias or lymphomas. The known virus isolates from the United States and Japan are closely related and are found in adults with an acute malignancy of mature T cells. A related retrovirus has been found in a patient (Mo) with a somewhat different disease (a T-cell variant of relatively benign hairy cell leukemia). Serum from Mo contains antibodies to the major internal core protein (p24) of HTLV. A T-cell line established from the spleen of Mo expresses HTLV antigens. However, HTLV from Mo is significantly different from all previous HTLV isolates in immunological cross-reactivity tests of p24. The usual prototype HTLV isolate is represented as HTLV-I, and the HTLV from Mo is represented as HTLV-II. Individual members of each subgroup may then be identified by subscript initials of the patient [for example, HTLV-I(CR), HTLV-I(MB), and HTLV-II(Mo)].
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