Transformation of human leukocytes by co-cultivation with HTLV-1-associated myelopathy patients' leukocytes.
K MiyamotoHiroyuki NishikawaTakeshi MiyataSumiko OtsukiNoriko TomitaCarolyn K. SuzukiAkio IshiiYoshio HirakiT. SugiharaK Kitajima
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Sera and cerebrospinal fluid (CSF) from patients with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM) were analyzed by Western blotting, and normal human leukocytes were transformed by co-cultivation with HAM patients' leukocytes. The sera and CSF from all HAM patients formed specific bands with HTLV-1 viral proteins, including p19, p24, p28, p32, p40 and p53. After 2-3 weeks of co-cultivation, scattered foci of cell aggregates were noted on macrophage sheets. Surface markers of the transformed cells were OKT3(+), OKT4(+), OKT8(-), IL-2 receptor(+) and EBNA(-). Chromosome analysis showed a normal karyotype. HTLV-1 viral genome was integrated into DNA isolated from transformed cell lines. Electron microscopy revealed type C virus particles in transformed T-cell lines. These results indicate that peripheral leukocytes from HAM patients can transform HTLV-1-negative leukocytes and HAM patients have the potential to acquire adult T-cell leukemia in the future.Cite
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Human T-lymphotropic virus
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Deltaretrovirus
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We report a 42-year-old Japanese woman with HTLV-I-associated myelopathy (HAM) combined with adult T-cell leukemia (ATL). Combination of the 2 diseases has been extremely rare. The infrequency is explained by HLA types unique to each disease. Our patient suggests that the HAM-associated HLA haplotype does not prevent the development of ATL.
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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.
Tropical spastic paraparesis
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Clonus
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Abstract Background Human T cell lymphotropic virus type I (HTLV‐I) is associated with specific manifestations such as adult T cell lymphoma/leukemia ( ATLL ), HTLV ‐I‐associated myelopathy/tropical spastic paraparesis ( HAM / TSP ), HTLV ‐I‐associated uveitis, and infective dermatitis associated with HTLV ‐I ( IDH ). Although ATLL and IDH are considered specific manifestations of HTLV ‐I infection, several dermatological manifestations have been described in HTLV ‐I seropositive patients. Objectives This study was conducted to determine the prevalences of skin lesions in patients infected with HTLV ‐I in an area of Brazil endemic for HTLV ‐I infection and to compare these prevalences with those in seronegative individuals in the same region. Methods A prevalence study was conducted between 2008 and 2010 with two groups of individuals comprising, respectively, 179 HTLV ‐I seropositive (positive enzyme‐linked immunosorbent assay [ ELISA ] and positive Western blot analysis) and 193 HTLV ‐I seronegative individuals ( ELISA ‐negative). The subjects were selected on a random basis and evaluated using a questionnaire to obtain epidemiological and clinical data. A physical examination was performed to verify the presence of skin lesions. Results Superficial mycoses were found in 54 (30.2%) seropositive subjects and in 26 (13.5%) of the seronegative group ( P < 0.001). Xerosis was found in 39.1% of HTLV ‐I infected subjects and in 9.3% of seronegative controls ( P < 0.001). Ichthyosis was diagnosed in nine (5.0%) HTLV ‐I seropositive subjects but in none of the control group ( P = 0.001). A diagnosis of seborrheic dermatitis was made in 43 (24.0%) HTLV ‐I infected subjects and in 24 (12.4%) seronegative controls ( P = 0.004). Furthermore, dermatological manifestations were more intense in the HTLV ‐I seropositive group. Conclusions Several dermatological manifestations are more common and more severe in HTLV ‐I seropositive subjects. The presence of these manifestations in an area endemic for HTLV ‐I infection may provide some clues in the investigation of this infection.
Tropical spastic paraparesis
Seborrheic Dermatitis
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Sixteen human T-cell lines were studied for the expression of a cell-adhesion molecule ICAM-1 and its counter-receptor LFA-1. The cell lines included 3 human T-cell-leukemia-virus-type-I (HTLV-1)-negative cell lines derived from acute lymphoblastic leukemia (ALL) and 13 HTLV-1-positive cell lines, 7 of them established from cord- or peripheral-blood T cells by in vitro transformation with HTLV-1, 2 derived from HTLV-1 carriers, and 4 derived from patients with adult T-cell leukemia (ATL). In sharp contrast to a basal level of ICAM-1 in 3 HTLV-1-negative ALL cell lines, strong induction of ICAM-1 was seen in all HTLV-1-positive T-cell lines except for MT-1, one of the 4 ATL cell lines used in the present study. On the other hand, the expression of LFA-1 (CD11a and CD18) was more or less similar among the cell lines with and without HTLV-1. Interestingly, however, 3 out of 4 ATL cell lines (TL-Om1, H582, HUT102) revealed striking depression of LFA-1 expression. Several lines of evidence strongly argued against direct involvement of the viral transactivator p40tax or some autocrine cytokines in the induction of ICAM-1 in HTLV-1-positive T-cell lines. It was also found that ICAM-1 and LFA-1 were involved in syncytium formation induced in the co-culture of HTLV-1-positive and HTLV-1-negative human T-cell lines. Implications of constitutive expression of ICAM-1 for certain clinical manifestations of ATL and of depression of either ICAM-1 or LFA-1 during progression of ATL are discussed.
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Human T‐cell leukemia virus type 1 (HTLV‐1) is the etiologic agent for adult T‐cell leukemia and HTLV‐1‐associated myelopathy/tropical spastic paraparesis. Recently we infected newborn mice by inoculating HTLV‐1‐producing human cells, and found that T‐cells, B‐cells and granulocytes were infected in vivo. To understand the mechanism of viral‐cell interaction and the pathogenesis of HTLV‐1 using the mouse model, it is important to clarify the cellular tropism using a cell‐free HTLV‐1 transmission system. We employed a highly transmissible cell‐free HTLV‐1 produced by a feline kidney cell line, c77, and studied the susceptibility of 9 kinds of mouse cell lines, EL4, RLml, CTLL‐2, J774.1, DA‐1, Ba/F3, WEHI‐3, NIH3T3 and Bl, and two kinds of human cell lines, Molt‐4 and Hut78. HTLV‐1 proviral sequence was found by PCR in all 9 mouse cell lines as well as in 2 human cell lines and viral entry was blocked with sera from an HTLV‐1 carrier and an adult T‐cell leukemia patient. Unexpectedly, mouse cell lines EL4 and RLml and human cell lines Molt‐4 and Hut78 showed similar efficiency for viral entry. These results suggest a wide distribution of HTLV‐1 receptor in mouse cells.
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Adult T-cell leukemia/lymphoma (ATL) responds poorly to conventional chemotherapy, but allogeneic stem cell transplantation (allo-SCT) may improve disease prognosis. Herein, we report a female patient with human T-cell leukemia virus type I (HTLV-I)-associated myelopathy (HAM)-like myelopathy following allo-SCT for ATL.She developed crural paresis 14 months after allo-SCT. Initially, she was diagnosed with central nervous system (CNS) relapse of ATL and treated with intrathecal injection and whole brain and spine irradiation. Her symptoms recurred 5 months later, when a cerebrospinal fluid (CSF) specimen showed increased CD4 + CXCR3 + CCR4+ cell numbers and levels of neopterin and CXCL10 (IP-10).These results suggest the possible involvement of a certain immunological mechanism such as HAM in her symptoms, irrespective of the lack of anti-HTLV-I antibody in her CSF. Because a definitive diagnosis of CNS manifestation of ATL is sometimes difficult, multi-modal laboratory data are required for differential diagnosis.
Adult T-cell leukemia/lymphoma
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Because there are limited clinical reports on the impact of human T-lymphotropic virus type 1 (HTLV-1) on organ transplantation, its effects on the development of adult T-cell leukemia-lymphoma (ATL), post-transplantation lymphoproliferative disorder (PTLD) and HTLV-1-associated myelopathy (HAM) or atypical HAM after organ transplantation remain unclear.We retrospectively analyzed the impact of HTLV-1 in 54 allogeneic hematopoietic stem cell transplantation (allo-HSCT) cases and 31 renal transplantation cases between January 2006 and December 2016.Among the 54 allo-HSCT cases, nine recipients with ATL tested positive for HTLV-1, and one was found to be an HTLV-1 carrier. All donors tested negative for HTLV-1. Only one HTLV-1 carrier did not present with ATL or HAM development after allo-HSCT. Among nine ATL cases after allo-HSCT, four eventually relapsed due to proliferation of recipient-derived ATL cells. However, in one ATL case, atypical HAM developed rapidly at 5 months after allo-HSCT.Among the 31 renal transplantation cases, all donors tested negative for HTLV-1, and only recipients tested positive. Only one HTLV-1 carrier recipient did not present with ATL or HAM development after renal transplantation. However, one HTLV-1-negative recipient developed PTLD in the brain 10 years after renal transplantation.In clinical practice, careful follow-up of HTLV-1 infected recipients after organ transplantation is important because atypical HAM can develop in ATL patients after allo-HSCT. Furthermore, to clarify the risk of ATL or HAM development in HTLV-1 infected recipients, we prospectively followed up our cohort.
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Familial cases of HTLV-I-associated myelopathy (HAM) and adult T-cell leukemia (ATL), developing in a daughter and father, respectively, are reported. The coexistence of both diseases in a family has not been reported before. This supports the recent findings that ATL and HAM may be brought about by an identical virus on an apparently different immunogenetic background.
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