Presence of HTLV‐I proviral DNA in central nervous system of patients with HTLV‐I–associated myelopathy

Kira, Jun‐ichi; Itoyama, Yasuto; Koyanagi, Yoshio; Tateishi, Jun; Kishikawa, Masao; Akizuki, Shin’ichiro; Kobayashi, I; Toki, Naoyuki; Sueishi, Katsuo; Sato, Hiroyuki; Sakaki, Yoshiyuki; Yamamoto, Naoki; Goto, Ikuo

doi:10.1002/ana.410310108

Cited by 84 publications

(32 citation statements)

References 17 publications

(4 reference statements)

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“…Further, Hasunuma et al (33) have recently reported the presence of specific cytotoxic T cells against Tax-bearing synoviocytes and augmentation of HLA class II molecules on the cell surface of HTLV-1 synoviocytes. Although latent viral replication in circulating infected T lymphocytes is a common feature of HTLV infection, the percentage of circulating HTLV-infected T lymphocytes is significantly increased in HAM/TSP patients (27,39,45) as compared to in asymptomatic carriers. In addition, HTLV-1-specific CD4 ϩ HLA class II-restricted and CD8…”

Section: Discussionmentioning

confidence: 99%

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Pise-Masison

Dittmer

Clemens

et al. 1997

Molecular and Cellular Biology

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Human T-cell lymphotrophic virus type 1 (HTLV-1) is the causative agent of the aggressive, usually fatal adult T-cell leukemia (see references 22, 23, 48 and 86 and references therein). Recent reports have linked HTLV-1 with additional and clinically diverse human diseases (31,46,53,59,63,65). The best characterized of these is a progressive demyelinating syndrome termed HTLV-1-associated myelopathy (HAM) or tropical spastic paraparesis (TSP) (see references 22, 23, 48, and 86 and references therein). Because of the long incubation period between viral exposure and disease onset, the mechanism of HTLV-1 pathogenesis is still unclear. It is clear that host cell control of HTLV-1 replication is a primary determinant of virus expression and subsequent disease. Studies on the variation of viral sequences among different infected groups have not revealed any particular determinant which distinguishes onset of a particular HTLV-1 associated disease (18,44,60,74,87,88).In vitro, HTLV-1 has been shown to activate and immortalize human T lymphocytes, resulting in the polyclonal proliferation of infected cells and subsequent oligoclonal or monoclonal growth (26, 43). HTLV-1 contains no known cellular protooncogene, and because there is no preferential site of integration among infected individuals, it is unlikely that insertional mutagenesis is responsible for viral transformation. Several lines of evidence suggest that the viral transcriptional activator Tax contributes to the development of disease (23,28,29,82).Tax, which is essential for viral replication (22,23,48,86), has recently been shown to transform established rodent fibroblasts to anchorage-independent growth (77, 82, 85). Moreover, Tax can transform primary rat embryo fibroblasts in cooperation with activated ras (67) as well as immortalize normal human T lymphocytes when expressed from a herpes simplex virus-based vector (28,29). Finally, transgenic mice carrying the Tax gene frequently develop mesenchymal tumors and neurofibromas (34, 62). These findings suggest that Tax plays a critical role in HTLV-1-associated leukemogenesis.Tax is believed to exert its effect by stimulating viral gene expression and by deregulating expression of cellular genes (22,23,48,86). Tax has been shown to activate transcription of a number of cellular genes involved in cell proliferation, such as those for interleukin-3 (IL-3), IL-2, the IL-2 receptor, granulocyte-macrophage colony-stimulating factor, c-Fos, c-Jun, parathyroid-related protein, and the major histocompatibility complex (MHC) class I (see references 22, 23, 48, and 86 and references therein). The aberrant expression of these growthrelated genes has been implicated in contributing to the establishment of HTLV-1-associated pathogenesis. While Tax does not bind DNA directly, it appears to stimulate RNA synthesis through protein-protein interactions with host cell transcription factors. The most well studied of these interactions is with the ATF/CREB family of transcription factors, which bind to cyclic AMP-responsive...

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Section: Discussionmentioning

confidence: 99%

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Pise-Masison

Dittmer

Clemens

et al. 1997

Molecular and Cellular Biology

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“…HTLV-I infection of the CNS has been related to the etiology of HAM/TSP. The HTLV-I causes a persistent infection in CNS and the virus has been demonstrated in peripheral blood lymphocytes and CSF cells 9,11 . The intrathecal synthesis of HTLV-I antibodies may be an indicator of the presence of this virus in CNS and differentiates HAM/TSP from other chronic myelopathies such as MS.…”

Section: Discussionmentioning

confidence: 99%

The value of csf analysis for the differential diagnosis of HTLV-I associated myelopathy and multiple sclerosis

Puccioni-Sohler

Kitze

Felgenhauer

et al. 1995

Arq. Neuro-Psiquiatr.

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SUMMARY -Cerebrospinal fluid (CSF) and serum of 17 patients with HAM/TSP (HTLV-I associated myelopathy/ tropical spastic paraparesis), six with multiple sclerosis and six with idiopathic epilepsy (non inflammatory control) from Brazil were analysed for the presence of intrathecal synthesis of virus-specific antibodies against measles, rubella, varicella zoster virus and herpes simplex virus by enzyme-linked immunosorbent assay (ELISA). All HAM/TSP and multiple sclerosis cases had an intrathecal immune response (oligoclonal IgG). In HAM/TSP, only 1/17 case showed a polyspecific intrathecal immune response against measles and rubella virus. In multiple sclerosis, specific antibodies against measles and rubella (MRZ response) were observed in all patients but not in the control with idiopathic epilepsy. The diagnostic and theoretical relevance of mono-and polyspecific immune responses is discussed for these chronic neurological diseases. KEY WORDS: HTLV-I, HAM/TSP, cerebrospinal fluid, antibody indexValor da análise do LCR para o diagnóstico diferencial de mielopatia associada ao HTLV-I e esclerose múltipla RESUMO -Amostras de líquido cefalorraquidiano (LCR) e soro de 17 pacientes brasileiros com HAM/TSP, seis com esclerose múltipla e seis com epilepsia idiopática (controle não-inflamatório) foram analisadas para a presença de anticorpos para os vírus do sarampo, rubéola, varicela zoster e herpes simples pelo método de ELISA. Todos os casos de HAM/TSP e esclerose múltipla tinham resposta imune intratecal (IgG oligoclonal). Somente 1/17 casos de HAM/TSP apresentavam resposta imune poliespecifica intratecal para sarampo e rubéola. Anticorpos específicos para sarampo e rubeola (resposta MRZ) foram observados em todos os pacientes com esclerose múltipla, mas não nos controles com epilepsia idiopática. A relevância das respostas poliespecifica e monoespecifica é discutida para essas doenças neurológicas crônicas. PALAVRAS-CHAVE: HTLV-I, HAM/TSP, líquido cefalorraquidiano, índice de anticorpos.The sensitive detection of intrathecally synthesized antibodies increased the relevance of CSF analysis for diagnosis of neurological diseases 17 . The sucessful concepts for discrimination of blood derived and brain derived CSF fractions 16 of immunoglobulin could be extended to the detection of brain defined specific antibodies exceeding the theoretical upper concentration of blood derived antibody species in CSF. An immune response against virus antigens within the central nervous system (CNS) has been demonstrated in different neurological diseases 1 " 4 -6,7 . This reaction may be

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“…This is re¯ected in the high antibody titer to HTLV-I proteins, increased levels of activated T cells, and the oligoclonal expansion of Tax (11±19)-speci®c CD8 CTL in the PB and, relevant to CNS disease, in CSF. Additionally, HAM/TSP patients exhibit elevated levels of in¯amma-tory cytokines and an increase in proviral DNA load in both the PB and CSF as compared to ATL patients and asymptomatic carriers (Ohbo et al, 1991;Kira et al, 1992;Nakamura et al, 1993;Umehara et al, 1994a;Fox et al, 1996;Nagai et al, 1998;Furuya et al, 1999). Clearly, the immunologic response to HTLV-I infection in HAM/ TSP patients is signi®cantly different from that of ATL patients or asymptomatic carriers.…”

Section: Emerging Model Of Htlv-induced Neurologic Disease and Directmentioning

confidence: 99%

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

Grant

Barmak

Alefantis

et al. 2002

Journal Cellular Physiology

101

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Human T cell lymphotropic/leukemia virus type I (HTLV‐I) has been identified as the causative agent of both adult T cell leukemia (ATL) and HTLV‐I‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the exact sequence of events that occur during the early stages of infection are not known in detail, the initial route of infection may predetermine, along with host, environmental, and viral factors, the subset of target cells and/or the primary immune response encountered by HTLV‐I, and whether an HTLV‐I‐infected individual will remain asymptomatic, develop ATL, or progress to the neuroinflammatory disease, HAM/TSP. Although a large number of studies have indicated that CD4+ T cells represent an important target for HTLV‐I infection in the peripheral blood (PB), additional evidence has accumulated over the past several years demonstrating that HTLV‐I can infect several additional cellular compartments in vivo, including CD8+ T lymphocytes, PB monocytes, dendritic cells, B lymphocytes, and resident central nervous system (CNS) astrocytes. More importantly, extensive latent viral infection of the bone marrow, including cells likely to be hematopoietic progenitor cells, has been observed in individuals with HAM/TSP as well as some asymptomatic carriers, but to a much lesser extent in individuals with ATL. Furthermore, HTLV‐I+ CD34+ hematopoietic progenitor cells can maintain the intact proviral genome and initiate viral gene expression during the differentiation process. Introduction of HTLV‐I‐infected bone marrow progenitor cells into the PB, followed by genomic activation and low level viral gene expression may lead to an increase in proviral DNA load in the PB, resulting in a progressive state of immune dysregulation including the generation of a detrimental cytotoxic Tax‐specific CD8+ T cell population, anti‐HTLV‐I antibodies, and neurotoxic cytokines involved in disruption of myelin‐producing cells and neuronal degradation characteristic of HAM/TSP. J. Cell. Physiol. 190: 133–159, 2002. © 2002 Wiley‐Liss, Inc.

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Presence of HTLV‐I proviral DNA in central nervous system of patients with HTLV‐I–associated myelopathy

Cited by 84 publications

References 17 publications

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

The value of csf analysis for the differential diagnosis of HTLV-I associated myelopathy and multiple sclerosis

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

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Presence of HTLV‐I proviral DNA in central nervous system of patients with HTLV‐I–associated myelopathy

Cited by 84 publications

References 17 publications

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax1 Protein and the CCAAT Binding Protein NF-Y

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax1 Protein and the CCAAT Binding Protein NF-Y

The value of csf analysis for the differential diagnosis of HTLV-I associated myelopathy and multiple sclerosis

Human T cell leukemia virus type I and neurologic disease: Events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation

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Product

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Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y