Human T-Lymphotropic Virus

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Yuetsu Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • pseudotyping of hiv 1 with Human t lymphotropic Virus 1 htlv 1 envelope glycoprotein during hiv 1 htlv 1 coinfection facilitates direct hiv 1 infection of female genital epithelial cells implications for sexual transmission of hiv 1
    mSphere, 2018
    Co-Authors: Yuyang Tang, Yuetsu Tanaka, Alvin M George, Franklin J Nouvet, Stephanie Sweet, Oksana Petrechko, Brian S Imbiakha, Guochun Jiang, Wei Gao, Kathryn Anastos
    Abstract:

    Female genital epithelial cells cover the genital tract and provide the first line of protection against infection with sexually transmitted pathogenic Viruses. These cells normally are impervious to HIV-1. We report that coinfection of cells by HIV-1 and another sexually transmitted Virus, Human T-Lymphotropic Virus 1 (HTLV-1), led to production of HIV-1 that had expanded cell tropism and was able to directly infect primary vaginal and cervical epithelial cells. HIV-1 infection of epithelial cells was blocked by neutralizing antibodies against the HTLV-1 envelope (Env) protein, indicating that the infection was mediated through HTLV-1 Env pseudotyping of HIV-1. Active replication of HIV-1 in epithelial cells was demonstrated by inhibition with anti-HIV-1 drugs. We demonstrated that HIV-1 derived from peripheral blood of HIV-1-HTLV-1-coinfected subjects could infect primary epithelial cells in an HTLV-1 Env-dependent manner. HIV-1 from subjects infected with HIV-1 alone was not able to infect epithelial cells. These results indicate that pseudotyping of HIV-1 with HTLV-1 Env can occur in vivo Our data further reveal that active replication of both HTLV-1 and HIV-1 is required for production of pseudotyped HIV-1. Our findings indicate that pseudotyping of HIV-1 with HTLV-1 Env in coinfected cells enabled HIV-1 to directly infect nonpermissive female genital epithelial cells. This phenomenon may represent a risk factor for enhanced sexual transmission of HIV-1 in regions where Virus coinfection is common.IMPORTANCE Young women in certain regions of the world are at very high risk of acquiring HIV-1, and there is an urgent need to identify the factors that promote HIV-1 transmission. HIV-1 infection is frequently accompanied by infection with other pathogenic Viruses. We demonstrate that coinfection of cells by HIV-1 and HTLV-1 can lead to production of HIV-1 pseudotyped with HTLV-1 Env that is able to directly infect female genital epithelial cells both in vitro and ex vivo Given the function of these epithelial cells as genital mucosal barriers to pathogenic Virus transmission, the ability of HIV-1 pseudotyped with HTLV-1 Env to directly infect female genital epithelial cells represents a possible factor for increased risk of sexual transmission of HIV-1. This mechanism could be especially impactful in settings such as Sub-Saharan Africa and South America, where HIV-1 and HTLV-1 are both highly prevalent.

  • mogamulizumab an anti ccr4 antibody targets Human t lymphotropic Virus type 1 infected cd8 and cd4 t cells to treat associated myelopathy
    The Journal of Infectious Diseases, 2015
    Co-Authors: Junji Yamauchi, Ariella Colerreilly, Tomoo Sato, Natsumi Araya, Naoko Yagishita, Yasuo Kunitomo, Katsunori Takahashi, Yuetsu Tanaka, Hitoshi Ando, Yugo Shibagaki
    Abstract:

    BACKGROUND: Human T-Lymphotropic Virus type 1 (HTLV-1) can cause chronic spinal cord inflammation, known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since CD4(+)CCR4(+) T cells are the main HTLV-1 reservoir, we evaluated the defucosylated Humanized anti-CCR4 antibody mogamulizumab as a treatment for HAM/TSP. METHODS: We assessed the effects of mogamulizumab on peripheral blood mononuclear cells from 11 patients with HAM/TSP. We also studied how CD8(+) T cells, namely CD8(+) CCR4(+) T cells and cytotoxic T lymphocytes, are involved in HTLV-1 infection and HAM/TSP pathogenesis and how they would be affected by mogamulizumab. RESULTS: Mogamulizumab effectively reduced the HTLV-1 proviral load (56.4% mean reduction at a minimum effective concentration of 0.01 µg/mL), spontaneous proliferation, and production of proinflammatory cytokines, including interferon γ (IFN-γ). Like CD4(+)CCR4(+) T cells, CD8(+)CCR4(+) T cells from patients with HAM/TSP exhibited high proviral loads and spontaneous IFN-γ production, unlike their CCR4(-) counterparts. CD8(+)CCR4(+) T cells from patients with HAM/TSP contained more IFN-γ-expressing cells and fewer interleukin 4-expressing cells than those from healthy donors. Notably, Tax-specific cytotoxic T lymphocytes that may help control the HTLV-1 infection were overwhelmingly CCR4(-). CONCLUSIONS: We determined that CD8(+)CCR4(+) T cells and CD4(+)CCR4(+) T cells are prime therapeutic targets for treating HAM/TSP and propose mogamulizumab as a new treatment.

  • separate cellular localizations of Human t lymphotropic Virus 1 htlv 1 env and glucose transporter type 1 glut1 are required for htlv 1 env mediated fusion and infection
    Journal of Virology, 2015
    Co-Authors: Yosuke Maeda, Yuetsu Tanaka, Hiromi Terasawa, Chisho Mitsuura, Kaori Nakashima, Keisuke Yusa, Shinji Harada
    Abstract:

    Interaction of the envelope glycoprotein (Env) of Human T-Lymphotropic Virus 1 (HTLV-1) with the glucose transporter type 1 (GLUT1) expressed in target cells is essential for viral entry. This study found that the expression level of GLUT1 in Virus-producing 293T cells was inversely correlated with HTLV-1 Env-mediated fusion activity and infectivity. Chimeric studies between GLUT1 and GLUT3 indicated that the extracellular loop 6 (ECL6) of GLUT1 is important for the inhibition of cell-cell fusion mediated by Env. When GLUT1 was translocated into the plasma membrane from intracellular storage sites by bafilomycin A1 (BFLA1) treatment in 293T cells, HTLV-1 Env-mediated cell fusion and infection also were inhibited without the overexpression of GLUT1, indicating that the localization of GLUT1 in intracellular compartments rather than in the plasma membrane is crucial for the fusion activity of HTLV-1 Env. Immunoprecipitation and laser scanning confocal microscopic analyses indicated that under normal conditions, HTLV-1 Env and GLUT1 do not colocalize or interact. BFLA1 treatment induced this colocalization and interaction, indicating that GLUT1 normally accumulates in intracellular compartments separate from that of Env. Western blot analyses of FLAG-tagged HTLV-1 Env in Virus-producing cells and the incorporation of HTLV-1 Env in Virus-like particles (VLPs) indicate that the processing of Env is inhibited by either overexpression of GLUT1 or BFLA1 treatment in Virus-producing 293T cells. This inhibition probably is due to the interaction of the Env with GLUT1 in intracellular compartments. Taken together, separate intracellular localizations of GLUT1 and HTLV-1 Env are required for the fusion activity and infectivity of HTLV-1 Env. IMPORTANCE The deltaretroVirus HTLV-1 is a causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although HTLV-1 is a complex retroVirus that has accessory genes, no HTLV-1 gene product has yet been shown to regulate its receptor GLUT1 in Virus-producing cells. In this study, we found that a large amount of GLUT1 or translocation of GLUT1 to the plasma membrane from intracellular compartments in Virus-producing cells enhances the colocalization and interaction of GLUT1 with HTLV-1 Env, leading to the inhibition of cell fusion activity and infectivity. The results of our study suggest that GLUT1 normally accumulates in separate intracellular compartments from Env, which is indeed required for the proper processing of Env.

  • Human t lymphotropic Virus type 1 tax protein triggers microtubule reorientation in the virological synapse
    Journal of Biological Chemistry, 2005
    Co-Authors: Mohamed Nejmeddine, Yuetsu Tanaka, Graham P. Taylor, Amanda L Barnard, Charles R. M. Bangham
    Abstract:

    We showed recently that the Human T-Lymphotropic Virus, type 1 (HTLV-1), spreads directly from cell to cell via a virological synapse. The HTLV-1 virological synapse resembles the immunological synapse; each is a specialized contact between a lymphocyte and another cell that contains organized protein microdomains, and each involves repolarization of the T-cell microtubule cytoskeleton. However, formation of the virological synapse is not triggered by T-cell receptor-mediated antigen recognition. On the basis of our previous data, we postulated that formation of the viral synapse was triggered by a conjunction of two signals, one from HTLV-1 infection of the T-cell and one from cell-cell contact. We have recently identified ICAM-1 engagement as a cell-contact signal that causes the microtubule polarization associated with the virological synapse. Here we used confocal microscopy of T-lymphocytes naturally infected with HTLV-1 or transfected with individual HTLV-1 genes to investigate the role of the viral transcriptional transactivator protein Tax. Polarization of the microtubules was induced by cell-cell contact or by cross-linking T-cell surface molecules with monoclonal antibodies adsorbed to latex beads. We show that Tax, which is mainly found in the nucleus, is also present at two specific extranuclear sites as follows: around the microtubule organizing center in association with the cis-Golgi and in the cell-cell contact region. We show that expression of Tax provides an intracellular signal that synergizes with ICAM-1 engagement to cause the T-cell microtubule polarization observed at the virological synapse.

  • A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in Human T-Lymphotropic Virus type 1 proviral load.
    The Journal of general virology, 2005
    Co-Authors: Becca Asquith, Yuetsu Tanaka, Graham P. Taylor, Angelina J. Mosley, Anna Barfield, Sara E. Marshall, Adrian Heaps, Peter Goon, Emmanuel Jules Hanon, Charles R. M. Bangham
    Abstract:

    The CD8+ lymphocyte response is a main component of host immunity, yet it is difficult to quantify its contribution to the control of persistent Viruses. Consequently, it remains controversial as to whether CD8+ cells have a biologically significant impact on viral burden and disease progression in infections such as Human immunodeficiency Virus-1 and Human T-Lymphotropic Virus type I (HTLV-I). Experiments to ascertain the impact of CD8+ cells on viral burden based on CD8+ cell frequency or specificity alone give inconsistent results. Here, an alternative approach was developed that directly quantifies the impact of CD8+ lymphocytes on HTLV-I proviral burden by measuring the rate at which HTLV-I-infected CD4+ cells were cleared by autologous CD8+ cells ex vivo. It was demonstrated that CD8+ cells reduced the lifespan of infected CD4+ cells to 1 day, considerably shorter than the 30 day lifespan of uninfected cells in vivo. Furthermore, it was shown that HTLV-I-infected individuals vary considerably in the rate at which their CD8+ cells clear infected cells, and that this was a significant predictor of their HTLV-I proviral load. Forty to 50 % of between-individual variation in HTLV-I proviral load was explained by variation in the rate at which CD8+ cells cleared infected cells. This novel approach demonstrates that CD8+ cells are a major determinant of HTLV-I proviral load. This assay is applicable to quantifying the CD8+ cell response to other Viruses and malignancies and may be of particular importance in assessing vaccines.

Steven Jacobson - One of the best experts on this subject based on the ideXlab platform.

  • Human t lymphotropic Virus type 1 htlv 1 and cellular immune response in htlv 1 associated myelopathy tropical spastic paraparesis
    Journal of NeuroVirology, 2020
    Co-Authors: Satoshi Nozuma, Ryuji Kubota, Steven Jacobson
    Abstract:

    Human T-Lymphotropic Virus type 1 (HTLV-1) is associated with adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is an inflammatory disease of the spinal cord and clinically characterized by progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. The interaction between the host immune response and HTLV-1-infected cells regulates the development of HAM/TSP. HTLV-1 preferentially infects CD4+ T cells and is maintained by proliferation of the infected T cells. HTLV-1-infected cells rarely express viral antigens in vivo; however, they easily express the antigens after short-term culture. Therefore, such Virus-expressing cells may lead to activation and expansion of antigen-specific T cell responses. Infected T cells with HTLV-1 and HTLV-1-specific CD8+ cytotoxic T lymphocytes invade the central nervous system and produce various proinflammatory cytokines and chemokines, leading to neuronal damage and degeneration. Therefore, cellular immune responses to HTLV-1 have been considered to play important roles in disease development of HAM/TSP. Recent studies have clarified the viral strategy for persistence in the host through genetic and epigenetic changes by HTLV-1 and host immune responses including T cell function and differentiation. Newly developed animal models could provide the opportunity to uncover the precise pathogenesis and development of clinically effective treatment. Several molecular target drugs are undergoing clinical trials with promising efficacy. In this review, we summarize recent advances in the immunopathogenesis of HAM/TSP and discuss the perspectives of the research on this disease.

  • neuroimmunology of Human t lymphotropic Virus type 1 associated myelopathy tropical spastic paraparesis
    Frontiers in Microbiology, 2019
    Co-Authors: Satoshi Nozuma, Steven Jacobson
    Abstract:

    Human T-Lymphotropic Virus type 1 (HTLV-1) is the etiologic agent of both adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is clinically characterized by chronic progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. Given its well-characterized clinical presentation and pathophysiology, which is similar to the progressive forms of multiple sclerosis (MS), HAM/TSP is an ideal system to better understand other neuroimmunological disorders such as MS. Since the discovery of HAM/TSP, large numbers of clinical, virological, molecular, and immunological studies have been published. The host-Virus interaction and host immune response play an important role for the development with HAM/TSP. HTLV-1-infected circulating T-cells invade the central nervous system (CNS) and cause an immunopathogenic response against Virus and possibly components of the CNS. Neural damage and subsequent degeneration can cause severe disability in patients with HAM/TSP. Little progress has been made in the discovery of objective biomarkers for grading stages and predicting progression of disease and the development of molecular targeted therapy based on the underlying pathological mechanisms. We review the recent understanding of immunopathological mechanism of HAM/TSP and discuss the unmet need for research on this disease.

  • Neuroimmunology of Human T-Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis
    Frontiers Media S.A., 2019
    Co-Authors: Satoshi Nozuma, Steven Jacobson
    Abstract:

    Human T-Lymphotropic Virus type 1 (HTLV-1) is the etiologic agent of both adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is clinically characterized by chronic progressive spastic paraparesis, urinary incontinence, and mild sensory disturbance. Given its well-characterized clinical presentation and pathophysiology, which is similar to the progressive forms of multiple sclerosis (MS), HAM/TSP is an ideal system to better understand other neuroimmunological disorders such as MS. Since the discovery of HAM/TSP, large numbers of clinical, virological, molecular, and immunological studies have been published. The host-Virus interaction and host immune response play an important role for the development with HAM/TSP. HTLV-1-infected circulating T-cells invade the central nervous system (CNS) and cause an immunopathogenic response against Virus and possibly components of the CNS. Neural damage and subsequent degeneration can cause severe disability in patients with HAM/TSP. Little progress has been made in the discovery of objective biomarkers for grading stages and predicting progression of disease and the development of molecular targeted therapy based on the underlying pathological mechanisms. We review the recent understanding of immunopathological mechanism of HAM/TSP and discuss the unmet need for research on this disease

  • interferon beta1a therapy in Human t lymphotropic Virus type i associated neurologic disease
    Annals of Neurology, 2005
    Co-Authors: Yoshihisa Yamano, Carlos A. Mora, Joan Ohayon, Francesca Bagnato, John A Butman, James M Dambrosia, Thomas Leist, Henry F Mcfarland, Steven Jacobson
    Abstract:

    Human T-Lymphotropic Virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune-mediated inflammatory disorder of the central nervous system. Immune activation in the host, which results from high levels of persistent antigenic stimulation and from transactivation of host immunoregulatory genes by HTLV-I, appears important in the pathogenesis of HAM/TSP. In a single-center, open-label trial, 12 patients with HAM/TSP were treated with doses of interferon-beta1a of up to 60mug twice weekly, based on its antiviral and immunomodulatory effects. Primary end points were immunological and virological measures that are potential biomarkers for HAM/TSP. Interferon-beta1a therapy reduced the HTLV-I tax messenger RNA load and the frequency of potentially pathogenic HTLV-I-specific CD8(+) cells. The HTLV-I proviral DNA load remained unchanged. Spontaneous lymphoproliferation, a marker of T-cell activation in HAM/TSP, also was reduced. Some measures of motor function were improved, and no significant clinical progression occurred during therapy. These results indicate that interferon-beta1a may beneficially affect the immune mechanisms central to the pathogenesis of HAM/TSP.

  • detection of Human t lymphotropic Virus type i htlv i tax rna in the central nervous system of htlv i associated myelopathy tropical spastic paraparesis patients by in situ hybridization
    Annals of Neurology, 1995
    Co-Authors: Tanya Lehky, Shuji Izumo, Cecil H Fox, Scott Koenig, Michael Levin, Nicholas Flerlage, Eiichi Sato, Cedric S Raine, Mitsuhiro Osame, Steven Jacobson
    Abstract:

    Autopsy specimens from 3 patients with Human T-Lymphotropic Virus (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) were examined for the presence of HTLV-I in the central nervous system (CNS). In situ hybridization using an HTLV-I tax RNA probe detected cells containing HTLV-I RNA in spinal cord and cerebellar sections. HTLV-I infected cells were located within the white matter and, in particular, within the anterior and lateral funiculi of the spinal cord. Consistent with previously described HAM/TSP pathology, there were perivascular infiltrates in these CNS specimens. Significantly, HTLV-I RNA was not localized to these infiltrates but was detected deeper within the neural tissue. Furthermore, phenotypic analysis demonstrated that at least some of the infected cells were astrocytes. While previous polymerase chain reaction studies have demonstrated the presence of proviral HTLV-I in CNS specimens, here we provide evidence for the in situ expression of HTLV-I RNA in the CNS of HAM/TSP patients.

Charles R. M. Bangham - One of the best experts on this subject based on the ideXlab platform.

  • Human t lymphotropic Virus type 1c subtype proviral loads chronic lung disease and survival in a prospective cohort of indigenous australians
    PLOS Neglected Tropical Diseases, 2018
    Co-Authors: Lloyd Einsiedel, Antoine Gessain, Charles R. M. Bangham, Jocelyn Turpin, Hai Pham, Kim Wilson, Rebecca Walley, Richard J Woodman
    Abstract:

    Background The Human T-Lymphotropic Virus type 1c subtype (HTLV-1c) is highly endemic to central Australia where the most frequent complication of HTLV-1 infection in Indigenous Australians is bronchiectasis. We carried out a prospective study to quantify the prognosis of HTLV-1c infection and chronic lung disease and the risk of death according to the HTLV-1c proviral load (pVL). Methodology/Principal findings 840 Indigenous adults (discharge diagnosis of bronchiectasis, 154) were recruited to a hospital-based prospective cohort. Baseline HTLV-1c pVL were determined and the results of chest computed tomography and clinical details reviewed. The odds of an association between HTLV-1 infection and bronchiectasis or bronchitis/bronchiolitis were calculated, and the impact of HTLV-1c pVL on the risk of death was measured. Radiologically defined bronchiectasis and bronchitis/bronchiolitis were significantly more common among HTLV-1-infected subjects (adjusted odds ratio = 2.9; 95% CI, 2.0, 4.3). Median HTLV-1c pVL for subjects with airways inflammation was 16-fold higher than that of asymptomatic subjects. There were 151 deaths during 2,140 person-years of follow-up (maximum follow-up 8.13 years). Mortality rates were higher among subjects with HTLV-1c pVL ≥1000 copies per 105 peripheral blood leukocytes (log-rank χ2 (2df) = 6.63, p = 0.036) compared to those with lower HTLV-1c pVL or uninfected subjects. Excess mortality was largely due to bronchiectasis-related deaths (adjusted HR 4.31; 95% CI, 1.78, 10.42 versus uninfected). Conclusion/Significance Higher HTLV-1c pVL was strongly associated with radiologically defined airways inflammation and with death due to complications of bronchiectasis. An increased risk of death due to an HTLV-1 associated inflammatory disease has not been demonstrated previously. Our findings indicate that mortality associated with HTLV-1c infection may be higher than has been previously appreciated. Further prospective studies are needed to determine whether these results can be generalized to other HTLV-1 endemic areas.

  • in vivo expression of Human t lymphotropic Virus type 1 basic leucine zipper protein generates specific cd8 and cd4 t lymphocyte responses that correlate with clinical outcome
    The Journal of Infectious Diseases, 2011
    Co-Authors: Silva Hilburn, Becca Asquith, Charles R. M. Bangham, Aileen G Rowan, Mariaantonietta Demontis, Aidan Macnamara, Graham P. Taylor
    Abstract:

    Background. The roles of the Human T-Lymphotropic Virus type 1 (HTLV-1) basic leucine zipper (HBZ) gene are not clearly understood. We examined CD8+ and CD4+ T cell responses to HBZ and compared these with Tax responses. Method.Interferon (IFN)-γ and interleukin (IL)-2–secreting T cells were detected by enzyme-linked immunosorbent spot (ELISpot) assays of freshly isolated peripheral blood mononuclear cells (PBMCs) stimulated with synthetic HBZ or Tax peptides. Ten patients with HTLV-1–associated myelopathy (HAM) and 20 asymptomatic HTLV-1 carriers (ACs), (10 high, 10 low viral load). Results. Of 30 study participants, 17 had detectable HBZ-specific CD4+ T cells and 12 had HBZ-specific CD8+ T cell responses. Detection of Tax-specific CD4+ T cells (IL-2- or IFN-γ-secreting) did not differ by disease status, but Tax-specific CD8+ T cell responses were more commonly detected in patients with HAM. HBZ-specific CD4+ or CD8+ T cells were less likely to be detected than Tax-specific T cells. IL-2-secreting Tax-specific CD8+ T cells, and IFN-γ–secreting Tax-specific CD4+ T cells were associated with HAM. Low viral load, asymptomatic HTLV-1 carriage was associated with IL-2–secreting CD8+ T cells specific for HBZ. Conclusion. HBZ protein is expressed in vivo in patients with HAM and in ACs. Our results are consistent with the idea that the T cell response to HBZ plays an important part in restricting HTLV-1 viral load.

  • Human t lymphotropic Virus type 1 tax protein triggers microtubule reorientation in the virological synapse
    Journal of Biological Chemistry, 2005
    Co-Authors: Mohamed Nejmeddine, Yuetsu Tanaka, Graham P. Taylor, Amanda L Barnard, Charles R. M. Bangham
    Abstract:

    We showed recently that the Human T-Lymphotropic Virus, type 1 (HTLV-1), spreads directly from cell to cell via a virological synapse. The HTLV-1 virological synapse resembles the immunological synapse; each is a specialized contact between a lymphocyte and another cell that contains organized protein microdomains, and each involves repolarization of the T-cell microtubule cytoskeleton. However, formation of the virological synapse is not triggered by T-cell receptor-mediated antigen recognition. On the basis of our previous data, we postulated that formation of the viral synapse was triggered by a conjunction of two signals, one from HTLV-1 infection of the T-cell and one from cell-cell contact. We have recently identified ICAM-1 engagement as a cell-contact signal that causes the microtubule polarization associated with the virological synapse. Here we used confocal microscopy of T-lymphocytes naturally infected with HTLV-1 or transfected with individual HTLV-1 genes to investigate the role of the viral transcriptional transactivator protein Tax. Polarization of the microtubules was induced by cell-cell contact or by cross-linking T-cell surface molecules with monoclonal antibodies adsorbed to latex beads. We show that Tax, which is mainly found in the nucleus, is also present at two specific extranuclear sites as follows: around the microtubule organizing center in association with the cis-Golgi and in the cell-cell contact region. We show that expression of Tax provides an intracellular signal that synergizes with ICAM-1 engagement to cause the T-cell microtubule polarization observed at the virological synapse.

  • A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in Human T-Lymphotropic Virus type 1 proviral load.
    The Journal of general virology, 2005
    Co-Authors: Becca Asquith, Yuetsu Tanaka, Graham P. Taylor, Angelina J. Mosley, Anna Barfield, Sara E. Marshall, Adrian Heaps, Peter Goon, Emmanuel Jules Hanon, Charles R. M. Bangham
    Abstract:

    The CD8+ lymphocyte response is a main component of host immunity, yet it is difficult to quantify its contribution to the control of persistent Viruses. Consequently, it remains controversial as to whether CD8+ cells have a biologically significant impact on viral burden and disease progression in infections such as Human immunodeficiency Virus-1 and Human T-Lymphotropic Virus type I (HTLV-I). Experiments to ascertain the impact of CD8+ cells on viral burden based on CD8+ cell frequency or specificity alone give inconsistent results. Here, an alternative approach was developed that directly quantifies the impact of CD8+ lymphocytes on HTLV-I proviral burden by measuring the rate at which HTLV-I-infected CD4+ cells were cleared by autologous CD8+ cells ex vivo. It was demonstrated that CD8+ cells reduced the lifespan of infected CD4+ cells to 1 day, considerably shorter than the 30 day lifespan of uninfected cells in vivo. Furthermore, it was shown that HTLV-I-infected individuals vary considerably in the rate at which their CD8+ cells clear infected cells, and that this was a significant predictor of their HTLV-I proviral load. Forty to 50 % of between-individual variation in HTLV-I proviral load was explained by variation in the rate at which CD8+ cells cleared infected cells. This novel approach demonstrates that CD8+ cells are a major determinant of HTLV-I proviral load. This assay is applicable to quantifying the CD8+ cell response to other Viruses and malignancies and may be of particular importance in assessing vaccines.

  • presentation of a new h 2dk restricted epitope in the tax protein of Human t lymphotropic Virus type i is enhanced by the proteasome inhibitor lactacystin
    Journal of General Virology, 2002
    Co-Authors: Mehnaaz Lomas, Yuetsu Tanaka, Charles R. M. Bangham, Emmanuel Hanon, Keith G Gould
    Abstract:

    Tax, the trans-activator of Human T-Lymphotropic Virus type I (HTLV-I), is the dominant target antigen for cytotoxic T lymphocytes (CTLs) in the majority of infected individuals, although the reason for this immunodominance is not clear. Tax has been shown to associate physically with the proteasome, a protease that is responsible for the generation of the majority of major histocompatibility complex (MHC) class I ligands recognized by CTLs. This association could lead to the preferential targeting of Tax to the MHC class I pathway and account for its high immunogenicity. Here, the CTL response to Tax was investigated in mice by priming with a Tax expression vector and boosting with a Tax recombinant vaccinia Virus (modified vaccinia Virus Ankara strain). This approach led to the identification of a new H-2D k -restricted epitope in Tax, amino acid residues 38-46, sequence ARLHRHALL. Surprisingly, presentation of this epitope was found to be enhanced by the proteasome inhibitor lactacystin, although Tax was shown to associate with proteasomes in murine cells. The difficulties encountered in generating Tax-specific CTL responses and the results of enzyme-linked immunospot (ELISpot) analysis suggested that Tax is only poorly immunogenic for CTLs in mice. Therefore, the immunodominance of Tax in Human CTL responses to HTLV-I is probably not due to an intrinsic property of the protein itself, such as an association with the proteasome, but instead may result from the fact that Tax is the predominant protein synthesized early after infection.

Shuji Izumo - One of the best experts on this subject based on the ideXlab platform.

  • inclusion body myositis associated with Human t lymphotropic Virus type i infection eleven patients from an endemic area in japan
    Journal of Neuropathology and Experimental Neurology, 2008
    Co-Authors: Eiji Matsuura, Fujio Umehara, Hirohisa Nose, Itsuro Higuchi, E Matsuoka, Koutarou Izumi, Ryuji Kubota, Mineki Saito, Shuji Izumo, Kimiyoshi Arimura
    Abstract:

    The objective of this study was to investigate the association of Human T-Lymphotropic Virus-type I (HTLV-I) infection with sporadic inclusion body myositis in 11 patients from an endemic area in Japan. The clinical features were consistent with sporadic inclusion body myositis, and anti-HTLV-I antibodies were present in the sera of all patients. Their muscle biopsies showed the diagnostic features of inclusion body myositis, including endomysial T-cell infiltration, rimmed vacuoles, deposits of phosphorylated tau, and abnormal filaments in the nuclei and cytoplasm of the myofibers. The fibers expressed major histocompatibility complex class I antigens and were invaded by CD8 and CD4 cells. In a single Human leukocyte antigen-A2-positive patient, in situ Human leukocyte antigen-A*0201 / Tax11-19-pentamer staining showed pentamer-positive cells surrounding the muscle fibers. Double-immunogold silver staining and polymerase chain reaction in situ hybridization revealed that HTLV-I proviral DNA was localized on helper-inducer T cells, but not on muscle fibers. Human T-Lymphotropic Virus-type I proviral loads in peripheral blood mononuclear cells from each patient were similar to those in HTLV-I-associated myelopathy/tropical spastic paraparesis. This study suggests that HTLV-I infection may be one of the causes of sporadic inclusion body myositis, as has been reported in Human immunodeficiency Virus type-1 infection.

  • usefulness of proviral load measurement for monitoring of disease activity in individual patients with Human t lymphotropic Virus type i associated myelopathy tropical spastic paraparesis
    Journal of NeuroVirology, 2003
    Co-Authors: Norihiro Takenouchi, Koichiro Usuku, Yoshihisa Yamano, Mitsuhiro Osame, Shuji Izumo
    Abstract:

    High Human T-Lymphotropic Virus type I (HTLV-I) proviral load in peripheral blood mononuclear cells (PBMCs) has been reported in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and the proviral load has been reported to fluctuate in individual patients during the course of the disease. Clinical symptoms usually became stable after a prolonged period of symptom progression. However, the authors have experienced having some patients whose clinical manifestations suddenly became worse during the course of the disease. To clarify the role of high proviral load and its fluctuation in the pathogenesis of HAM/TSP, the authors measured the proviral load of serially taken PBMCs as well as of cerebrospinal fluid (CSF) cells from patients with HAM/TSP on long-term follow-up and compared these with their clinical manifestations. There was a wide distribution of proviral load, from 0.3 to 37.8 copies/100 PBMCs; however, the proviral load in individual patients was relatively stable during the course of the disease. Eighty-three percent of the patients with clinical worsening showed an increase in proviral load at the time point when clinical worsening was recorded, or at the preceding time point. The proviral loads in CSF cells were higher than those in PBMCs in individual patients. The ratio of proviral loads in CSF cells/in PBMCs, but not the absolute load, in either compartment, was significantly associated with clinically progressive disease and with recent onset of HAM/TSP. These findings indicate that clinical progression of HAM/TSP is associated with increased proliferation or immigration of HTLV-I-infected lymphocytes in the central nervous system.

  • polygenic control of Human t lymphotropic Virus type i htlv i proVirus load and the risk of htlv i associated myelopathy tropical spastic paraparesis
    The Journal of Infectious Diseases, 2002
    Co-Authors: Alison M Vine, Sara E. Marshall, Aviva Witkover, Shuji Izumo, Alun L Lloyd, Katie Jeffery, Asna Siddiqui, Michael Bunce, Nobutaka Eiraku, Koichiro Usuku
    Abstract:

    Human T lymphotropic Virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of infection with HTLV-I. A population association study of 229 patients with HAM/TSP and 202 healthy carriers of HTLV-I in southern Japan showed that this outcome of HTLV-I infection and the HTLV-I proVirus load are under polygenic control. Of 58 polymorphic sites studied in 39 non-HLA candidate gene loci, 3 new host genetic factors that influenced the risk of HAM/TSP or the proVirus load of HTLV-I were identified. The promoter TNF 863A allele predisposed to HAM/TSP, whereas SDF-1 +801A 3 � UTR, and IL-15 191C alleles conferred protection. Knowledge of HTLV-I–infected individuals’ ages, sex, proVirus load, HTLV-I subgroup, and genotypes at the loci HLA-A, HLA-C, SDF-1, and TNF-a allowed for the correct identification of 88% of cases of HAM/TSP in this Japanese cohort. Human T lymphotropic Virus type I (HTLV-I), a member of the OncoVirus family, is the etiological agent of 2 diverse diseases: the neurological disorder HTLV-I–associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1, 2] and adult T cell leukemia/lymphoma [3]. The outcome of HTLV-I infection depends on both host genetic and viral factors. At best, an individual may exhibit a life-long asymptomatic infection; at worst, either an inflammatory disease or rapidly fatal leukemia may ensue. Here, we provide evidence for the involvement of host genetic and viral subgroup factors [4] in HAM/TSP in a region of southern Japan (Kagoshima) where HTLV-I is endemic, using an association study and appropriate statistical analyses to predict disease outcome and proVirus load. Although different Virus strains (denoted HTLV-I subgroups) can influence the risk of developing HAM/TSP [4], the impact of HTLV-I viral sequence variation in determining the risk of developing HAM/TSP in Kagoshima is limited, and no se

  • marked suppression of t cells by a benzothiophene derivative in patients with Human t lymphotropic Virus type i associated myelopathy tropical spastic paraparesis
    Clinical and Vaccine Immunology, 1999
    Co-Authors: Masahiko Makino, Shuji Izumo, Miyuki Azuma, Shinichi Wakamatsu, Yukio Suruga, Mitchel M Yokoyama, Masanori Baba
    Abstract:

    In a search for new anti-autoimmune agents that selectively suppress activation of autoreactive T cells, one such agent, 5-methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide (CI-959-A), was found to be effective. This compound, which is known to suppress tumor necrosis factor alpha (TNF-α)-induced CD54 expression, inhibited the primary proliferative response of the T cell to antigen (Ag)-presenting cells (APCs) including allogenic dendritic cells (DCs), autologous Epstein-Barr Virus-infected B cells, and Human T lymphotropic Virus type I (HTLV-I)-infected T cells. Autoreactive T cells from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) spontaneously proliferate in vitro, and their activation is reported to be associated with CD54 expression. The spontaneous proliferation of T cells from patients with HAM/TSP was entirely blocked by CI-959-A. However, in this study, the T-cell proliferation in 15 patients with HAM/TSP was found to depend more extensively on major histocompatibility complex (MHC) class II and CD86 than on CD54 Ags. Since most important APCs for the development of HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on DC generation and on the expression of surface molecules on activated T cells is examined. CI-959-A suppressed recombinant granulocyte-macrophage colony stimulating factor (GM-CSF)- and recombinant interleukin-4-dependent differentiation of DCs from monocytes and inhibited the expression of CD54 and, more extensively, MHC class II and CD86 Ags. CI-959-A showed little toxicity toward lymphoma or HTLV-I-infected T-cell lines or toward monocytes and cultured DCs. These results suggest that CI-959-A might be a potent anti-HAM/TSP agent.

  • detection of Human t lymphotropic Virus type i htlv i tax rna in the central nervous system of htlv i associated myelopathy tropical spastic paraparesis patients by in situ hybridization
    Annals of Neurology, 1995
    Co-Authors: Tanya Lehky, Shuji Izumo, Cecil H Fox, Scott Koenig, Michael Levin, Nicholas Flerlage, Eiichi Sato, Cedric S Raine, Mitsuhiro Osame, Steven Jacobson
    Abstract:

    Autopsy specimens from 3 patients with Human T-Lymphotropic Virus (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) were examined for the presence of HTLV-I in the central nervous system (CNS). In situ hybridization using an HTLV-I tax RNA probe detected cells containing HTLV-I RNA in spinal cord and cerebellar sections. HTLV-I infected cells were located within the white matter and, in particular, within the anterior and lateral funiculi of the spinal cord. Consistent with previously described HAM/TSP pathology, there were perivascular infiltrates in these CNS specimens. Significantly, HTLV-I RNA was not localized to these infiltrates but was detected deeper within the neural tissue. Furthermore, phenotypic analysis demonstrated that at least some of the infected cells were astrocytes. While previous polymerase chain reaction studies have demonstrated the presence of proviral HTLV-I in CNS specimens, here we provide evidence for the in situ expression of HTLV-I RNA in the CNS of HAM/TSP patients.

John N. Brady - One of the best experts on this subject based on the ideXlab platform.

  • Human T-Lymphotropic Virus Type 1 Tax Protein Complexes with P-TEFb and Competes for Brd4 and 7SK snRNP/HEXIM1 Binding
    Journal of Virology, 2010
    Co-Authors: Won-kyung Cho, M Jang, Keven Huang, Cynthia A. Pise-masison, John N. Brady
    Abstract:

    Positive transcription elongation factor b (P-TEFb) plays an important role in stimulating RNA polymerase II elongation for viral and cellular gene expression. P-TEFb is found in cells in either an active, low-molecular-weight (LMW) form or an inactive, high-molecular-weight (HMW) form. We report here that Human T-Lymphotropic Virus type 1 (HTLV-1) Tax interacts with the cyclin T1 subunit of P-TEFb, forming a distinct Tax/P-TEFb LMW complex. We demonstrate that Tax can play a role in regulating the amount of HMW complex present in the cell by decreasing the binding of 7SK snRNP/HEXIM1 to P-TEFb. This is seen both in vitro using purified Tax protein and in vivo in cells transduced with Tax expression constructs. Further, we find that a peptide of cyclin T1 spanning the Tax binding domain inhibits the ability of Tax to disrupt HMW P-TEFb complexes. These results suggest that the direct interaction of Tax with cyclin T1 can dissociate P-TEFb from the P-TEFb/7SK snRNP/HEXIM1 complex for activation of the viral long terminal repeat (LTR). We also show that Tax competes with Brd4 for P-TEFb binding. Chromatin immunoprecipitation (ChIP) assays demonstrated that Brd4 and P-TEFb are associated with the basal HTLV-1 LTR, while Tax and P-TEFb are associated with the activated template. Furthermore, the knockdown of Brd4 by small interfering RNA (siRNA) activates the HTLV-1 LTR promoter, which results in an increase in viral expression and production. Our studies have identified Tax as a regulator of P-TEFb that is capable of affecting the balance between its association with the large inactive complex and the small active complex.

  • nrp optineurin cooperates with tax1bp1 to potentiate the activation of nf kappab by Human t lymphotropic Virus type 1 tax protein
    PLOS Pathogens, 2009
    Co-Authors: Chloé Journo, Frédégonde About, Frederic Tangy, Philippe V Afonso, John N. Brady, Alain Israel, Josina Cortereal Filipe, Sebastien Chevalier, David N Flynn, Pierre-olivier Vidalain
    Abstract:

    Nuclear factor (NF)-kappaB is a major survival pathway engaged by the Human T-Lymphotropic Virus type 1 (HTLV-1) Tax protein. Tax1 activation of NF-kappaB occurs predominantly in the cytoplasm, where Tax1 binds NF-kappaB Essential Modulator (NEMO/IKKgamma) and triggers the activation of IkappaB kinases. Several independent studies have shown that Tax1-mediated NF-kappaB activation is dependent on Tax1 ubiquitination. Here, we identify by co-immunoprecipitation assays NEMO-Related Protein (NRP/Optineurin) as a binding partner for Tax1 in HTLV-1 infected and Tax1/NRP co-expressing cells. Immunofluorescence studies reveal that Tax1, NRP and NEMO colocalize in Golgi-associated structures. The interaction between Tax1 and NRP requires the ubiquitin-binding activity of NRP and the ubiquitination sites of Tax1. In addition, we observe that NRP increases the ubiquitination of Tax1 along with Tax1-dependent NF-kappaB signaling. Surprisingly, we find that in addition to Tax1, NRP interacts cooperatively with the Tax1 binding protein TAX1BP1, and that NRP and TAX1BP1 cooperate to modulate Tax1 ubiquitination and NF-kappaB activation. Our data strongly suggest for the first time that NRP is a critical adaptor that regulates the assembly of TAX1BP1 and post-translationally modified forms of Tax1, leading to sustained NF-kappaB activation.

  • modulation of the brd4 p tefb interaction by the Human t lymphotropic Virus type 1 tax protein
    Journal of Virology, 2007
    Co-Authors: Won-kyung Cho, Keven Huang, Meisheng Zhou, Moon Kyoo Jang, Soojin Jeong, Keiko Ozato, John N. Brady
    Abstract:

    Positive transcription elongation factor (P-TEFb), which is composed of CDK9 and cyclin T1, plays an important role in cellular and viral gene expression. Our lab has recently demonstrated that P-TEFb is required for Tax transactivation of the viral long terminal repeat (LTR). P-TEFb is found in two major complexes: the inactive form, which is associated with inhibitory subunits 7SK snRNA and HEXIM1, and the active form, which is associated with, at least in part, Brd4. In this study, we analyzed the effect of Brd4 on Human T-Lymphotropic Virus type 1 (HTLV-1) transcription. Overexpression of Brd4 repressed Tax transactivation of the HTLV-1 LTR in a dose-dependent manner. In vitro binding studies suggest that Tax and Brd4 compete for binding to P-TEFb through direct interaction with cyclin T1. Tax interacts with cyclin T1 amino acids 426 to 533, which overlaps the region responsible for Brd4 binding. In vivo, overexpression of Tax decreased the amount of 7SK snRNA associated with P-TEFb and stimulates serine 2 phosphorylation of the RNA polymerase II carboxyl-terminal domain, suggesting that Tax regulates the functionality of P-TEFb. Our results suggest the possibility that Tax may compete and functionally substitute for Brd4 in P-TEFb regulation.