HTLV-1 &Cellular Factors in Neuroinflammatory Disease

Summary

Principal Investigator: Brian Wigdahl
Abstract: DESCRIPTION (provided by applicant): Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL) and the neurological disorder, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus preferentially targets CD4+ T cels, but also infects other secondary cell types such as CD8+ T cells, bone marrow progenitor cells, cells of the monocyte-macrophage lineage, and resident CNS cell populations. Previous studies from us and others have suggested that virus-induced alterations in these cell compartments play important roles in the genesis of the progressive neurological disorder HAM/TSP. However, little information exists concerning the molecular mechanisms of HTLV-1 promoter (long terminal repeat or LTR) regulation in these cells. Moreover, nearly all studies highlighting the importance of the cellular transcription factors in HTLV-1 Tax-mediated LTR activation and the ability of Tax protein to interact with these factors independently have been performed using transiently transfected viral reporter plasmids or in cell lines that do not represent the primary target for HTLV-1 in vivo. Studies performed with HIV-1 have indicated that the integrated provirus differs from a transfected viral plasmid both physically and in the requirement for certain cellular factors, especially those belonging to the chromatin remodeling histone acetyltransferase (HAT) family. Hence, to better understand HTLV-1 gene regulation and the complex interplay with the integrated provirus, we previously characterized a number of stable clones of CD4+ T-cell (Jurkat), monocyte (U-937), and progenitor (TF-1) cell lines carrying integrated copies of the HTLV-1 LTR driving luciferase gene expression. Preliminary investigations using these clones have highlighted novel interactions between the Tax protein and host microRNAs involved in regulating chromatin remodeling leading to the proposed studies. Our results are consistent with a novel hypothesis that Tax can modulate the cellular miRNA machinery in a cell-type specific manner involving chromatin remodeling effecting viral gene expression controled by the HTLV-1 LTR. The Specific Aims to validate this concept and to test our hypothesis are to (1) Investigate the mechanism of Tax- mediated DNA-protein interactions in the context of chromatin in primary and secondary target cell populations during the course of viral disease, (2) Define HTLV-1 Tax-modulated host miRNA expression linked to chromatin remodeling in primary and secondary cell populations targeted by HTLV-1, and (3) Validate role of Tax-miRNA-chromatin interactions in HTLV-1 disease in patient cohort(s). The proposed studies ofer the potential to answer basic key questions related to HTLV-1 pathogenesis and will provide novel insight into why many CD4+ T cells in infected individuals containing HTLV-1 proviral sequences do not express viral proteins. In addition, these studies will provide a comparative account of molecular mechanism(s) related to HTLV-1 gene regulation in T cells versus bone marrow progenitor cells and cells of the monocyte-macrophage lineage, which are critical cellular components involved in retroviral neuropathogenesis.
Funding Period: 1991-04-01 - 2017-03-31
more information: NIH RePORT

Top Publications

  1. ncbi CCAAT/enhancer-binding proteins modulate human T cell leukemia virus type 1 long terminal repeat activation
    Christian Grant
    Department of Microbiology and Immunology, The Pennsylvania State University, College of Medicine, Hershey, 17033, USA
    Virology 348:354-69. 2006
  2. pmc DC-SIGN mediates cell-free infection and transmission of human T-cell lymphotropic virus type 1 by dendritic cells
    Pooja Jain
    Department of Microbiology and Immunology, Institute of Molecular Medicine and Infectious Disease, Drexel University College of Medicine, New College Building, Rm 18311, 245 N 15th St, Philadelphia, PA 19102, USA
    J Virol 83:10908-21. 2009
  3. pmc Depletion of dendritic cells enhances susceptibility to cell-free infection of human T cell leukemia virus type 1 in CD11c-diphtheria toxin receptor transgenic mice
    Saifur Rahman
    Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, PA 19127, USA
    J Immunol 184:5553-61. 2010
  4. pmc Murine FLT3 ligand-derived dendritic cell-mediated early immune responses are critical to controlling cell-free human T cell leukemia virus type 1 infection
    Saifur Rahman
    Drexel Institute for Biotechnology and Virology Research, Doylestown, PA 18902, USA
    J Immunol 186:390-402. 2011
  5. pmc Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation
    Divya Sagar
    Drexel Institute for Biotechnology and Virology Research and Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
    J Neuroinflammation 9:245. 2012
  6. pmc Cotranscriptional Chromatin Remodeling by Small RNA Species: An HTLV-1 Perspective
    Nishat Aliya
    Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA
    Leuk Res Treatment 2012:984754. 2012
  7. pmc An altered maturation and adhesion phenotype of dendritic cells in diseased individuals compared to asymptomatic carriers of human T cell leukemia virus type 1
    Sharron L Manuel
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
    AIDS Res Hum Retroviruses 29:1273-85. 2013
  8. pmc Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1
    Sharron L Manuel
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, 19104, USA
    J Clin Immunol 33:1223-39. 2013
  9. pmc Epigenetics, drugs of abuse, and the retroviral promoter
    Jasmine Shirazi
    Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA, 18902, USA
    J Neuroimmune Pharmacol 8:1181-96. 2013
  10. pmc Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease
    Veronique Lepoutre
    Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA
    Front Biosci (Landmark Ed) 14:1152-68. 2009

Research Grants

  1. Define the role of dendritic cells in HTLV-1 associated neuroinflammatory disease
    Pooja Jain; Fiscal Year: 2013
  2. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
  3. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
  4. TRANSCRIPTIONAL REGULATION BY GEMININ
    Kristen L Kroll; Fiscal Year: 2013
  5. LANA and Cellular Gene Expression
    ROLF F RENNE; Fiscal Year: 2013

Detail Information

Publications21

  1. ncbi CCAAT/enhancer-binding proteins modulate human T cell leukemia virus type 1 long terminal repeat activation
    Christian Grant
    Department of Microbiology and Immunology, The Pennsylvania State University, College of Medicine, Hershey, 17033, USA
    Virology 348:354-69. 2006
    ..Inhibition of Tax-mediated transactivation of the HTLV-1 LTR was co-activator-independent, did not require C/EBP binding to the Tax-responsive elements, and may involve heterodimerization with CREB factors...
  2. pmc DC-SIGN mediates cell-free infection and transmission of human T-cell lymphotropic virus type 1 by dendritic cells
    Pooja Jain
    Department of Microbiology and Immunology, Institute of Molecular Medicine and Infectious Disease, Drexel University College of Medicine, New College Building, Rm 18311, 245 N 15th St, Philadelphia, PA 19102, USA
    J Virol 83:10908-21. 2009
    ....
  3. pmc Depletion of dendritic cells enhances susceptibility to cell-free infection of human T cell leukemia virus type 1 in CD11c-diphtheria toxin receptor transgenic mice
    Saifur Rahman
    Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, PA 19127, USA
    J Immunol 184:5553-61. 2010
    ....
  4. pmc Murine FLT3 ligand-derived dendritic cell-mediated early immune responses are critical to controlling cell-free human T cell leukemia virus type 1 infection
    Saifur Rahman
    Drexel Institute for Biotechnology and Virology Research, Doylestown, PA 18902, USA
    J Immunol 186:390-402. 2011
    ..Overall, these results highlight the critical early responses generated by FL-DCs on challenge with cell-free chimeric HTLV-1...
  5. pmc Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation
    Divya Sagar
    Drexel Institute for Biotechnology and Virology Research and Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
    J Neuroinflammation 9:245. 2012
    ..Chemokine ligand 2 (CCL2) is a potent chemoattractant known to be secreted by the BBB but has not been implicated in the recruitment of DCs specifically at the BBB...
  6. pmc Cotranscriptional Chromatin Remodeling by Small RNA Species: An HTLV-1 Perspective
    Nishat Aliya
    Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA
    Leuk Res Treatment 2012:984754. 2012
    ..Herein we explore the possible interplay between HTLV-1 infection and miRNA pathways resulting in chromatin reorganization as one of the mechanisms determining HTLV-1 cell specificity and viral fate in different cell types...
  7. pmc An altered maturation and adhesion phenotype of dendritic cells in diseased individuals compared to asymptomatic carriers of human T cell leukemia virus type 1
    Sharron L Manuel
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
    AIDS Res Hum Retroviruses 29:1273-85. 2013
    ....
  8. pmc Lack of recall response to Tax in ATL and HAM/TSP patients but not in asymptomatic carriers of human T-cell leukemia virus type 1
    Sharron L Manuel
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, 19104, USA
    J Clin Immunol 33:1223-39. 2013
    ....
  9. pmc Epigenetics, drugs of abuse, and the retroviral promoter
    Jasmine Shirazi
    Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA, 18902, USA
    J Neuroimmune Pharmacol 8:1181-96. 2013
    ....
  10. pmc Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease
    Veronique Lepoutre
    Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA
    Front Biosci (Landmark Ed) 14:1152-68. 2009
    ..This comprehensive review characterizes the available knowledge to date concerning the effects of HTLV-1 on CNS resident cell populations with emphasis on both viral and host factors contributing to the genesis of HAM/TSP...
  11. ncbi Identification of human T cell leukemia virus type 1 tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein
    Pooja Jain
    Department of Microbiology and Immunology, Center for Molecular Virology and Neuroimmunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
    J Biol Chem 282:34581-93. 2007
    ....
  12. pmc Differentiation of xenografted human fetal lung parenchyma
    Jelena Pavlovic
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Early Hum Dev 84:181-93. 2008
    ..This model in which xenografted lung tissue in different stages of development is available may facilitate the study of human fetal lung development and the impact of various pharmacological agents on this process...
  13. ncbi Use of human antigen presenting cell gene array profiling to examine the effect of human T-cell leukemia virus type 1 Tax on primary human dendritic cells
    Jaya Ahuja
    Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Center for Molecular Virology and Neuroimmunology, Center for Cancer Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    J Neurovirol 12:47-59. 2006
    ..These results have suggested that Tax-mediated DC gene regulation might play a critical role in cellular activation and the mechanisms resulting in HTLV-1-induced disease...
  14. ncbi Regulation of human T-cell leukemia virus type 1 gene expression by Sp1 and Sp3 interaction with TRE-1 repeat III
    Jing Yao
    Department of Microbiology and Immunology, College of Medicine, The Pennsylvania State University, Hershey, Pennsylvania, USA
    DNA Cell Biol 25:262-76. 2006
    ..These results suggest that both Sp1 and Sp3 transcription factor binding to TRE-1 repeat III participate in regulation of HTLV-1 viral gene expression...
  15. ncbi AP-1-directed human T cell leukemia virus type 1 viral gene expression during monocytic differentiation
    Christian Grant
    Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
    J Leukoc Biol 80:640-50. 2006
    ..These results have suggested that following infection of peripheral blood monocytes, HTLV-1 viral gene expression may become up-regulated by AP-1 during differentiation into macrophages or dendritic cells...
  16. pmc A novel high throughput quantum dot-based fluorescence assay for quantitation of virus binding and attachment
    Karan Kampani
    Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Center for Molecular Virology and Neuroimmunology, Center for Cancer Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    J Virol Methods 141:125-32. 2007
    ....
  17. pmc Induction of pro-inflammatory cytokines by human T-cell leukemia virus type-1 Tax protein as determined by multiplexed cytokine protein array analyses of human dendritic cells
    Jaya Ahuja
    Department of Microbiology and Immunology, Center for Cancer Biology, Institute of Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    Biomed Pharmacother 61:201-8. 2007
    ..Collectively, these findings suggest a role for Tax-induced cytokine secretion from MDDCs, which may be critical for the cellular activation and tissue damage that has been observed in HAM/TSP...
  18. pmc Interaction of HTLV-1 Tax protein with calreticulin: implications for Tax nuclear export and secretion
    Timothy Alefantis
    Vital Probes, Inc, 1300 Old Plank Road, Mayfield, PA 18433, USA
    Biomed Pharmacother 61:194-200. 2007
    ..Finally, a comparison of a number of HTLV-1-infected T cell lines to non-infected T cells revealed higher expression of calreticulin in infected cells implicating a direct role for this protein in HTLV-1 infection...
  19. pmc Modulation of dendritic cell maturation and function by the Tax protein of human T cell leukemia virus type 1
    Pooja Jain
    Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
    J Leukoc Biol 82:44-56. 2007
    ....
  20. ncbi Dendritic cells in autoimmune diseases and neuroinflammatory disorders
    Sharron L Manuel
    Department of Microbiology and Immunology, Center for Cancer Biology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA
    Front Biosci 12:4315-35. 2007
    ..Overall, the goal of this review is to establish DCs in the interface of tolerance and autoimmunity and generate a global interest in this field in order to exploit DC potential for the therapy of inflammatory diseases...
  21. pmc In vivo immunogenicity of Tax(11-19) epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine
    Divya Sagar
    Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, PA, USA
    Vaccine 32:3274-84. 2014
    ..Thus, Tax(11-19) epitope is a potential candidate for the DC-based anti-HTLV-1 vaccine and the newly hybrid mouse strain could be used for investigating DC involvement in human class-I-restricted immune responses. ..

Research Grants30

  1. Define the role of dendritic cells in HTLV-1 associated neuroinflammatory disease
    Pooja Jain; Fiscal Year: 2013
    ..Additionally the results of these studies will shed light on the dynamics of immune cell interactions during chronic viral infections such as HTLV-1, HIV-1, hepatitis virus and herpes simplex virus. ..
  2. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
    ..An Education and Outreach component trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. ..
  3. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
    ..The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight. ..
  4. TRANSCRIPTIONAL REGULATION BY GEMININ
    Kristen L Kroll; Fiscal Year: 2013
    ..They will inform our understanding of birth defects and provide an essential foundation for manipulating these regulatory networks to control neural cell specification in many biological contexts. ..
  5. LANA and Cellular Gene Expression
    ROLF F RENNE; Fiscal Year: 2013
    ..More specifically, we study how LANA supports the replication of the viral genome and how it helps to recruit the above mentioned factors. ..