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.

Public Health Relevance

The proposed investigations will provide novel information concerning the molecular pathogenesis of human T- cell leukemia virus type 1 (HTLV-1)-associated diseases. Additional information derived from these studies will facilitate the biomedical translational development of novel therapeutic initiatives to prevent and/or treat HTLV- 1-induced neuroinflammatory disease as well as neuroinflammatory diseases of other etiologies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA054559-19
Application #
8458525
Study Section
Special Emphasis Panel (ZRG1-AARR-E (03))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1991-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
19
Fiscal Year
2013
Total Cost
$282,037
Indirect Cost
$99,489
Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Jaworski, Elizabeth; Narayanan, Aarthi; Van Duyne, Rachel et al. (2014) Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein. J Biol Chem 289:22284-305
Sagar, Divya; Masih, Shet; Schell, Todd et al. (2014) In vivo immunogenicity of Tax(11-19) epitope in HLA-A2/DTR transgenic mice: implication for dendritic cell-based anti-HTLV-1 vaccine. Vaccine 32:3274-84
Manuel, Sharron L; Sehgal, Mohit; Connolly, John et al. (2013) 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. J Clin Immunol 33:1223-39
Shirazi, Jasmine; Shah, Sonia; Sagar, Divya et al. (2013) Epigenetics, drugs of abuse, and the retroviral promoter. J Neuroimmune Pharmacol 8:1181-96
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Rahman, Saifur; Manuel, Sharron L; Khan, Zafar K et al. (2010) 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. J Immunol 184:5553-61
Lepoutre, Veronique; Jain, Pooja; Quann, Kevin et al. (2009) Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease. Front Biosci 14:1152-68
Jain, Pooja; Manuel, Sharron L; Khan, Zafar K et al. (2009) DC-SIGN mediates cell-free infection and transmission of human T-cell lymphotropic virus type 1 by dendritic cells. J Virol 83:10908-21
Pavlovic, Jelena; Floros, Joanna; Phelps, David S et al. (2008) Differentiation of xenografted human fetal lung parenchyma. Early Hum Dev 84:181-93

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