HTLV-1 & Cellular Factors in Neuroinflammatory Disease

HTLV-1

• 批准号: 9287115
• 负责人: Pooja Jain
• 金额: $ 2.95万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9287115
• 关键词: Accounting; Adult T-Cell Leukemia/Lymphoma; Antigen-Presenting Cells; Automobile Driving; Biochemical; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Line; Cells; Chromatin; Chromatin Remodeling Factor; Clone Cells; Code; Communities; Complex; DNA; DNA-Protein Interaction; Development; Disease; EP300 gene; Etiology; Family; Family member; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genome; HIV-1; Histones; Human T-lymphotropic virus 1; Individual; Investigation; Life Cycle Stages; Link; Long Terminal Repeats; Luc Gene; Mediating; Messenger RNA; MicroRNAs; Molecular; Neuraxis; Neuropathogenesis; Nucleosomes; PCAF gene; Pathogenesis; Pathway interactions; Patients; Pattern; Plasmids; Play; Population; Primary Infection; Protein Biosynthesis; Proteins; Proviruses; Regulation; Reporter; Reporting; Role; Spinal Cord Diseases; Staging; Stem cells; T-Lymphocyte; Target Populations; Taxes; Testing; Therapeutic Intervention; Transcription Repressor/Corepressor; Tropical Spastic Paraparesis; Viral; Viral Genes; Viral Genome; Viral Proteins; Virus; Virus Diseases; Virus Latency; cell type; chromatin remodeling; cohort; comparative; histone acetyltransferase; in vivo; innovation; insight; macrophage; molecular marker; monocyte; nervous system disorder; neuroinflammation; novel; novel therapeutics; prevent; progenitor; promoter; reactivation from latency; research study; response; targeted treatment; tax Gene Products; tool; transcription factor

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.

描述（由申请人提供）：人类T细胞白血病病毒1型（HTLV-1）是成人T细胞白血病（ATL）和神经系统疾病的病因，HTLV-1相关的脊髓病/热带痉挛性痉挛（HAM/TSP）。该病毒优先靶向CD4+ T摄氏度，但还感染其他二级细胞类型，例如CD8+ T细胞，骨髓祖细胞，单核细胞巨噬细胞谱系的细胞和常驻CNS细胞群体。我们和其他人的先前研究表明，病毒诱导的这些细胞室的改变在进行性神经系统疾病的起源中起着重要作用。然而，关于这些细胞中HTLV-1启动子（长时间重复或LTR）调节的分子机制的信息很少。此外，几乎所有研究强调了细胞转录因子在HTLV-1税介导的LTR激活中的重要性以及使用瞬时转染的病毒报告质粒或不代表HTLV-1 In Vivo的主要靶标的细胞系中独立进行了与这些因素相互作用的能力。用HIV-1进行的研究表明，综合的病毒综合的身体和对某些细胞因子的要求，尤其是属于染色质重塑组蛋白乙酰基转移酶（HAT）家族的病毒质粒。因此，为了更好地理解HTLV-1基因调控和与综合病毒的复杂相互作用，我们先前表征了许多CD4+ T-Cell（Jurkat），单核细胞（U-937）和祖细胞（U-937）和祖细胞（TF-1）携带的携带HTLV-1 LTRV-1 LTR驾驶Lucififififififififerase Cermentase contisting副本的稳定克隆。使用这些克隆的初步研究强调了税收蛋白与宿主的微洋纳斯之间的新型相互作用，涉及调节染色质重塑，从而导致了拟议的研究。我们的结果与一个新的假设一致，即税收可以以细胞类型的特异性方式调节细胞miRNA机械，涉及由HTLV-1 LTR控制的染色质重塑的病毒基因表达。具体目的是验证这一概念并检验我们的假设是（1）在病毒疾病过程中染色质和次要靶细胞种群中征税中介导的DNA-蛋白相互作用的机制，（2）定义HTLV-1税收调节的宿主miRNA表达与二级细胞群中和二级细胞群中的构成量相结合的hots miRNA（3）患者队列中HTLV-1疾病中的税收 - 肉芽素 - 染色质相互作用。提出的研究可能回答与HTLV-1发病机理有关的基本关键问题的潜力，并将提供新的见解，说明为什么在含有HTLV-1前病毒序列的受感染个体中的许多CD4+ T细胞不表达病毒蛋白。此外，这些研究将提供与T细胞中与HTLV-1基因调节相关的分子机制与骨髓祖细胞和单核细胞巨噬细胞谱系的细胞相关的，这些细胞是关键的细胞成分参与后病毒神经性神经病。

项目成果

Murine FLT3 ligand-derived dendritic cell-mediated early immune responses are critical to controlling cell-free human T cell leukemia virus type 1 infection.

鼠FLT3配体衍生的树突状细胞介导的早期免疫反应对于控制无细胞人T细胞白血病病毒1型感染至关重要。

• DOI: 10.4049/jimmunol.1002570
• 发表时间: 2011
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Rahman,Saifur;Khan,ZafarK;Wigdahl,Brian;Jennings,StephenR;Tangy,Frederic;Jain,Pooja
• 通讯作者: Jain,Pooja

Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions.

• DOI: 10.1007/s11481-015-9617-x
• 发表时间: 2016-03
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Ginwala R;McTish E;Raman C;Singh N;Nagarkatti M;Nagarkatti P;Sagar D;Jain P;Khan ZK
• 通讯作者: Khan ZK

Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation.

• DOI: 10.1186/1742-2094-9-245
• 发表时间: 2012-10-26
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Sagar D;Lamontagne A;Foss CA;Khan ZK;Pomper MG;Jain P
• 通讯作者: Jain P

Identification of human T-cell lymphotropic virus type I 21-base-pair repeat-specific and glial cell-specific DNA-protein complexes.

人 T 细胞嗜淋巴细胞病毒 I 型 21 碱基对重复序列特异性和神经胶质细胞特异性 DNA 蛋白复合物的鉴定。

• DOI: 10.1128/jvi.68.7.4597-4608.1994
• 发表时间: 1994
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Tillmann,M;Wessner,R;Wigdahl,B
• 通讯作者: Wigdahl,B

Regulation of human T-cell leukemia virus type 1 gene expression by Sp1 and Sp3 interaction with TRE-1 repeat III.

Sp1 和 Sp3 与 TRE-1 重复序列相互作用调节人 T 细胞白血病病毒 1 型基因表达 III。

• DOI: 10.1089/dna.2006.25.262
• 发表时间: 2006
• 期刊: DNA and cell biology.
• 作者: Yao,Jing;Grant,Christian;Harhaj,Edward;Nonnemacher,Michael;Alefantis,Timothy;Martin,Joel;Jain,Pooja;Wigdahl,Brian
• 通讯作者: Wigdahl,Brian