Regulation of HTLV-I replication by the viral p30

病毒 p30 对 HTLV-I 复制的调节

• 批准号: 7590321
• 负责人: CHRISTOPHE P NICOT
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-08 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590321
• 关键词: Adult; Antigenic Variation; Binding; Biochemical; Biological Assay; Cell Nucleus; Cell division; Cells; Center Core Grants; Characteristics; Collaborations; Control Animal; Coupled; DNA; Data; Diagnosis; Disadvantaged; EP300 gene; Genetic Transcription; Goals; HIV; Hematological Disease; Human; Human T-lymphotropic virus 1; Immune; Immune response; In Vitro; Infection; Kinetics; Life; Lymphoid Tissue; Mediating; Messenger RNA; Modeling; Molecular; Molecular Cloning; Monitor; Mutagenesis; Mutate; Mutation; Neurologic; Nuclear; Patients; Post-Transcriptional Regulation; Proviruses; RNA; RNA Binding; RNA Sequences; RNA Splicing; Regulation; Relative (related person); Reporter; Reporting; Research Personnel; Saimiri; Spinal Cord Diseases; T-Cell Leukemia; T-Lymphocyte; Taxes; Tertiary Protein Structure; Time; Tissue Sample; Tissues; Tropical Spastic Paraparesis; Viral; Viral Proteins; Virus; Virus Replication; base; cell type; cellular imaging; gene repression; in vivo; leukemia/lymphoma; mutant; nervous system disorder; novel; prevent; programs; protein expression; ranpirnase; research study; response; viral RNA

DESCRIPTION (provided by applicant): The human T-cell lymphotropic virus type 1 (HTLV-I) is epidemiologically associated with an aggressive and fatal T-cell type leukemia/ lymphoma designated Adult T-cell Leukemia/ Lymphoma (ATLL). HTLV-I infection is also associated with a progressive myelopathy designated Tropical Spastic Paraparesis/ HTLV-I Associated Myelopathy (TSP/HAM). It is estimated that 20 to 30 million people worldwide are infected with HTLV-I. HTLV-I possesses unusual features that would not predict its survival in an immune-competent host: The virus is poorly infectious but elicits a vigorous humoral and cellular host immune response. In addition, HTLV-I is mainly replicated in vivo through division of infected cells and therefore presents a very low antigenic variability. However, in spite of these apparent disadvantages the virus has persisted in humans for more than 100,000 years, indicating that HTLV-I has efficiently adapted to its host. We have recently found that HTLV-I has evolved a protein, p30, that interacts specifically with the tax/rex viral RNA encoding positive regulators of virus expression. Because p30 is unable to shuttle out of the nucleus, tax/rex RNA is trapped in the nucleus and expression of these proteins is inhibited. The goals of this study are to uncover the molecular mechanisms involved in p30-viral RNA interactions and p30 effects on transcription leading to inhibition of virus replication and latency. Four specific aims are proposed. Aim 1) Investigate biochemical characteristics of p30-RNA interactions. Define the minimal p30-response RNA sequence within HTLV-I provirus and identify the domain(s) of the p30 protein involved in these interactions. Aim 2) Analyze transcriptional and post transcriptional effects of p30 on HTLV-I replication in vivo and in vitro. Specific mutants unable to interact with transcriptional regulator CBP/p300 or with viral RNA will be generated in order to discriminate each activity of p30. Aim 3) Investigate molecular determinants for the nuclear/nucleolar retention of p30 and the effects of p30 on Rex-RNA binding activity or Rex functions and vice versa. Aim 4) Study the kinetics of p30 and tax/rex RNA expression in relation to virus expression in vitro using molecular clones mutated for p30. Kinetics of viral RNA expression will be studied in vivo in different lymphoid tissues collected longitudinally from an infected squirrel monkey model and in asymptomatic or HTLV-I-infected patients with neurological or hematological disorders.

描述（由申请人提供）：人类 T 细胞嗜淋巴细胞病毒 1 型（HTLV-I）在流行病学上与一种侵袭性和致命性 T 细胞型白血病/淋巴瘤（称为成人 T 细胞白血病/淋巴瘤（ATLL））相关。 HTLV-I 感染还与称为热带痉挛性截瘫/HTLV-I 相关脊髓病 (TSP/HAM) 的进行性脊髓病相关。 据估计，全世界有 20 至 3000 万人感染 HTLV-I。 HTLV-I 具有不寻常的特征，无法预测其在具有免疫能力的宿主中的存活：该病毒传染性较差，但会引发强烈的体液和细胞宿主免疫反应。 此外，HTLV-I主要通过受感染细胞的分裂在体内复制，因此呈现出非常低的抗原变异性。 然而，尽管存在这些明显的缺点，该病毒仍然在人类体内持续存在了 10 万年以上，这表明 HTLV-I 已经有效地适应了其宿主。 我们最近发现HTLV-I进化出了一种蛋白质p30，它与编码病毒表达正调节因子的tax/rex病毒RNA特异性相互作用。 由于 p30 无法穿梭出细胞核，tax/rex RNA 被困在细胞核中，这些蛋白质的表达受到抑制。 本研究的目的是揭示 p30-病毒 RNA 相互作用的分子机制以及 p30 对转录的影响，从而抑制病毒复制和潜伏期。 提出了四个具体目标。目标 1) 研究 p30-RNA 相互作用的生化特征。 定义 HTLV-I 原病毒内的最小 p30 反应 RNA 序列，并识别参与这些相互作用的 p30 蛋白的结构域。 目标 2) 分析 p30 对 HTLV-I 体内和体外复制的转录和转录后影响。 将产生无法与转录调节因子 CBP/p300 或病毒 RNA 相互作用的特定突变体，以区分 p30 的每种活性。 目标 3) 研究 p30 核/核仁保留的分子决定因素以及 p30 对 Rex-RNA 结合活性或 Rex 功能的影响，反之亦然。 目标 4) 使用 p30 突变的分子克隆研究 p30 和tax/rex RNA 表达与体外病毒表达相关的动力学。 将在从受感染的松鼠猴模型纵向收集的不同淋巴组织以及无症状或患有神经或血液疾病的HTLV-I感染患者体内研究病毒RNA表达的动力学。

项目成果

HTLV-1 Yin and Yang: Rex and p30 master regulators of viral mRNA trafficking.

HTLV-1 阴阳：Rex 和 p30 主要调节病毒 mRNA 运输。

• 发表时间: 2008
• 期刊: AIDS reviews
• 影响因子: 2.2
• 作者: Baydoun,HichamH;Bellon,Marcia;Nicot,Christophe
• 通讯作者: Nicot,Christophe

HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin E-CDK2 interactions and delays cell cycle progression.

• DOI: 10.1186/1476-4598-9-302
• 发表时间: 2010-11-23
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Baydoun HH;Pancewicz J;Bai X;Nicot C
• 通讯作者: Nicot C

Human T-cell lymphotrophic virus type I rex and p30 interactions govern the switch between virus latency and replication.

人类 T 细胞淋巴病毒 I 型 rex 和 p30 相互作用控制病毒潜伏期和复制之间的转换。

• DOI: 10.1074/jbc.m611219200
• 发表时间: 2007
• 期刊: The Journal of biological chemistry
• 作者: Sinha-Datta,Uma;Datta,Abhik;Ghorbel,Sofiane;Dodon,MadeleineDuc;Nicot,Christophe
• 通讯作者: Nicot,Christophe