ETIOLOGY OF AIDS-RELATED EBV-ASSOCIATED T CELL LYMPHOMA

艾滋病相关 EBV 相关 T 细胞淋巴瘤的病因学

• 批准号: 2649286
• 负责人: EARL E HENDERSON
• 金额: $ 10万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-15 至 1999-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2649286
• 关键词: AIDS related neoplasm /cancer; Epstein Barr virus; T lymphocyte; cell line; disease /disorder etiology; human immunodeficiency virus 1; human tissue; nonHodgkin's lymphoma; transcription factor; virus replication

Improved survival of patients with acquired immunodeficiency syndrome (AIDS), due to combinational antiretroviral therapy and prophylaxis for opportunistic infections, is paralleled by an increasing number of AIDS- non-Hodgkin's lymphomas (AIDS-NHLs). Among AIDS-NHLs, Epstein-Barr virus (EBV)-associated T cell non-Hodgkin's lymphomas (T-NHLs) are recognized as a new distinct clinicopathological entity. EBV-associated T-NHL develop primarily in patients with AIDS. In contrast to EBV-associated B-NHL, little is known about the etiology, biology or therapy of EBV-associated T-NHL. We had previously demonstrated the ability of EBV to infect primary CD4+ and CD8+ T cells, and identified a partial EBV transcriptional program in T cells that included immediate-early transcriptional transactivators BZLF1 and BRLF1. More recently we have observed long-term proliferation of EBV-infected CD4+ lymphocytes leading to CD4+ T lymphoblastoid cell lines (LCLs) carrying latent EBV and encoding latent mRNA transcripts. In addition, we have engineered T cell lines that express B cell-derived CR2 (EBV receptor) that can be infected by EBV at a high efficiency. Using these three models, EBV infection of primary T cells, EBV-carrying T LCLs and CR2-expressing T cell lines, we propose to analyze EBV infection of T cells at the cellular and molecular level. Specifically we propose to study the fate of EBV virion DNA, viral transcriptional program and the effects of EBV - infection on T cell physiology, including cytokine profiles, NF-kappaB activation and ability to support HIV-1 replication. The proposed system of reproducing persistent EBV infection in T cells leading to EBV-carrying LCLs should be a good model for investigating the pathogenic role of EBV in T cell lymphomas and possible role in disease progression. The proposed studies will shed light on events that occur between EBV infection of T cells and the development of T cell lymphoma. Specifically, identification of the EBV transcriptional program in primary T cells and EBV-carrying T LCLs should lead to better understanding and treatment strategies for EBV- associated T-NHL, which is presently associated with poor prognosis.

获得性免疫缺陷综合征患者的生存率提高 （艾滋病），由于抗逆转录病毒疗法和预防 机会性感染与越来越多的艾滋病相似 非霍奇金的淋巴瘤（AIDS-NHLS）。在AIDS-NHLS中，Epstein-Barr病毒 （EBV）相关的T细胞非霍奇金的淋巴瘤（T-NHLS）被认为是 一个新的不同的临床病理实体。 EBV相关的T-NHL发展 主要是艾滋病患者。与与EBV相关的B-NHL相反， 关于EBV相关的病因，生物学或治疗知之甚少 T-NHL。我们以前已经证明了EBV感染主要的能力 CD4+和CD8+ T细胞，并确定了部分EBV转录 T细胞中的程序，包括即时的转录 反式激活器BZLF1和BRLF1。最近我们观察到了长期 EBV感染的CD4+淋巴细胞的增殖导致CD4+ T 载有潜在EBV并编码潜在的淋巴母细胞系（LCLS） mRNA转录本。此外，我们还设计了T细胞系 可以通过EBV感染的表达B细胞衍生的CR2（EBV受体） 高效率。使用这三个模型，EBV感染主要t 细胞，EBV携带T LCLS和表达CR2的T细胞系，我们建议 分析T细胞在细胞和分子水平上的EBV感染。 具体而言，我们建议研究EBV病毒DNA，病毒的命运 转录程序和EBV感染对T细胞的影响 生理学，包括细胞因子谱，NF-kappab激活和能力 支持HIV-1复制。提出的繁殖系统 T细胞中持续的EBV感染导致EBV携带LCL的持续感染应为 研究EBV在T细胞中的致病作用的好模型 淋巴瘤和在疾病进展中的可能作用。提出的研究 会阐明T细胞EBV感染之间发生的事件 T细胞淋巴瘤的发展。具体而言，识别 原代T细胞和EBV携带T LCLS中的EBV转录程序 应该为EBV提供更好的理解和治疗策略 相关的T-NHL，目前与预后不良有关。