Pathogenesis of Epstein-Barr Virus Infection

EB 病毒感染的发病机制

• 批准号: 7614988
• 负责人: Frederick C. Wang
• 金额: $ 41.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614988
• 关键词: Address; Alanine; Animal Model; Attenuated; Biological Models; Blood; Cells; Cytotoxic T-Lymphocytes; Defect; EBNA-1 immune evasion; EBV-associated disease; EBV-associated malignancy; EBV-encoded nuclear antigen 1; Epstein-Barr Virus Infections; Epstein-Barr pathogenesis; Genes; Glycine; Goals; Human Herpesvirus 4; Immune; Immune response; Immunosuppression; Individual; Infection; Laboratories; Lymphocryptovirus; Macaca mulatta; Mediating; Peptides; Phase; Process; Research; System; T-Lymphocyte; Testing; Therapeutic; Viral Genes; Viral Proteins; Virus; immune clearance; infected B cell; killings; latent gene expression; mutant; persistent EBV infection; prevent; promoter; therapy development; tool; virus episome maintenance

DESCRIPTION (provided by the applicant): The overall goal of our research is to better understand the pathogenesis of Epstein-Barr virus (EBV) infection in order to develop therapies that can reduce, control, or prevent EBV-associated diseases. EBNA-1 is an EBV protein important for the maintenance of the virus episome. EBNA-1 is expressed in all phases of EBV infection, is one of only a few viral genes expressed by infected B cells circulating in the blood of persistently infected hosts, and is the gene most consistently expressed in EBV associated malignancies. EBNA-1 specific cytotoxic T cells are present in persistently EBV infected individuals, but these T cells are unable to effectively kill EBV infected cells due in part to an inhibitory effect of the EBNA-1 glycine-alanine repeat (GAR) domain that prevents appropriate processing and presentation of EBNA-1 peptides to T cells. This application focuses on the importance of EBNA-1 for persistent EBV infection, the importance of EBNA-1 immune evasion for persistent infection, and the possibility of manipulating the EBNA-1 immune response as a therapeutic tool against EBV-associated malignancies. We will use the rhesus lymphocryptovirus (LCV) animal model system for EBV pathogenesis and other laboratory systems to address these issues in the following specific aims: Specific Aim #1. Test whether the ability to downregulate LCV latent gene expression to an EBNA- 1 only promoter is essential for persistent LCV infection. Specific Aim #2. Test whether immune evasion mediated by the EBNA-1 glycine-alanine repeat domain is essential for persistent LCV infection. Specific Aim #3. Use immunosuppression to test whether the EBNA-1 mutant viruses are attenuated due to more effective immune clearance versus a functional defect required for persistent infection. Specific Aim #4. Explore strategies to enhance EBNA-1 recognition and killing of EBV infected B cells by EBNA-1 specific CTLs as a potential therapeutic.

描述（由申请人提供）：我们研究的总体目标是更好地了解Epstein-Barr病毒（EBV）感染的发病机理，以开发可以减少，控制或预防EBV相关疾病的疗法。 EBNA-1是一种EBV蛋白，对于维持病毒曲线症很重要。 EBNA-1在EBV感染的所有阶段表达，是仅有的少数几个病毒基因之一，这些病毒基因由感染的B细胞表达，这些基因在持续感染的宿主的血液中循环，并且是在EBV相关的恶性肿瘤中最始终如一的基因。 EBNA-1特异性细胞毒性T细胞存在于持续的EBV感染个体中，但是这些T细胞无法有效地杀死EBV感染的细胞，部分原因是EBNA-1甘氨酸 - 丙氨酸重复（GAR）结构域的抑制作用，可预防适当的处理和EBNA-1肽对T细胞的适当处理和表现。该应用的重点是EBNA-1对持续性EBV感染的重要性，EBNA-1免疫逃避对持续感染的重要性以及操纵EBNA-1免疫反应作为针对EBV相关的恶性肿瘤的治疗工具的可能性。我们将使用EBV发病机理和其他实验室系统的恒河猴淋巴结病毒（LCV）动物模型系统来解决这些问题： 特定目标＃1。测试将LCV潜伏基因表达下调到EBNA-1仅启动子的能力对于持续的LCV感染至关重要。 特定目标＃2。测试由EBNA-1甘氨酸 - 丙氨酸重复结构域介导的免疫逃避，对于持续的LCV感染至关重要。 特定目标＃3。使用免疫抑制来测试EBNA-1突变病毒是否由于更有效的免疫清除率而与持续感染所需的功能缺陷有关。 特定目标＃4。探索通过EBNA-1特异性CTL作为潜在的治疗方法来增强EBNA-1识别和杀死EBV感染的B细胞的策略。