Mechanisms of Epstein-Barr Virus Persistence

EB 病毒持续存在的机制

• 批准号: 8728373
• 负责人: JEFFERY T SAMPLE
• 金额: $ 34.44万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-11 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728373
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; B-Lymphocytes; Binding; Biology; Cellular Immunity; Control Locus; Cytoplasm; Data; Development; Disease; Elements; Epitopes; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Equilibrium; Family; Foundations; Gene Expression; Genes; Genetic Transcription; Genome; Health; Herpesviridae; Human; Human Herpesvirus 4; Immune; Immune response; Immunologic Surveillance; Individual; Infection; Infectious Mononucleosis; Introns; Knowledge; LMP1; Life; Literature; Lymphoma; Lymphoproliferative Disorders; Lytic Phase; Maintenance; Malignant Neoplasms; Medical; Memory B-Lymphocyte; Messenger RNA; Modeling; Nature; Nuclear; Nuclear Proteins; Oncogenic; Patients; Phase; Process; Property; Proteins; RNA; RNA Splicing; Recombinants; Regulation; Repression; Research; Risk Factors; Role; T-Lymphocyte; Testing; Therapeutic immunosuppression; Transcript; Transcription Initiation Site; Translations; Untranslated RNA; Viral; Viral Genome; Viral Proteins; Virus; Virus Latency; Work; base; cell growth regulation; cofactor; defined contribution; design; latency-associated protein; latent infection; novel; pathogen; persistent EBV infection; programs; promoter; protein expression; superinfection; transcription factor; viral RNA

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is an extremely successful pathogen, being able to establish a lifelong latent infection within B lymphocytes of its human host, with overt disease in healthy individuals restricted to a self- limiting mononucleosis in ~40% of individuals when infection is delayed until the second decade of life. However, a breakdown in cellular immunity, particularly as a consequence of AIDS, remains a significant risk factor for development of EBV-associated lymphoma and lymphoproliferative disease, underscoring the highly evolved equilibrium that exists between EBV and its host. Establishment of this equilibrium is dependent initially on a highly coordinated and controlled expression of the nine EBV latency-associated proteins and a subset of the viral miRNAs - the latency III (Lat III) program. The long-term objective of the research proposed in this application is to fully understand the mechanisms that contribute to EBV persistence through regulating the Lat III program, i.e., during the early establishment phase of persistent infection. Central to this phase are a family of six EBV nuclear proteins (EBNAs) that are expressed from one of two common promoters (Wp and Cp). The EBNAs primarily function as transcription factors (EBNA1 is also the viral genome-maintenance protein) to promote virus persistence through their regulation of cellular and viral latency-gene expression. The foundation for this application are our recent discoveries of two novel and apparent posttranscriptional regulatory mechanisms of controlling EBNA expression, and the discovery of a novel family of latency- associated EBV RNAs that may contribute to Lat III through a potential regulatory function and/or novel protein expression. Under Aim 1, we propose to identify the EBV gene responsible for the trans-repression of protein expression dependent on the EBNA promoter Wp, and ultimately its mechanism of action and importance to EBV biology and persistence. In Aim 2 we propose to define the contribution of the EBV BHLF1 gene locus of the virus genome to latent infection, expanding on preliminary data that suggests BHLF1 may function during latent infection as long noncoding RNA (lncRNA) important for the proper splicing of the EBNA mRNAs. Finally, in Aim 3 we will characterize and explore the contribution to EBV latency of a family of novel RNA transcripts that span the EBNA promoter Cp.

描述（由申请人提供）： 爱泼斯坦 - 巴尔病毒（EBV）是一种非常成功的病原体，能够在其人类宿主的B淋巴细胞内建立终生的潜在感染，健康个体中的明显疾病仅限于〜40％的个体中的自我限制的单核细胞增多症，而当感染延迟至 生命的第二个十年。然而，细胞免疫的细分，特别是由于艾滋病的结果，仍然是EBV相关淋巴瘤和淋巴增生性疾病发展的重要危险因素，强调了EBV与宿主之间存在的高度发展的平衡。该平衡的建立最初取决于九个EBV潜伏期相关蛋白的高度协调和受控的表达和病毒miRNA的子集 - 潜伏期III（LAT III）程序。本应用程序提出的研究的长期目标是充分了解通过调节LAT III计划（即在持续性感染的早期建立阶段）通过调节LAT III计划来促进EBV持久性的机制。该阶段的核心是由六个EBV核蛋白（EBNA）组成的家族，这些家族是从两个共同启动子之一（WP和CP）中表达的。 EBNA主要用作转录因子（EBNA1也是病毒基因组维持蛋白），可通过调节细胞和病毒潜伏期 - 基因表达来促进病毒持久性。该应用的基础是我们最近发现了两个新型且明显的转录后调节机制控制EBNA表达的机制，以及发现了一个新型潜伏期 - 与EBV RNA家族的发现，这些家族可能通过潜在的调节功能和/或新型蛋白质表达来促进LAT III。在AIM 1下，我们建议确定负责EBNA启动子WP的蛋白质表达的反式抑制的EBV基因，并最终其作用机理和对EBV生物学和持久性的重要性和重要性。在AIM 2中，我们建议定义病毒基因组的EBV BHLF1基因基因座对潜在感染的贡献，并根据初步数据扩展，这表明BHLF1在潜在感染期间可能在长期非编码RNA（LNCRNA）中起作用，这对于对EBNA MRNA的适当剪接很重要。最后，在AIM 3中，我们将表征和探索跨越EBNA启动子CP的新型RNA转录家族的EBV潜伏期的贡献。