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，能够在其宿主的B淋巴细胞内建立终生潜伏感染，在健康个体中的显性疾病限制在约40%的个体中，当感染延迟到 生命的第二个十年。然而，细胞免疫功能的崩溃，特别是由于艾滋病，仍然是EBV相关淋巴瘤和淋巴增殖性疾病发展的一个重要风险因素，突显了EBV和其宿主之间存在的高度进化的平衡。这种平衡的建立最初依赖于9种EBV潜伏期相关蛋白和病毒miRNAs的子集-潜伏期III(Lat III)程序的高度协调和受控表达。本申请中提出的研究的长期目标是通过调节Lat III计划，即在持续感染的早期建立阶段，充分了解促进EBV持续存在的机制。这个阶段的中心是一个由六个EBV核蛋白(EBNAs)组成的家族，它们由两个常见的启动子(WP和CP)之一表达。EBNAs主要作为转录因子(EBNA1也是病毒基因组维持蛋白)，通过调节细胞和病毒潜伏基因的表达来促进病毒的持久性。这一应用的基础是我们最近发现了两种控制EBNA表达的新的和明显的转录后调控机制，以及发现了一类新的潜伏期相关的EBV RNA家族，它们可能通过潜在的调节功能和/或新的蛋白表达而参与LAT III。在目标1下，我们建议确定依赖于EBNA启动子WP的EBV基因负责反式抑制蛋白质表达，并最终确定其作用机制及其对EBV生物学和持久性的重要性。在目标2中，我们建议定义病毒基因组的EBV BHLF1基因位点对潜伏感染的贡献，扩大初步数据，表明BHLF1可能在潜伏感染期间作为长非编码RNA(LncRNA)发挥作用，对EBNA mRNAs的正确剪接至关重要。最后，在目标3中，我们将表征和探索跨越EBNA启动子CP的一族新的RNA转录本对EBV潜伏期的贡献。