microRNA Regulation of Gamma-herpesvirus Latency and Reactivation

microRNA 对 γ-疱疹病毒潜伏期和再激活的调节

• 批准号: 10084264
• 负责人: Rebecca L Skalsky
• 金额: $ 40.17万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-22 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084264
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adult; Antiviral Agents; Autoimmune Diseases; B-Cell Antigen Receptor; B-Lymphocytes; Biological Assay; Biological Process; Carcinoma; Cells; Chronic; Defense Mechanisms; Development; Environment; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Event; Gene Expression; Genetic; Genetic Transcription; Herpesviridae; Human Herpesvirus 4; Immune response; Immunoprecipitation; In Vitro; Individual; Infection; Interferons; Lead; Life; Life Cycle Stages; Link; Lymphocryptovirus; Lymphoma cell; Lytic; Macaca mulatta; Maintenance; Malignant Neoplasms; Malignant lymphoid neoplasm; Maps; Mediating; MicroRNAs; Modeling; Molecular; Molecular Analysis; Molecular Target; Monitor; Nucleotides; Organ Transplantation; Pathogenesis; Pathway interactions; Patients; Periodicity; Phase; Phenotype; Primates; Process; Proteins; RNA; Receptor Signaling; Recombinants; Regulation; Rhesus; Ribonucleosides; Risk; Role; Shapes; Signal Pathway; Signal Transduction; Small RNA; Stimulus; Surface Immunoglobulins; Technology; Testing; Therapeutic; Untranslated RNA; Viral; Viral Load result; Viral Proteins; Virulence Factors; Virus; Virus Diseases; base; cellular targeting; chronic infection; crosslink; desensitization; experimental study; gammaherpesvirus; in vivo; loss of function; lytic replication; nonhuman primate; programs; protein expression; recombinant virus; success; therapeutic target; transcriptome; vaccine development

PROJECT SUMMARY Epstein-Barr virus (EBV) persistently infects >90% of adults worldwide. In individuals with congenital or acquired immune deficiencies, such as patients undergoing organ transplant or living with HIV/AIDS, life-long persistent infection can lead to a variety of cancers. Like all herpesviruses, EBV has both a latent and a lytic replication phase; the ability to switch between these programs is key to long-term viral persistence. Periodically, latent EBV reactivates to produce infectious virus, which is thought to increase the pool of infected cells and sustain persistent infection. Molecular mechanisms regulating latency and the switch to lytic replication are not entirely understood. MicroRNAs (miRNAs) are small, non-coding regulatory RNAs that govern many biological processes including cell state transitions and the development of immune responses. EBV encodes evolutionarily conserved viral miRNAs that are active during stages of the viral life cycle when viral proteins are highly restricted and that can interfere with host signaling pathways and anti-viral defense mechanisms on multiple levels, leading us postulate that viral miRNAs represent an important part of why host immune responses fail to clear persistent infection. Despite significant efforts advancing our understanding of EBV miRNA functions, little is known about their contributions to infection in vivo. Based on preliminary findings, we hypothesize that EBV miRNAs act as virulence factors and coordinate aspects of latency and reactivation that facilitate virus persistence within a host. In this project, we will examine regulatory non-coding RNA interactions, asking specifically how viral and cellular miRNAs cooperatively shape dynamic cell states during EBV infection, and determine the miRNAs influencing critical decisions that impact virus reactivation. We aim to elucidate the critical miRNAs and miRNA-mediated mechanisms (targets and pathways) regulating the EBV latent to lytic switch. To test our hypothesis that viral miRNAs facilitate persistence in vivo, we will leverage the rhesus lymphocryptovirus model to examine viral miRNA phenotypes in a natural primate host. Studies proposed herein have utility in developing RNA-based therapeutic strategies against viral disease and important implications for advancing g- herpesvirus vaccine development.

项目总结 爱泼斯坦-巴尔病毒(EBV)持续感染全球90%的成年人。患有先天性或后天性疾病的个体 免疫缺陷，如接受器官移植或感染艾滋病毒/艾滋病的患者，终生持续 感染可能导致多种癌症。像所有疱疹病毒一样，EBV既有潜伏的复制，也有裂解的复制 阶段；在这些程序之间切换的能力是病毒长期持续存在的关键。定期的，潜伏的 EBV重新激活以产生传染性病毒，这被认为增加了感染细胞池并持续 持续性感染。调节潜伏期和切换到裂解复制的分子机制并不完全 明白了。MicroRNAs(MiRNAs)是一种小的、非编码的调控RNA，它控制着许多生物 包括细胞状态转变和免疫反应发展的过程。EBV编码 进化上保守的病毒miRNAs，在病毒生命周期的阶段活跃，当病毒蛋白 高度受限，可能会干扰宿主信号通路和抗病毒防御机制 多个水平，导致我们假设病毒miRNAs代表为什么宿主免疫反应的重要部分 未能清除持续性感染。尽管我们对EBV miRNA的功能有了很大的了解， 关于它们在体内感染中的作用，人们知之甚少。根据初步调查结果，我们假设 EBV miRNA充当毒力因子，协调潜伏期和重新激活的各个方面，从而促进病毒 主机内的持久性。在这个项目中，我们将检查调控的非编码RNA相互作用，询问 特别是病毒和细胞miRNAs如何在EBV感染期间协同塑造动态细胞状态，以及 确定哪些miRNA会影响影响病毒重新激活的关键决策。我们的目标是阐明关键的 MiRNAs和miRNA介导的机制(靶点和途径)调节EBV潜伏的裂解开关。至 测试我们的假设，即病毒miRNAs有助于体内的持久性，我们将利用恒河猴淋巴病毒 用于检测自然灵长类宿主中的病毒miRNA表型的模型。本文提出的研究对 发展基于RNA的病毒病治疗策略及其对推进G-G-R的重要意义 疱疹病毒疫苗研发。