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: 10319587
• 负责人: Rebecca L Skalsky
• 金额: $ 71.48万
• 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/10319587
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adult; 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; 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 RNA; 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.

项目概要 EB 病毒 (EBV) 持续感染全球 90% 以上的成年人。对于先天性或后天性的个体 免疫缺陷，例如接受器官移植或感染艾滋病毒/艾滋病的患者，终身持续存在 感染可导致多种癌症。与所有疱疹病毒一样，EBV 具有潜伏复制和裂解复制 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。周期性、潜伏性 EBV 重新激活产生传染性病毒，这被认为会增加受感染细胞的数量并维持 持续感染。调节潜伏期和裂解复制转换的分子机制并不完全 明白了。 MicroRNA (miRNA) 是一种小型非编码调节 RNA，可控制许多生物体 过程包括细胞状态转变和免疫反应的发展。 EBV 编码 进化上保守的病毒 miRNA，在病毒生命周期的各个阶段（当病毒蛋白被激活时）处于活跃状态。 高度限制，可以干扰宿主信号通路和抗病毒防御机制 多个层面，使我们假设病毒 miRNA 是宿主免疫反应的重要组成部分 无法清除持续感染。尽管我们付出了巨大的努力来增进我们对 EBV miRNA 功能的理解， 关于它们对体内感染的贡献知之甚少。根据初步调查结果，我们假设 EBV miRNA 充当毒力因子并协调潜伏期和重新激活的各个方面，从而促进病毒的生长 宿主内的持久性。在这个项目中，我们将检查监管非编码 RNA 相互作用，询问 具体来说，病毒和细胞 miRNA 在 EBV 感染期间如何协同塑造动态细胞状态，以及 确定影响病毒重新激活的关键决策的 miRNA。我们的目标是阐明关键的 miRNA 和 miRNA 介导的机制（靶点和途径）调节 EBV 潜在的裂解开关。到 检验我们的假设，即病毒 miRNA 促进体内持久性，我们将利用恒河猴淋巴隐病毒 模型来检查自然灵长类宿主中的病毒 miRNA 表型。本文提出的研究具有实用性 开发基于 RNA 的病毒性疾病治疗策略及其对推进 g- 的重要意义 疱疹病毒疫苗的开发。