Mechanism for virus persistence after acute infections

急性感染后病毒持续存在的机制

• 批准号: 9221735
• 负责人: Carolina B. Lopez
• 金额: $ 24.15万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221735
• 关键词: Acute; Animals; Antiviral Agents; Antiviral Response; Antiviral Therapy; Asthma; Automobile Driving; Biological Assay; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Characteristics; Chronic Disease; Chronic lung disease; Clinical; Coronaviridae; Coronavirus; Coxsackie Viruses; Custom; Development; Disease; Ebola virus; Elements; Encephalitis; Generations; Genes; Genome; Heart Diseases; Human; Immune response; Immune system; Immunologic Receptors; Immunosuppression; In Vitro; Individual; Infection; Knock-out; Laboratory Study; Lead; Length; Lung; Maintenance; Measles virus; Mediating; Mus; Pathway interactions; Population; Process; Production; RNA Virus Infections; RNA Viruses; Respiratory syncytial virus; Rhinovirus; Role; Sendai virus; Small Interfering RNA; System; Technology; Testing; Therapeutic Intervention; Viral; Viral Genome; Viral reservoir; Virus; Virus Diseases; Virus Replication; West Nile virus; antiviral immunity; base; biochemical tools; cell type; differential expression; experimental study; improved; in vivo; insight; mouse model; new technology; novel; pathogen; respiratory; response; success; transcriptome; viral detection

Summary Evidence of persistent viral genomes in humans after infection with acute RNA viruses is increasing as technological advances with enhanced sensitivity permit the detection of viral reservoirs. Such evidence challenges the dogma that acute viruses are completely cleared by the immune system. In parallel, evidence of a role for persistent viruses in promoting disease is growing. For example, persistent respiratory syncytial virus in humans is associated with asthma, persistent coxsackie virus causes cardiac disease, and persistent measles virus or West Nile virus cause encephalitis. Persistent viral genomes are also a major obstacle for eradicating virus from infected individual following antiviral therapies. Despite much speculation, the mechanisms driving the generation and maintenance of long-term viral reservoirs during infections with RNA viruses are completely unknown. Resolving these mechanisms is critical for limiting or eliminating persistent viral reservoirs and for reducing their impact in disease. Evidence suggests that defective viral genomes (DVGs) that are generated during viral replication are pivotal in the generation of persistent viral reservoirs. Specifically, we observed that while some cells become enriched in DVGs upon virus infection, others maintain a predominantly full-length viral genome content. Furthermore, despite showing initial potent antiviral responses, cells dominated by DVGs survive the infection and generate long-term viral reservoirs, while cells dominated by full-length viral genomes died. In this exploratory proposal we take advantage of powerful technology to differentiate full-length viral genomes from DVGs in infected cells to 1.Identify cellular mechanisms mediating the persistence of infected cells dominated by DVGs and 2. Identify and characterize in vivo viral genome reservoirs. Overall, we expect to establish the role of DVGs in the generation of long-term viral reservoirs, break ground in our understanding of the mechanisms promoting survival of cells destined to allow virus persistence, and determine if pathways driving persistently infected cells in vitro are also active in vivo.

总结 感染急性RNA病毒后人类中持续存在病毒基因组的证据越来越多， 具有增强的灵敏度的技术进步允许检测病毒储库。此类证据 挑战了急性病毒会被免疫系统完全清除的教条。与此同时， 持久性病毒在促进疾病方面的作用越来越大。例如，持续性呼吸道合胞病毒 在人类中与哮喘有关，持续存在的科萨基病毒引起心脏病， 麻疹病毒或西尼罗河病毒引起脑炎。持久的病毒基因组也是一个主要障碍， 在抗病毒治疗后从受感染个体中根除病毒。尽管有很多猜测， 在RNA感染期间驱动长期病毒储库的产生和维持的机制 病毒是完全未知的。解决这些机制对于限制或消除持久性 病毒储存库和减少它们对疾病的影响。有证据表明，有缺陷的病毒基因组 病毒复制过程中产生的病毒性血管生成细胞（DVG）在持久性病毒储库的产生中是关键的。 具体地说，我们观察到，虽然一些细胞在病毒感染后富含DVG，但其他细胞在病毒感染后保持DVG。 主要是全长病毒基因组内容。此外，尽管最初显示出有效的抗病毒， 在免疫应答中，由DVG主导的细胞在感染中存活并产生长期的病毒库，而细胞 由全长病毒基因组控制的病毒死亡。在这个探索性的建议中，我们利用强大的 技术区分全长病毒基因组与感染细胞中的DVG，以1. 机制介导的持久性感染的细胞为主的DVG和2。识别和表征 体内病毒基因组库。总的来说，我们希望建立DVG在产生长期 病毒库，突破我们对促进细胞存活机制的理解， 允许病毒持续存在，并确定在体外驱动持续感染细胞的途径是否也活跃， vivo.