VIral and host mechanisms that tilt the HSV lytic/latent balance

导致 HSV 裂解/潜伏平衡倾斜的病毒和宿主机制

• 批准号: 10460505
• 负责人: DONALD M COEN
• 金额: $ 213万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460505
• 关键词: Affect; Alzheimer' s Disease; Animal Experiments; Animals; Antibodies; Area; Attenuated Vaccines; Autophagocytosis; Autophagosome; Back; Behavioral; Biogenesis; Biological Assay; Biology; CCCTC-binding factor; Chromatin; Collaborations; Cultured Cells; Encephalitis; Ensure; Equilibrium; Experimental Designs; Ganglia; Gene Expression; Genetic Transcription; Herpesvirus 1; Heterochromatin; Human; Immediate-Early Genes; Immune; Immune response; Immunity; In Vitro; Investigation; Keratitis; Laboratories; Lead; Life; Lytic; Lytic Phase; Lytic Virus; Maintenance; MicroRNAs; Mitochondrial Proteins; Mus; Nervous system structure; Neurodegenerative Disorders; Neurons; Nuclear Export; Pathogenesis; Play; Proteins; RNA; Regulation; Repression; Role; Series; Simplexvirus; System; Testing; Vaccines; Viral; Viral Genes; Viral Genome; Viral Proteins; Virus; Virus Diseases; Virus Latency; Virus Replication; Widespread Disease; Work; adaptive immune response; combat; gene product; human disease; in vitro Model; in vivo; latency associated transcript; latent infection; lytic gene expression; mutant; novel strategies; pre-miRNA; prevent; programs; reactivation from latency; response; statistics; viral DNA

Summary/Abstract for Overall Program The long-term objective of this program project is to determine how herpes simplex virus 1 (HSV-1) can switch between a highly active "lytic" infection that produces infectious virus and a more silent latent infection. There are several hypotheses regarding mechanisms that can tilt the balance in favor of lytic infection or latent infection. These mechanisms include viral gene products that affect the chromatin status of the viral genome, post-transcriptional mechanisms that can affect viral and host gene expression, and immune responses and viral gene products that combat those responses. None of these mechanisms is solely responsible for the lytic/latent balance, and each of these mechanisms is highly likely to be connected. For example, immune responses can affect viral gene expression, and post-transcriptional mechanisms can repress the expression of viral gene products that affect chromatin status and combat immune responses. Thus, an integrated approach to the lytic/latent balance is needed. In this Program Project proposal, three senior herpesvirologists with complementary areas of expertise will conduct a series of highly collaborative studies to investigate these mechanisms in three intertwined projects with the aid of three cores. Project 1 will study (including collaborative studies with Project 2) how viral latency- associated transcripts (LATs), the viral protein ICP0, and the host protein CTCF effect a chromatin configuration poised for reactivation during establishment and maintenance of latency in vivo, and with Project 3, in cultured mouse neurons, and in human neurons. Project 2 will focus on how post-transcriptional regulatory mechanisms can repress lytic gene expression and affect chromatin status (with Project 1) and a viral gene product that counteracts immunity (with Projects 3 and 1) and contribute to latency, and a virus block to nuclear export of miRNAs (with Project 1) and the targets of viral miRNAs in cultured cells including mouse and human neurons (Projects 3 and 1). Project 3 will use an in vitro model of latency using cultured neurons from mice, including genetically altered strains, and viral mutants (some from Projects 1 and 2) to test roles of neuron-specific autophagosomes, viral proteins that counter immunity, and antibodies in the nervous system (including those generated by a vaccine from Project 1) in control of viral replication, latency, reactivation, and, gene expression.

总体计划摘要/摘要 该计划项目的长期目标是确定单纯疱疹病毒如何 1 (HSV-1) 可以在高度活跃的“裂解性”感染之间切换，从而产生传染性 病毒和更无声的潜伏感染。关于以下问题有几种假设 可以使平衡倾斜以有利于溶解感染或潜伏感染的机制。这些 机制包括影响病毒染色质状态的病毒基因产物 基因组，可以影响病毒和宿主基因表达的转录后机制， 以及对抗这些反应的免疫反应和病毒基因产物。没有一个 这些机制仅负责裂解/潜在平衡，并且每一个机制 机制很可能是相互关联的。例如，免疫反应可以影响 病毒基因表达，转录后机制可以抑制表达 影响染色质状态和对抗免疫反应的病毒基因产物。因此， 需要一种实现裂解/潜在平衡的综合方法。在本计划项目中 根据提议，三名具有互补专业领域的资深疱疹病毒学家将 进行一系列高度合作的研究，以研究三个方面的这些机制 在三个核心的帮助下相互交织的项目。 项目 1 将研究（包括与项目 2 的合作研究）病毒潜伏期如何- 相关转录本 (LAT)、病毒蛋白 ICP0 和宿主蛋白 CTCF 效应 染色质构型在建立和维持过程中准备重新激活 体内潜伏期，以及项目 3、培养的小鼠神经元和人类神经元中的潜伏期。 项目 2 将重点研究转录后调控机制如何抑制裂解 基因表达并影响染色质状态（项目 1）和病毒基因产物 抵消免疫力（项目 3 和 1）并导致延迟，以及病毒 阻止 miRNA 的核输出（项目 1）和病毒 miRNA 的靶标 培养细胞，包括小鼠和人类神经元（项目 3 和 1）。 项目 3 将使用体外培养的小鼠神经元模型，包括 基因改变的菌株和病毒突变体（一些来自项目 1 和 2）来测试 神经元特异性自噬体、对抗免疫的病毒蛋白和抗体 神经系统（包括由项目 1 的疫苗产生的神经系统）控制 病毒复制、潜伏期、重新激活和基因表达。