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: 9791972
• 负责人: DONALD M COEN
• 金额: $ 216.47万
• 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/9791972
• 关键词: Affect; Alzheimer' s Disease; Animal Experiments; Animals; Antibodies; Area; Attenuated Live Virus Vaccine; 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; Latent Virus; 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.

总体方案摘要/摘要 该项目的长期目标是确定单纯疱疹病毒 1（HSV-1）可以在高度活跃的“溶解性”感染之间转换， 病毒和更隐蔽的潜伏感染。有几种假设， 这种机制可以使平衡倾向于溶解性感染或潜伏性感染。这些 其机制包括影响病毒的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， 免疫反应和对抗这些反应的病毒基因产物。没有一 这些机制单独负责溶解/潜伏平衡，并且这些机制中的每一个 这些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，在本发明中， 需要采取综合办法来实现溶解性/潜在性平衡。在本计划项目中 建议，三名具有互补专业领域的高级疱疹病毒学家将 进行一系列高度合作的研究，以调查这些机制在三个 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- 相关转录物（LAT），病毒蛋白ICP 0和宿主蛋白CTCF的影响， 染色质构型在建立和维持过程中重新激活， 潜伏期在体内，并与项目3，在培养的小鼠神经元，并在人类神经元。 项目2将集中在转录后调节机制如何抑制裂解 基因表达和影响染色质状态（与项目1）和病毒基因产物 对抗免疫（项目3和项目1）并导致潜伏期，以及病毒 阻断miRNAs的核输出（与项目1）和病毒miRNAs的靶点， 培养细胞，包括小鼠和人类神经元（项目3和1）。 项目3将使用一个体外模型的潜伏期使用培养的神经元从小鼠，包括 基因改变的菌株和病毒突变体（一些来自项目1和2），以测试 神经元特异性自噬体，对抗免疫的病毒蛋白， 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、再激活和基因表达。