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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

整体程序的摘要/摘要该计划项目的长期目标是确定单纯疱疹病毒 1（HSV-1）可以在产生传染性的高活动“裂解”感染之间切换病毒和更沉默的潜在感染。有几个关于可以将平衡倾斜的机制有利于裂解感染或潜在感染。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，转录后机制，可能影响病毒和宿主基因表达，以及对抗这些反应的免疫反应和病毒基因产物。没有这些机制完全负责裂解/潜在平衡，每一种机制很有可能是连接的。例如，免疫反应会影响病毒基因表达和转录后机制可以抑制表达影响染色质状态和作战免疫反应的病毒基因产物的。因此，需要采用裂解/潜在平衡的综合方法。在这个程序项目中提案，三位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协作研究以研究三个机制借助三个核心，交织的项目交织在一起。项目1将研究（包括与项目2的合作研究）相关转录本（LATS），病毒蛋白ICP0和宿主蛋白CTCF效应A 在建立和维护期间，染色质配置有望重新激活体内潜伏期和项目3，在培养的小鼠神经元和人类神经元中。项目2将重点关注转录后调节机制如何压制裂解基因表达并影响染色质状态（具有项目1）和病毒基因产物这抵消了免疫力（项目3和1）并有助于潜伏期和病毒阻止miRNA的核出口（带有项目1）和病毒miRNA的靶包括小鼠和人类神经元在内的培养细胞（项目3和1）。项目3将使用来自小鼠的培养神经元（包括遗传改变的菌株和病毒突变体（一些项目1和2）以测试角色神经元特异性自噬体，对抗免疫力的病毒蛋白和抗体神经系统（包括项目1的疫苗生成的系统）控制病毒复制，潜伏期，重新激活和基因表达。