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

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型单纯疱疹病毒(HSV-1)可以在一种高度活跃的“裂解”感染之间切换，从而产生传染性 病毒和一种更安静的潜伏感染。有几个假设是关于 可以使平衡向溶血性感染或潜伏性感染倾斜的机制。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， 以及免疫反应和对抗这些反应的病毒基因产品。没有一个 这些机制是唯一负责溶解/潜伏平衡的，并且每一个 机制极有可能是相互连接的。例如，免疫反应可能会影响 病毒的基因表达和转录后机制可以抑制其表达 影响染色质状态和对抗免疫反应的病毒基因产品。因此， 需要一种综合的方法来处理溶解/潜在平衡。在此计划项目中 提议，三名具有互补专业领域的资深疱疹病毒学家将 进行一系列高度协作的研究，以在三个方面研究这些机制 在三个核心的帮助下交织在一起的项目。 项目1将研究(包括与项目2的协作研究)病毒延迟- 相关转录本(LAT)、病毒蛋白ICP0和宿主蛋白CTCF的作用 染色质配置准备在建立和维持期间重新激活 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酶 基因表达和影响染色质状态(项目1)和一种病毒基因产物 这抵消了免疫力(项目3和项目1)，并导致了潜伏期，以及病毒 阻止miRNAs的核出口(项目1)和病毒miRNAs的靶标 培养的细胞包括小鼠和人的神经元(项目3和1)。 项目3将使用体外培养的小鼠神经元潜伏期模型，包括 转基因菌株和病毒突变株(其中一些来自项目1和2)，以测试 神经元特异性自噬小体，对抗免疫的病毒蛋白，以及 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。

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.