Ocular HSV: Mechanism of virus reactivation

眼部 HSV：病毒再激活机制

• 批准号: 10649980
• 负责人: HOMAYON GHIASI
• 金额: $ 41.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649980
• 关键词: Affect; Afferent Neurons; Apoptosis; Binding; Blindness; Cell surface; Cells; Clinical; Data; Developed Countries; Development; Eye Infections; Eye diseases; Funding; Genes; Glycoproteins; Goals; Health; Herpesvirus 1; Herpetic Keratitis; Human; Immune Evasion; Infection; Link; Maps; Mediating; Mediator; Modality; Modeling; Molecular Target; Mus; Neurons; Oryctolagus cuniculus; Pathway interactions; Persons; Play; Primary Infection; Productivity; Proteins; Publishing; RNA; Recombinants; Recurrence; Recurrent disease; Regulation; Role; Structure of trigeminal ganglion; TNF gene; Testing; Transcript; Untranslated RNA; Up-Regulation; Validation; Viral; Viral Genome; Virus; clinically relevant; clinically significant; exhaustion; herpesvirus entry mediator; in vivo; innovation; insight; latency associated transcript; member; mouse model; new therapeutic target; novel; prevent; promoter; reactivation from latency; receptor; recombinant virus; response; simplexvirus receptor

Project Summary Reactivation of HSV in latently infected sensory neurons is of considerable clinical importance especially with respect to eye disease. Development of effective alternative strategies to limit reactivation has been limited by an insufficient understanding of mechanisms that regulate intermittent reversion from the latent to the infectious state. HSV latency associated transcript (LAT) plays a critical role in latency-reactivation and is the only viral transcript detected at high levels in infected sensory neurons of humans, mice, and rabbits. Because the viral genome, but no detectable infectious virus, is present in latent HSV infection, it is clear that the viral genome is not fully quiescent in latently infected cells. Our previous studies, and those published in the current funding period, established an important link between gD expression and the ability of LAT to enhance herpes virus entry mediator (HVEM) expression in TG of latently infected mice. Our findings suggest a novel model, in which gD expression and LAT enhanced upregulation of HVEM expression contribute to HSV reactivation in TG of latently infected mice. In this proposal, we hypothesize that low level gD expression and its binding to HVEM contribute to ocular HSV reactivation. Our progress during the current funding period has provided novel insights into potential mechanisms by which LAT regulation of HVEM expression defines the extent of latency-reactivation and eye disease. Based on our data, we have formulated a bimodal model in which the increased reactivation effects of sncRNA1&2 during latency are mediated by two different, but inter-related, mechanisms: (i) sncRNA1&2 binding to the HVEM promoter leads to higher levels of HVEM expression; and (ii) higher expression of HVEM enhances gD binding to HVEM and increases reactivation. We will test our model using clinically relevant recombinant viruses in mouse models that control for the complexity of the latent microenvironment in TG and its potential relationships with the primary infection as follows: (1) Determine whether sncRNA1&2 are both required to upregulate HVEM and increase reactivation from latency; and (2) Determine whether gD expression during latency and its binding to HVEM is required for efficient reactivation from latency in TG of latently infected mice. Validation of this hypothetical model will identify previously undescribed mechanisms that contribute to HSV-1 reactivation and will provide the framework for identification of molecular targets and viral immune evasion response that could be exploited to better manage latent HSV infection. CLINICAL SIGNIFICANCE AND

项目摘要 HSV在潜伏感染的感觉神经元中的再激活具有相当重要的临床意义 特别是对于眼疾。开发有效的替代策略来限制再激活， 由于对调节间歇性逆转的机制理解不足， 传染状态。HSV潜伏期相关转录本（LAT）在潜伏期再激活和 是唯一在人类、小鼠和兔子的受感染感觉神经元中检测到高水平的病毒转录物。 因为潜伏的HSV感染中存在病毒基因组，但没有可检测到的感染性病毒，所以很明显， 病毒基因组在潜伏感染的细胞中不是完全静止的。我们以前的研究，以及那些发表在 在当前的资助期内，在gD表达和LAT的能力之间建立了重要的联系， 增强潜伏感染小鼠TG中疱疹病毒进入介体（HVEM）的表达。我们的研究结果表明 一种新的模型，其中gD表达和LAT增强HVEM表达的上调有助于HSV 在潜伏感染小鼠的TG中重新激活。在这个建议中，我们假设低水平的gD表达 并且其与HVEM的结合有助于眼部HSV再活化。我们在当前融资期间的进展 这一时期的研究为LAT调节HVEM表达的潜在机制提供了新的见解。 定义了潜伏期再激活和眼部疾病的程度。根据我们的数据，我们制定了一个双峰 模型，其中在潜伏期期间增加的sncRNA 1和2的再激活作用由两种不同的， 但相互关联的机制：（i）sncRNA 1和2与HVEM启动子的结合导致更高水平的HVEM （ii）HVEM的更高表达增强gD与HVEM的结合并增加再活化。我们 将在小鼠模型中使用临床相关的重组病毒来测试我们的模型， TG潜伏微环境的变化及其与原发感染的潜在关系如下：（1） 确定sncRNA 1和2是否都需要上调HVEM和增加从HVEM的再激活。 潜伏期;和（2）确定在潜伏期期间是否需要gD表达及其与HVEM的结合 用于从潜伏感染小鼠的TG中的潜伏有效再激活。验证这个假设模型 将确定以前未描述的机制，有助于HSV-1的再激活，并将提供 用于鉴定分子靶点和病毒免疫逃避反应的框架，可用于 更好地管理潜伏的HSV感染。 临床意义及