Ocular HSV: Mechanism of virus reactivation

眼部 HSV：病毒再激活机制

基本信息

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
项目类别：
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

项目摘要

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

项目概要潜伏感染的感觉神经元中 HSV 的重新激活具有相当大的临床重要性尤其是对于眼部疾病。开发有效的替代策略来限制重新激活已经由于对调节潜伏间歇性逆转的机制了解不足而受到限制到传染状态。 HSV 潜伏期相关转录本 (LAT) 在潜伏期重新激活和是在人类、小鼠和兔子受感染的感觉神经元中检测到高水平的唯一病毒转录本。因为潜伏的 HSV 感染中存在病毒基因组，但没有检测到感染性病毒，因此很明显病毒基因组在潜伏感染的细胞中并未完全静止。我们之前的研究以及发表在在当前的资助期间，建立了 gD 表达和 LAT 能力之间的重要联系增强潜伏感染小鼠 TG 中疱疹病毒进入介质 (HVEM) 的表达。我们的研究结果表明一种新模型，其中 gD 表达和 LAT 增强 HVEM 表达的上调，从而促进 HSV 潜伏感染小鼠的 TG 重新激活。在这个提议中，我们假设低水平的 gD 表达它与 HVEM 的结合有助于眼部 HSV 的重新激活。我们在当前融资期间取得的进展时期对 LAT 调节 HVEM 表达的潜在机制提供了新的见解定义潜伏期再激活和眼部疾病的程度。根据我们的数据，我们制定了双峰模型中 sncRNA1&2 在潜伏期增加的再激活效应是由两种不同的介导的，但相互关联的机制：(i) sncRNA1&2 与 HVEM 启动子结合导致更高水平的 HVEM 表达; (ii) HVEM 的较高表达增强了 gD 与 HVEM 的结合并增加了再激活。我们将在控制复杂性的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潜伏微环境及其与原发感染的潜在关系如下：（1）确定 sncRNA1 和 2 是否都需要上调 HVEM 并增加从延迟； (2)确定潜伏期是否需要gD表达及其与HVEM的结合用于从潜伏感染小鼠的 TG 潜伏状态中有效地重新激活。验证该假设模型将识别先前未描述的有助于 HSV-1 重新激活的机制，并将提供识别分子靶标和病毒免疫逃避反应的框架，可用于更好地控制潜伏性 HSV 感染。临床意义和