Differential targeting of the HSV1 vhs endoribonuclease - preferential degradation of cellular transcripts on the endoplasmic reticulum?

HSV1 vhs 核糖核酸内切酶的差异靶向 - 在内质网上优先降解细胞转录物？

• 批准号: MR/T001038/1
• 负责人: Gill Elliott
• 金额: $ 65.14万
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT001038%2F1
• 关键词: Differential; targeting; HSV1; vhs; endoribonuclease

Herpes simplex virus (HSV) is an important human pathogen of medical and economic impact. HSV infection is life-long and once acquired it remains dormant in the body, poised to re-emerge and cause disease. It is the causative agent of recurring oral and genital herpes, both of which have profound effects on the quality of life of sufferers. Upon activation, HSV can also have much more serious consequences. For example, it is a pioneer infection for human immunodeficiency virus (HIV), making individuals more susceptible to HIV infection. It is the major cause of infectious blindness, and viral encephalitis that results in death or devastating brain damage. In developing countries neonatal herpes remains a cause of death in newborns. Individuals who have a suppressed immune system, such as transplant, cancer chemotherapy, and AIDS patients, are particularly susceptible to complications of HSV. With 24 million new cases globally each year, this virus is a huge economic burden on our health systems. However, efforts to develop an HSV vaccine have, without exception, failed. Moreover, although drug treatments for HSV have existed for decades, their use has made no impact on this HSV epidemic and resistance is growing. It is therefore vital that new ways to treat HSV are identified.To understand how to treat virus infections, it is first important to understand how they cause disease. HSV produces a number of factors that are considered non-essential for infection in cells in the lab, but are vital for the virus to cause disease in the host animal. These factors represent new targets for therapuetic intervention. One of these is virion host shutoff (vhs), which has a role in controlling the global cellular environment to make it favourable for efficient virus growth. Nonetheless, it is not yet clear how vhs activity influences the outcome of the disease process in a balanced fashion, such that it does not create a hostile environment for the virus. Using a global approach to look at cellular changes in HSV1 infection, we have discovered that vhs appears to target specific groups of cellular factors involved in pathways that determine the make-up of the environment outside the cell. Here, we propose to use state-of-the-art technology to define in detail the targets that are highly susceptible to vhs activity. New tools will be developed to identify the infected cell components that interact with vhs to understand how vhs is targeted to its site of action. Finally, we will determine if the activity of vhs prepares the cell to make large numbers of virus structual components thereby enabling the efficient production of new virus particles. In this way we aim to unravel the complexities of vhs activity to further our understanding of its role in virus infection and identify target interactions to potentially inhibit therapeutically.

单纯疱疹病毒（HSV）是一种重要的人类病原体，对医学和经济都有很大影响。HSV感染是终身的，一旦获得，它在体内保持休眠状态，随时可能重新出现并引起疾病。它是复发性口腔和生殖器疱疹的病原体，两者对患者的生活质量都有深远的影响。一旦激活，HSV也可能产生更严重的后果。例如，它是人类免疫缺陷病毒（HIV）的先驱感染，使个人更容易感染HIV。它是传染性失明和病毒性脑炎的主要原因，病毒性脑炎导致死亡或毁灭性的脑损伤。在发展中国家，新生儿疱疹仍然是新生儿死亡的一个原因。免疫系统受抑制的个体，如移植、癌症化疗和艾滋病患者，特别容易患HSV并发症。全球每年有2400万新病例，这种病毒给我们的卫生系统带来了巨大的经济负担。然而，开发HSV疫苗的努力无一例外都失败了。此外，尽管HSV的药物治疗已经存在了几十年，但它们的使用对HSV的流行没有影响，而且耐药性正在增长。因此，找到治疗HSV的新方法是至关重要的。要了解如何治疗病毒感染，首先要了解它们是如何引起疾病的。HSV产生许多因子，这些因子被认为是实验室中细胞感染的非必需因子，但对于病毒在宿主动物中引起疾病至关重要。这些因素代表了治疗干预的新目标。其中之一是病毒体宿主关闭（vhs），它在控制整个细胞环境中发挥作用，使其有利于病毒的有效生长。尽管如此，目前还不清楚vhs活性如何以平衡的方式影响疾病过程的结果，这样它就不会为病毒创造一个敌对的环境。使用全局方法来观察HSV 1感染中的细胞变化，我们发现vhs似乎靶向参与决定细胞外环境组成的途径的特定细胞因子组。在这里，我们建议使用最先进的技术来详细定义对vhs活动高度敏感的目标。将开发新的工具来识别与vhs相互作用的感染细胞成分，以了解vhs是如何靶向其作用部位的。最后，我们将确定vhs的活性是否使细胞准备好制造大量的病毒结构成分，从而使新病毒颗粒的有效生产成为可能。通过这种方式，我们的目标是解开vhs活性的复杂性，以进一步了解其在病毒感染中的作用，并确定潜在的治疗抑制靶点相互作用。

项目成果

Translational arrest and mRNA decay are independent activities of alphaherpesvirus virion host shutoff proteins

翻译停滞和 mRNA 衰减是 α-疱疹病毒病毒粒子宿主关闭蛋白的独立活动

• DOI: 10.1101/2024.02.02.578636
• 发表时间: 2024
• 作者: Eke L

Dysregulated nuclear export of the late herpes simplex virus 1 transcriptome through the vhs-VP22 axis uncouples virus cytopathic effect and virus production

晚期单纯疱疹病毒1转录组通过vhs-VP22轴的核输出失调，使病毒细胞病变效应和病毒产生脱钩

• DOI: 10.1101/2022.11.02.514834
• 发表时间: 2022
• 作者: Pheasant K

Herpes Simplex Virus 1 Expressing GFP-Tagged Virion Host Shutoff (vhs) Protein Uncouples the Activities of RNA Degradation and Differential Nuclear Retention of the Virus Transcriptome.

• DOI: 10.1128/jvi.01926-21
• 发表时间: 2022-07-27
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Wise, Emma L.;Samolej, Jerzy;Elliott, Gillian
• 通讯作者: Elliott, Gillian

Herpes simplex virus 1 expressing GFP-tagged virion host shutoff (vhs) protein uncouples the activities of degradation and nuclear retention of the infected cell transcriptome

单纯疱疹病毒 1 表达 GFP 标记的病毒颗粒宿主关闭 (vhs) 蛋白，解开受感染细胞转录组的降解和核保留活动

• DOI: 10.1101/2022.01.04.475014
• 发表时间: 2022
• 作者: Wise E