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

单纯疱疹病毒（HSV）是一种影响医疗和经济的重要人类病原体。HSV感染是终身的，一旦获得，它在体内保持休眠状态，准备重新出现并引起疾病。它是复发性口腔疱疹和生殖器疱疹的病原体，这两种疾病对患者的生活质量都有深远的影响。一旦被激活，单纯疱疹病毒也会产生更严重的后果。例如，它是人类免疫缺陷病毒（HIV）的先驱感染，使个体更容易感染HIV。它是导致传染性失明和病毒性脑炎的主要原因，病毒性脑炎会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。免疫系统受到抑制的个体，如移植、癌症化疗和艾滋病患者，特别容易受到HSV并发症的影响。全球每年有2400万新病例，这一病毒给我们的卫生系统带来了巨大的经济负担。然而，研制HSV疫苗的努力无一例外地失败了。此外，尽管针对单纯疱疹病毒的药物治疗已经存在了几十年，但它们的使用并没有对这种单纯疱疹病毒的流行产生任何影响，而且耐药性正在增长。因此，确定治疗单纯疱疹病毒的新方法至关重要。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。单纯疱疹病毒产生的许多因子被认为是实验室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。其中之一是病毒粒子宿主关闭（vhs），它在控制全局细胞环境中起作用，使其有利于病毒的有效生长。尽管如此，目前尚不清楚vhs的活动如何以平衡的方式影响疾病过程的结果，从而不为病毒创造不利的环境。使用一种全局方法来观察HSV1感染中的细胞变化，我们发现vhs似乎针对与决定细胞外环境构成的途径有关的特定细胞因子群。在这里，我们建议使用最先进的技术来详细定义高度易受vhs活动影响的目标。将开发新的工具来识别与vhs相互作用的受感染细胞成分，以了解vhs如何靶向其作用部位。最后，我们将确定vhs的活性是否使细胞能够制造大量的病毒结构成分，从而能够有效地生产新的病毒颗粒。通过这种方式，我们旨在揭示vhs活动的复杂性，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目标相互作用。

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.