How herpesviruses sense stress in their hosts

疱疹病毒（人类单纯疱疹病毒，HSV-1就是一个例子）的感染开始于病毒在皮肤细胞中进入部位的活跃复制。然后病毒感染支配病毒复制区域的感觉神经，并在神经细胞中建立潜伏感染。它静静地呆在这里，免受宿主的防御。神经细胞中的潜伏病毒对环境或生理压力的反应是周期性地重新激活，复制并重新感染皮肤细胞。潜伏期建立的分子基础长期以来一直是病毒学家的一个有趣和令人困惑的难题，这个难题至今尚未解决。我们研究的目的是确定HSV-1在宿主受到压力时的感觉。我们的工作不仅将帮助我们了解疱疹病毒如何建立潜伏期并从中重新激活，还将告诉我们神经系统细胞如何对压力做出反应。我们发现了两种人类蛋白质，它们可能是疱疹病毒潜伏期和重新激活的关键。我们以京剧中的神话人物命名这些蛋白质为鲁曼和张飞。 我们认为，在无压力的动物痛觉神经细胞（HSV潜伏的细胞）中，章飞似乎抑制了HSV-1的复制，并将其引导至潜伏期。鲁曼能够激活HSV-1基因的表达，我们认为它在应激动物的神经细胞中重新激活潜伏的病毒。在我们的研究中，我们发现了一些有趣的事情，关于张飞在动物中的正常作用可能是什么。它似乎与发育中的胚胎中痛觉神经细胞的发育有关。在髓母细胞瘤（一种儿童神经细胞癌）中，没有章飞。然而，如果我们现在让这些快速分裂的细胞来制造章飞，它们会停止分裂，开始看起来像成熟的神经细胞。在接下来的五年里，我们计划研究章飞和鲁曼如何影响HSV-1的复制，潜伏期和再激活。我们还将试图找出这两种蛋白质在正常的未感染的神经细胞中的作用。

Infection with a herpesvirus (the human herpes simplex virus, HSV-1 is an example) begins with active replication of the virus in skin cells at the site of entry. The virus then infects sensory nerves innervating the area of virus replication and establishes a latent infection in nerve cells. Here it quietly remains, protected from the host's defenses. In response to environmental or physiological stress the latent virus in nerve cells reactivates periodically to replicate and reinfect skin cells. The molecular basis for the establishment of latency has long been an intriguing and perplexing puzzle for virologists, a puzzle that has not as yet been solved. The objective of our research is to determine how HSV-1 senses when its host is stressed. Our work will not only help us to understand how herpesviruses establish latency and reactivate from it, it will also tell us how cells of the nervous system respond to stress.We have discovered two human proteins, which may hold the key to herpesvirus latency and reactivation. We have named these proteins Luman and Zhangfei after mythical characters in the Beijing opera.  In pain-sensing nerve cells (the very cells in which HSV becomes latent) in unstressed animals Zhangfei appears to suppress HSV-1 replication and, we think, directs it into latency. Luman is capable of activating HSV-1 gene expression and we think that in the nerve cells of stressed animals it reactivates latent virus.During our studies we have discovered some interesting things about what Zhangfei's normal role in the animal might be. It seems to be involved in the development of the pain-sensing nerve cells in the developing embryo. In medulloblastoma (a childhood nerve cell cancer) no Zhangfei is made. However, if we now get these rapidly dividing cells to make Zhangfei, they stop dividing and start looking like mature nerve cells.Over the next five years we propose to investigate how Zhangfei and Luman influence HSV-1 replication, latency and reactivation. We will also try to find out what the two proteins do in normal, uninfected nerve cells.