Characterising the Mode of Action of VP22 - a Novel Herpes Simplex Virus Virulence Factor Important for In Vivo Replication.

单纯疱疹病毒(HSV)因其在口腔和生殖器疱疹中的作用而闻名。然而，感染单纯疱疹病毒也会产生一些非常严重的后果，这一点并没有广泛宣传。例如，它有能力导致极端的脑损伤、失明甚至死亡。它也是艾滋病毒感染背后的主要驱动力。一旦HSV感染了人体，它就无法被消除，它终生潜伏在神经系统中，准备在人特别脆弱的时候再次出现新的症状。免疫系统受到抑制的人，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。全球每年新增病例2400万例，这种病毒给我们的卫生系统带来了巨大的经济负担。然而，尽管制药业付出了极大的努力，但还没有成功的HSV疫苗被开发出来。此外，尽管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次单纯疱疹病毒的流行产生任何影响。因此，找到新的单纯疱疹病毒治疗方法是至关重要的。要开发新的治疗方法，了解单纯疱疹病毒是如何致病的很重要。当病毒进入体内的细胞时，攻击病毒和防御细胞之间的战斗就开始了，看哪一个能赢。如果病毒获胜，结果就是疾病。在这个过程中，细胞和病毒都会用它们制造的蛋白质相互攻击。在我们研究HSV如何导致疾病的工作中，我们发现一种名为VP22的病毒蛋白，它不是病毒在动物来源的细胞中良好生长所必需的，而是病毒在人类来源的自然细胞中生长所必需的。我们认为VP22是必需的，因为它攻击一种只有人类细胞才能在HSV感染期间到位的特定防御机制，在没有VP22的情况下，这种防御机制获胜。利用最先进的大规模实验，我们将识别当VP22缺失时HSV感染细胞中所有开启的细胞基因，以研究VP22可能阻断的细胞防御机制。然后，我们将找出VP22是否与特定的细胞蛋白结合，并研究这是否是VP22允许HSV在这些人类细胞中生长的方法。最后，当VP22被包装到病毒的结构中时，我们将询问病毒是否在病毒进入细胞的第一阶段就提供了强大的细胞防御机制攻击者。如果我们证明VP22是人类细胞中细胞防御的有效抑制因子，这将为HSV疫苗和药物开发开辟新的途径。就疫苗而言，可以想象，缺乏VP22的病毒将足够弱，足以引起有限的疾病，同时激发良好的免疫反应，以保护人类免受未来的感染。此外，如果我们发现VP22的功能，就有可能开发出结合和抑制VP22活性的药物，从而阻止HSV致病的能力。我们的研究将有益于全球人群的健康和福祉--那些遭受单纯疱疹病毒感染的严重并发症的人，那些因生殖器单纯疱疹病毒感染而感染艾滋病毒的人，以及那些经常爆发令人衰弱的口疮或生殖器疱疹的人。最终，这项工作将对HSV患者的痛苦以及HSV感染给英国和其他国家的医疗服务带来的成本产生重大影响。

Herpes simplex virus (HSV) is well known for its role in oral and genital herpes. However, it is not widely publicised that infection with HSV can also have some very serious outcomes. For example, it has the ability to cause extreme brain damage, blindness or even death. It is also a major driving force behind HIV infection. Once HSV has infected the human body it cannot be eliminated, and lies dormant in the nervous system for life, ready to strike again with new symptoms when the person is especially vulnerable. People, whose immune systems are suppressed, 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, despite extreme effort from the pharmaceutical industry, no successful HSV vaccine has yet been developed. Moreover, although drug treatments for HSV have existed for decades, their use has made no impact on this HSV epidemic. It is therefore vital that new HSV treatments are found.To develop new treatments, it is important to understand how HSV causes disease. When a virus enters a cell in the body, a battle begins between the attacking virus and the defending cell to see which one can win. If the virus wins, the result is disease. During this process, both the cell and the virus attack each other with proteins they have made. In our work to investigate how HSV causes disease, we have discovered that one virus protein called VP22, which is not needed for the virus to grow well in cells of animal origin, is required for the virus to grow in natural cells of human origin. We propose that VP22 is required because it attacks a particular defence mechanism that only the human cells can put in place during HSV infection, and that in the absence of VP22, this defence mechanism wins. Using state-of-the art, large-scale experimentation, we will identify all cellular genes that are switched on in HSV infected cells when VP22 is missing, to investigate the cellular defence mechanisms that VP22 might block. We will then find out if VP22 binds specific cellular proteins and work out if this is the method by which VP22 allows HSV to grow in these human cells. Finally, as VP22 is packaged into the structure of the virus, we will ask if the virus delivers a powerful attacker of cellular defence mechanisms at the very first stage of virus entry into a cell.If we prove that VP22 is a potent inhibitor of a cellular defence in human cells, this will open up new avenues for HSV vaccine and drug development. In the case of vaccines, it is conceivable that virus lacking VP22 will be sufficiently weak to cause limited disease while invoking a good immune response to protect against future infections in the human. Furthermore, if we discover how VP22 functions, it will be possible to develop drugs that bind and inhibit the activity of VP22, thereby stopping the ability of HSV to cause disease. Our research will benefit the health and wellbeing of the global population - those who suffer serious complications from HSV infection, those who contract HIV as a result of genital HSV infection, and those that suffer frequent and debilitating outbreaks of cold sores or genital herpes. Ultimately, this work will have a significant impact on both the suffering of patients with HSV and the cost of HSV infection to the health service in the UK and beyond.