Identifying and Characterizing Antiretroviral Interferon Stimulated Genes (ISGs)

病毒感染通常会产生负面后果。这些疾病从干扰我们日常生活的普通感冒到可能导致残疾(如脊髓灰质炎)、癌症(如丙型肝炎)和死亡(如艾滋病毒)的衰弱感染。地球上的所有生命很可能在数亿年里一直受到病毒的困扰。为了生存，人类和动物开发出了新的、更具创造性的方法来抵抗感染。这些抗病毒防御是随着时间的推移而积累起来的，因此现在我们的细胞中存在着一个抗病毒防御的武器库。这些防御是强有力的和有组织的。一旦我们的身体感觉到感染，干扰素(干扰病毒复制的蛋白质)就会释放出来，增加我们抗病毒防御的表达。然而，病毒已经开发出了自己的巧妙方法来克服这些抗病毒防御。因此，我们今天在地球上观察到的异常多样化的病毒代表了那些已经适应了在这种敌对的宿主环境中茁壮成长的病毒。并不是每个人都同样容易受到病毒感染。有些人比其他人更容易感染，不同的人感染相同的病毒，可能会有不同的临床结果。许多因素，如营养、潜在的健康状况或以前的病毒暴露，都可能影响病毒疾病的临床进程。然而，如果我们要真正了解宿主和病毒是如何相互作用的，我们就必须了解细胞的内在抗病毒防御。更好地了解这些相互作用可能有助于解释病毒流行是如何发生的，以及为什么有些人死于感染，而另一些人不死。在这个项目中，我将研究病毒与它们感染的人和动物之间的相互作用。首先，我将重点寻找我们人类为抵抗人类免疫缺陷病毒(HIV-1)感染而开发的新的抗病毒因子。以前的研究表明，我们对病毒感染的内在免疫力通常是由单一因素引起的。干扰素可以增加这些因子的表达，因此它们被称为干扰素刺激基因(ISGs)。这些ISGs中绝大多数的身份和功能尚不清楚，因此我认为还有更多的抗病毒因子尚未确定。我之前收集了一组人类和猕猴的ISG，其中大多数功能未知。在为这个项目做准备的过程中，我研究了数百种不同的ISG抑制HIV-1的能力。现在，我将把这种方法扩展到更广泛的逆转录病毒，试图确定新的抗病毒因素。至关重要的是，人类病毒已经适应了在人类抗病毒防御系统存在的情况下进行复制，因此检查动物病毒增加了识别人类抗病毒基因的可能性。相反，人类病毒不适合在猕猴抗病毒防御系统存在的情况下复制，因此使用猕猴ISG筛选人类病毒增加了识别抗人类病毒活性基因的可能性。我已经成功地利用这种筛选方法鉴定了一种名为CNP的新蛋白质，这种蛋白质在人脑中大量表达，可以抑制HIV-1的复制。在这次联谊会的过程中，我希望能够找到更多的抗病毒因子，并解释它们的作用机制如何帮助人类和动物抵御病毒感染。我的长期抱负是利用我产生的信息来帮助设计新的药物和治疗方法，以减少病毒疾病对人类和动物的影响。这一雄心壮志不会在这次奖学金的时间框架内实现，但我相信，我将在这里开展的工作将为这些未来的利益奠定基础。

Viral infections often have negative consequences. These can range from common colds that interfere with our daily lives, right through to debilitating infections that can lead to disability (such as polio), cancer (such as Hepatitis C) and death (such as HIV). It is likely that all life on Earth has been continually plagued by viruses for hundreds of millions of years. In order to survive, humans and animals have developed new and ever more inventive ways to resist infections. These antiviral defences have accumulated over time, such that an arsenal of antiviral defences now exists within our cells. These defences are potent and organized. As soon as our body senses an infection, interferons (proteins that "interfere" with viral replication) are released that increase the expression of our antiviral defences. Viruses, however, have developed their own ingenious ways of overcoming these antiviral defences. Thus, the extraordinary diversity of viruses we observe on Earth today represent those that have adapted to thrive in this hostile host environment. Not everybody is equally susceptible to viral infection. Some individuals are more readily infected than others, and different people, infected with the same virus, can have different clinical outcomes. Many factors, such as nutrition, underlying health conditions, or previous viral exposure, can influence the clinical course of a viral-disease. However, if we are to ever truly understand how hosts and viruses interact, we must understand a cell's built-in antiviral defences. A better understanding of these interactions might help explain how viral epidemics occur and why some people die from an infection and others do not. In this project I will investigate the interactions between viruses and the humans and animals they infect. Initially, I will focus on finding the novel antiviral factors that we humans have developed in order to resist infection by human immunodeficiency virus (HIV-1). Previous studies have shown that our in-built immunity to virus infection is often conferred by a single factor. Expression of such factors can be increased by interferons, and so they are referred to as interferon stimulated genes (ISGs). The identity and function of the vast majority of these ISGs remains unknown and so I believe that many more antiviral factors are yet to be identified. I have previously assembled a collection of human and macaque ISGs, most of which have unknown functions. In preparation for this project, I have examined the ability of hundreds of different ISGs to inhibit HIV-1. Now I will extend this approach to a wider range of retroviruses in an attempt to identify new antiviral factors. Crucially, human viruses have adapted to replicate in the presence of human antiviral defences so examining animal viruses increases the likelihood of identifying human antiviral genes. Conversely, human viruses are not adapted to replicate in the presence of macaque antiviral defences so screening human viruses using macaque ISGs increases the likelihood of identifying genes active against human viruses. I have already successfully used this screening approach to identify a new protein called CNP, which is abundantly expressed in the human brain and inhibits HIV-1 replication.During the course of this fellowship, I hope to be able to find more antiviral factors and explain how their mechanism of action helps humans and animals resist virus infection. It is my long-term ambition to use the information I produce to help design new drugs and treatments to reduce the impact of viral disease in humans and animals. This ambition will not be realised within the timeframe of this fellowship, but I believe that the work I will undertake here will lay the foundations for these future benefits