Identifying and Characterizing Antiretroviral Interferon Stimulated Genes (ISGs)

抗逆转录病毒干扰素刺激基因 (ISG) 的识别和表征

• 批准号: MR/K024752/1
• 负责人: Sam Wilson
• 金额: $ 133.31万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK024752%2F1
• 关键词: Identifying; Characterizing; Antiretroviral; Interferon; Stimulated

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

病毒感染往往会带来负面后果。这些疾病包括干扰我们日常生活的普通感冒，以及可能导致残疾（如脊髓灰质炎）、癌症（如丙型肝炎）和死亡（如艾滋病毒）的衰弱性感染。地球上的所有生命都可能在数亿年的时间里不断受到病毒的困扰。为了生存，人类和动物开发了新的和更具创造性的方法来抵抗感染。这些抗病毒防御随着时间的推移而积累，因此我们的细胞中存在抗病毒防御的武器库。这些防御是有力和有组织的。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，病毒已经发展出了自己独特的方式来克服这些抗病毒防御。因此，我们今天在地球上观察到的病毒的非凡多样性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。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，不同的人感染同一种病毒，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，可以影响病毒性疾病的临床过程。然而，如果我们要真正了解宿主和病毒如何相互作用，我们必须了解细胞的内置抗病毒防御。更好地理解这些相互作用可能有助于解释病毒流行病是如何发生的，以及为什么有些人死于感染，而另一些人则不会。在这个项目中，我将研究病毒与它们感染的人类和动物之间的相互作用。首先，我将集中精力寻找我们人类为了抵抗人类免疫缺陷病毒（HIV-1）感染而开发的新型抗病毒因子。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赋予的。这些因子的表达可以通过干扰素增加，因此它们被称为干扰素刺激基因（ISG）。这些ISG中的绝大多数的身份和功能仍然未知，因此我相信还有更多的抗病毒因子有待确定。我以前收集了一系列人类和猕猴的ISG，其中大部分功能未知。在准备这个项目时，我已经检查了数百种不同的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中，试图识别新的抗病毒因子。至关重要的是，人类病毒已经适应了在人类抗病毒防御存在的情况下复制，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存在下复制，因此使用猕猴ISG筛选人类病毒增加了鉴定对人类病毒有活性的基因的可能性。我已经成功地利用这种筛选方法鉴定出一种在人脑中大量表达并抑制HIV-1复制的新蛋白质CNP，在此次研究期间，我希望能够发现更多的抗病毒因子，并解释它们的作用机制如何帮助人类和动物抵抗病毒感染。我的长期目标是利用我产生的信息来帮助设计新的药物和治疗方法，以减少病毒性疾病对人类和动物的影响。这个抱负不会在这个奖学金的时间范围内实现，但我相信我在这里所做的工作将为这些未来的利益奠定基础

项目成果

Interferon-Stimulated Gene (ISG)-Expression Screening Reveals the Specific Antibunyaviral Activity of ISG20.

• DOI: 10.1128/jvi.02140-17
• 发表时间: 2018-07-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Feng J;Wickenhagen A;Turnbull ML;Rezelj VV;Kreher F;Tilston-Lunel NL;Slack GS;Brennan B;Koudriakova E;Shaw AE;Rihn SJ;Rice CM;Bieniasz PD;Elliott RM;Shi X;Wilson SJ
• 通讯作者: Wilson SJ

BTN3A3 evasion promotes the zoonotic potential of influenza A viruses

• DOI: 10.1038/s41586-023-06261-8
• 发表时间: 2023-06-28
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Pinto, Rute Maria;Bakshi, Siddharth;Palmarini, Massimo
• 通讯作者: Palmarini, Massimo

Insights into Circovirus Host Range from the Genomic Fossil Record.

洞察电路病毒宿主的范围从基因组化石记录范围。

• DOI: 10.1128/jvi.00145-18
• 发表时间: 2018-08-15
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Dennis TPW;Flynn PJ;de Souza WM;Singer JB;Moreau CS;Wilson SJ;Gifford RJ
• 通讯作者: Gifford RJ

The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block.

• DOI: 10.1128/jvi.02254-16
• 发表时间: 2017-04-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Rihn SJ;Foster TL;Busnadiego I;Aziz MA;Hughes J;Neil SJD;Wilson SJ
• 通讯作者: Wilson SJ

MX2 is an interferon-induced inhibitor of HIV-1 infection.

• DOI: 10.1038/nature12653
• 发表时间: 2013-10-24
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Kane, Melissa;Yadav, Shalini S.;Bitzegeio, Julia;Kutluay, Sebla B.;Zang, Trinity;Wilson, Sam J.;Schoggins, John W.;Rice, Charles M.;Yamashita, Masahiro;Hatziioannou, Theodora;Bieniasz, Paul D.
• 通讯作者: Bieniasz, Paul D.