Identifying and Characterizing Antiretroviral Interferon Stimulated Genes (ISGs)

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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