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RNA viruses are major pathogens that represent the majority of new viruses emerging over time. They are particularly good at evading the host's response to infection. A better understanding of the interaction between virus and host can lead to a better control of viral infections. Recent discoveries on viral genome composition and structure might allow us to manipulate this interaction and generate new, safer vaccines.

Q: Why is it important to understand how RNA viruses evolve?

Peter Simmonds: RNA viruses are very important medical and veterinary pathogens, and they ravage crops. We need to understand why they are pathogenic and how they spread. Importantly they also represent the majority of new viruses that are emerging over time - over the last century and before. We really need to understand how this happens and how we can predict when viruses are going to emerge, how we might then control them and how we might develop vaccines for them.

Q: How do viruses manage to be so successful?

PS: RNA viruses are small in the sense that their genomes are perhaps only a few thousand bases long. For comparison, the human genome is three billion bases long and contains 25-30,000 genes. RNA viruses might only have 5. Yet they have this extraordinary complex relationship with the host, which means that they can actually go into a cell and have mechanisms that we do not understand to evade the host's response to the infection. They cause widespread infections of humans and systemic disease and so on, in ways that the immune system cannot control. Research is extremely important: understanding how this interaction occurs and what factors allow a virus to escape from these sophisticated host cell defences.

Q: What are the most important lines of research that have developed over the last 5-10 years?

PS: In our research group we have been very interested in the interaction between viruses and hosts. We have been exploring ways in which this interaction might be modified by other, more exotic attributes of RNA virus genomes. We imagine an RNA virus genome to be simply a piece of RNA to code for protein, but actually the RNA molecule is structured and has compositional features, which we think also modify the way in which the virus interacts. The RNA itself for example can actually form complex internal RNA structures, and we know that viruses that show this property are persistent in their hosts. For example, Hepatitis C virus which causes liver disease over a long period of time has an intensely structured genome. We think the structure somehow modifies the interaction of the RNA with RNA sensors in the cell and prevents in effect an immune response developing that would clear the virus.

The other feature which we believe is important is the composition. RNA is made up of four bases. You can count bases or dinucleotides, where you are looking at frequencies of one base followed by another. Of these, C followed by G, or CpG dinucleotides, seems to be extremely important. It looks, in literary terms, like RNA viruses have tried to avoid having this in their genomes. It has nothing to do with protein coding, it seems as if this is a recognition site for host cell defence. In fact, if we make artificial viruses where we increase the number of CpGs in the genome, the viruses can barely replicate themselves because it seems as though the cell can recognise it is foreign and eliminate them. This translates through to in vivo models where, if we use a live host system, we can show that disease can be attenuated by infection. The importance of this is that we can now precisely control replication in a quite novel way. That means for example we can generate viruses which fail to replicate properly and are therefore attenuated; this would be a fantastic way to make a safe vaccine. We can infect humans, livestock and so on with these viruses. They become infected but disease cannot develop, and they actually develop a substantial immune response to the virus that protects them. Modifying polio vaccine to make it safe would be a great application of this process.

Q: Why does your line of research matter and why should we fund it?

PS: I think it is important that we understand more about how RNA viruses work. I know that sounds a bit blue sky but nevertheless it does underpin so much of our current understanding of human disease, veterinary disease and so on. If we can understand how this host cell interaction works, we can then understand a bit more about how to control virus infections. The other point would be that we can, using some of these discoveries that we have made recently on composition and structure, precisely manipulate the way in which a virus interacts with a cell and host. We can generate these new vaccines which are going to be safe and non-reverting for human and animal use.

Q: How does your research fit into translational medicine within the department?

PS: I mentioned the vaccine applications for the work we have done. There are other translational aspects. By background a medical doctor I work one session at the hospital in clinical virology. One of the programmes starting there is to explore the use of deep sequencing as a diagnostic technique. The idea behind that is that rather than do targeted screening for individual viruses we can actually look at the entire virome of a individual sample and be able to screen much more effectively for a wide range of different pathogens and carrier viruses that a patient might be infected with. I think in the long term it is going to fit very well with developments in molecular medicine and diagnostics which will improve patient treatment and monitoring.

Peter Simmonds

Pathogen Research

Professor Peter Simmonds studies the epidemiology, evolution and emergence of a wide range of human pathogenic viruses. He investigates the evolutionary and functional basis for the suppression of specific dinucleotides in RNA viruses; this suppression represents a defence mechanisms against the innate immune system. He also studies RNA secondary structures in viruses, which is associated with host persistence.

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