Mathematical Virology: A new mathematical approach to viral evolution grounded in experiment

Lead Research Organisation: University of Leeds
Department Name: Astbury Centre

Abstract

Society faces a number of major challenges due to the impact of global warming on world climate. One consequence is the spread of otherwise rare and poorly characterised viral infections into economically advanced areas of the world. Examples include Bluetongue virus, which arrived in the UK after years of being restricted to much warmer climates. This poses a threat to public and animal health from both existing viruses and newly emerging ones.
A major problem in the design of anti-viral therapies is the emergence of viral strains that are resistant to anti-viral drugs soon after initial treatment. Research into the mechanisms that could prevent such viral escape is therefore urgently required in order to develop therapeutics with long-term action. Moreover, viruses can evolve strains that cross the species barrier, for example from an animal to a human host as in the case of bird flu, and it is important to be able to develop strategies to prevent this. Insights into virus evolution could shed light on both issues. In particular, we need to better understand the constraints that viruses face when their genomes evolve, and find ways of predicting such evolutionary behaviour.
In our previous research we have gained fundamentally new insights into the constraints underlying virus structure and function. In an interdisciplinary research programme, combining the modelling expertise of the Twarock group at the York Centre for Complex Systems Analysis at the University of York with the experimental know-how of the Stockley and Rowlands Labs at the Astbury Centre for Structural Molecular Biology In Leeds, we investigate here their impact on the evolution of viruses, working with a number of viruses including picornaviridae that contain important human and animal viruses, such as foot-and-mouth virus. Our research programme aims at improving our understanding of the factors that determine the evolutionary behaviour of viruses, and we will use these results to explore strategies to misdirect viral evolution. In particular, we will assess in which ways the structural constraints we have discovered earlier lead to evolutionary bottlenecks, i.e. correspond to constraints that the viral escape mutants cannot avoid, and that a new generation of anti-viral therapeutics could target. Moreover, we plan to develop methods to predict how viruses may react to a drug, and use this to test the impact of different anti-viral strategies. This research has the potential to lead to a new generation of "evolutionarily-stable" therapeutics that are less susceptible to the problem of escape mutants.

Publications

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Dykeman EC (2013) Building a viral capsid in the presence of genomic RNA. in Physical review. E, Statistical, nonlinear, and soft matter physics

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Dykeman EC (2014) Solving a Levinthal's paradox for virus assembly identifies a unique antiviral strategy. in Proceedings of the National Academy of Sciences of the United States of America

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Patel N (2015) Revealing the density of encoded functions in a viral RNA. in Proceedings of the National Academy of Sciences of the United States of America

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Patel N (2017) Rewriting nature's assembly manual for a ssRNA virus. in Proceedings of the National Academy of Sciences of the United States of America

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Rolfsson Ó (2016) Direct Evidence for Packaging Signal-Mediated Assembly of Bacteriophage MS2. in Journal of molecular biology

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Rolfsson Ó (2016) Direct Evidence for Packaging Signal-Mediated Assembly of Bacteriophage MS2. in Journal of molecular biology

 
Description We have demonstrated that RNA packaging signal-viral coat protein interactions in the family of positive sense single stranded RNA viruses can be novel drug targets. This group includes major human pathogens such as polio, HIV, hepatitis B etc.
Exploitation Route In addition to teh previous patents filed by teh Universities of Leeds and York our work has now extended to the HBV virus and in a collabaortion with the NIH has led to a further patent application led by the NIH in which the Pi/co-I on nthis grant are named inventors.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Our results have led to a new paradigm in virus assembly that has identified novel anti-viral drug targets, having implications for viral assembly and evolution.
First Year Of Impact 2015
Sector Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Cultural

 
Description • In situ Structural & Mechanistic Interrogation of dsDNA synthesis in Hepatitis B Virus
Amount £291,000 (GBP)
Funding ID MRF-044-0002-RG-PATEL 
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 05/2018 
End 04/2021
 
Title A novel anti-viral strategy against RNA viruses 
Description Our mathematical models resulted in the discovery of a new anti-viral strategy against single-stranded RNA viruses, including Hepatitis C and HIV. 
IP Reference GB1315785.4 
Protection Patent application published
Year Protection Granted
Licensed Commercial In Confidence
Impact This patent application initiated a cascade of subsequent applications al targeted at exploiting the novel aspect of virion assembly in ssRNA viruses we have discovered, namely RNA Packaging Signal-mediated Assembly. There are many aspects of this mechanism that are potentially exploitable, from directly-acting anti-virals targeting the RNA-CP contacts that drive the mechanism to recoding therapeutic RNAs as good assembly substrates for gene delivery and editing.
 
Title METHODS OF TREATING HBV 
Description In collaboration with colleagues at the US NIH Frederick we screened for small molecule ligands that bind the major RNA RNA PS. We then characterised their affinities for the free RNA and assessed their ability to inhibit HBV replication in vivo (with the Dorner laboratory, Imperial College). On the basis of teh initial results our NIH colleagues filed this patent application for teh use of ligands based around their library as treatments for HBV infection. The in vivo data failed to be reproducible leading to abandonment of the patent since the ligand library used was fairly generic. 
IP Reference U.S. Application No. 62/685,145 
Protection Patent application published
Year Protection Granted
Licensed No
Impact We are in discussions to develop our understanding of the HBV virus to develop bespoke delivery systems for mRNAs.