The team are the first to observe at a single-molecule level how the genetic material (genome) that forms the core of a single-strand RNA virus particle packs itself into its outer shell of proteins. Lead researcher Professor Peter Stockley said their results overturn accepted thinking about the process and could open a chink in the armour of a wide range of viruses.
"If we can target this process, it could lead to a completely new class of anti-virals that would be less likely to create resistant viruses than existing drugs, which tend to target individual proteins," Professor Stockley said.
A number of important viruses like the common cold and polio have RNA (ribonucleic acid) instead of DNA as their genetic material. The observations reveal that the viruses' RNA initially has a much greater volume than the virus particles created after they are packed inside their protein shell.
"We realised that the RNA genome must have to be intricately folded to fit into the final container, just like when you pack to go on holiday and need to fold your clothes to fit into the space in your suitcase," said co-author Dr Roman Tuma from the University of Leeds' Faculty of Biological Sciences.
When the team added proteins to the viral RNA they saw an immediate collapse in its volume.
"It seems that viral RNAs have evolved a self-folding mechanism that makes closing the 'viral suitcase' very efficient. It's as though 'the suitcase and the clothes' work together to close the lid and protect the content," Dr Tuma said.
"The viral RNAs, and only the viral RNAs, can do this trick of folding up to fit as soon as they see the 'suitcase' coming. That's the important thing. If we can interfere in that process we've got a completely novel drug target in the lifecycle of viruses," Professor Stockley said.
"At the moment there are relatively few antiviral drugs and they tend to target enzymes that the virus encodes in its genome. The problem is that the drugs target one enzyme initially and, within the year, scientists are identifying strains that have become resistant. Individual proteins are extremely susceptible to this mutation. A fundamental process like the one we're looking at opens the possibility of targeting the collective behaviour of essential molecules, which could be much less susceptible to developing resistance," explained Professor Stockley.
The same phenomenon is seen in both bacterial and plant viruses. "While we have not proved it yet, I would put money on animal viruses showing the same mechanism too," Professor Stockley added.
The team used sophisticated instrumentation custom built at the University that allowed them to make the first ever single-molecule measurements of viral assembly. This allowed researchers to observe individual viral particles one at a time. "The specific collapse, which can only be seen in such assays, was totally unexpected and overturns the current thinking about assembly," Professor Stockley said.
The team also includes PhD student Alexander Borodavka, whose Wellcome Trust studentship funded the new research. They have recently secured a grant from the Biotechnology and Biological Sciences Research Council (BBSRC) to extend their research.
"We're now perfectly positioned to pursue questions about how this mechanism works in other viruses and we're already thinking about ways to start designing new antiviral drugs that would target this newly recognised feature of viral lifecycles," Professor Stockley said.
The research is published in the Proceedings of the National Academy of Sciences (PNAS).
Dave Westhead and colleagues in Experimental Haematology, Cancer Research UK (Jan 2015), £700,521
Sheena Radford, Mark Harris, Peter Stockley, Alan Berry, Alex O'Neill, Thomas Edwards, Adrian Goldman, Anastasia Zhuravleva, Wellcome Trust (Jan 2015), £443,015
Bill Kunin, EU (Jan 2015), £157,490
John Colyer, Leeds Teaching Hospitals Charitable Fund (Jan 2015), £40,000
Chris Hassall, Royal Society (Dec 2014), £14,500
Ryan Seipke, Royal Society (Nov 2014), £13,700
Alan Berry, Wellcome Trust (Oct 2014), £749,865
Ian Hope, Marie-Anne Shaw, BBSRC (Oct 2014), £396,565
Alison Ashcroft, Peter Stckley, Sheena Radford, Nic Stonehouse, David Brockwell, Darren Tomlinson, BBSRC (Oct 2014), £340,937
Les Firbank, Joe Holden, BBSRC (Oct 2014), £210,302
Darren Tomlinson and colleagues in Chemistry and Pathology, anatomy and Tumour Biology, Dr Hadwen Trusy (Oct 2014), £194,475
Paul Knox, EU (Oct 2014), £167,229
Martin Stacey and colleagues in Medicine & Health, Pfizer (Oct 2014), £90,453
Darren Tomlinson and colleagues in Experimental Oncology, YCR (Oct 2014), £69,480
Andrew Macdonald, Jamel Mankouri, Kidney Research Fund UK (Oct 2014), £58,878
Mike McPherson and colleagues in Dentistry and Engineering, Wellcome Trust (Oct 2014), £58,437
Dave Westhead and colleagues in Experimental Haemotology, Leukaemia & Lymphoma Research (Sep 2014), £281,424
Emmanuel Paci and colleagues in Chemistry, BBSRC (Sep 2014), £636,759
Andrew Peel, BBSRC (Sep 2014), £371,598
Lars Jeuken, Stephen Evans, BBSRC (Sep 2014), £333,684
Lars Jeuken, BBSRC (Sep 2014), £313,463
Michelle Peckham, Mark Harris, Rao Sivaprasadarao, Eileen Ingham, Nic Stonehouse, Nikita Gamper, Wellcome Trust (Sep 2014), £192,763
Neil Ranson, BBSRC (Aug 2014), £355,253
Stuart Egginton, BHF (Aug 2014), £271,094
Darren Tomlinson, Mike McPherson, Technology Strategy Board (Aug 2014), £98,665
Peter Henderson, Leverhulme Trust (Aug 2014), £15,222
Mike McPherson (and colleagues in the School of Chemistry), EPSRC (Jul 2014), £819,880
Peter Stockley, Neil Ranson, BBSRC (Jul 2014), £455,787
Sheena Radford, Univesity of Michigan (Jul 2014), £138,452
Ryan Seipke, British Society Antimicrobial Chemistry (Jun 2014), £11,960
John Trinick, BHF (Jun 2014), £222,614
Chris West, Leverhulme Trust (Jun 2014), £181,241
Jon Lippiat, Darren Tomlinson, BBSRC (May 2014), £125,174
Christine Foyer, Royal Society (May 2014), £24,000
David Brockwell, Sheena Radford, Medimmune Ltd (Apr 2014), £337,661
Peter Stockley, Wellcome Trust (Apr 2014), £251,019
Mike McPherson, Wellcome Trust (Apr 2014), £146,596
Andrew Macdonald, Kidney Research Fund UK (Apr 2014), £127,237
Elwyn Isaac, DEFRA (Apr 2014), £126,512
Mike McPherson (and colleagues in School of Design), Technology Strategy Board (Apr 2014), £114,350
Paul Millner, Peter Stockley, Darren Tomlinson, YCR (Apr 2014), £95,874
Carrie Ferguson, Karen Birch, Shaunna Burke, Heart Research UK (Apr 2014), £60,140
Tim Benton, Technology Strategy Board (Apr 2014), £24,969
Bill Kunin, Technology Strategy Board (Apr 2014), £21,244
Dave Westhead, MRC (Apr 2014), £18,304