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Virus in focus – protecting precious donated kidneys

27 April 2018

Researchers have discovered a way to target a virus which can cause kidney transplants to fail.

A team at the University of Leeds has revealed the structure of the BK polyomavirus (BKV), which affects kidney and bone marrow transplant patients, in near-atomic levels of detail, for the first time.

Seeing the virus structure at a molecular-level means they will be able to look for potential targets for antiviral therapies or drugs. With this knowledge, they can target chemical compounds at it in such a way that they bond with it precisely, stopping the virus from working. The more detailed the structure they have to work with, the more precision they can apply.

Researchers, Dan Hurdiss and Neil Ranson

Researchers, Dan Hurdiss and Neil Ranson

Astbury Centre PhD researcher Dan Hurdiss, said: “This detailed information serves as a structural roadmap, allowing us to visualise several potential targets for antiviral therapies.

“These may include drugs which block BKV from entering our cells or which prevent proper assembly of the virus particle. Going forward, these structures may also be used to identify how antibodies from patients with other diseases recognise the BKV virus particle and thus aid in the development of a vaccine.”

About 80 per cent of the world’s adult population is infected with BKV, but the virus rarely causes illness in people with a healthy immune system. However, in immunocompromised individuals, BKV can ‘reactivate’ and cause serious diseases.

One example of a BKV-associated diseases is polyomavirus-associated nephropathy (PVAN). Around 10 per cent of people who receive a kidney transplant will be affected by PVAN. Of those affected by PVAN, up to 90 per cent of these will go on to have their transplant organs rejected. At present, there are limited treatment options available for individuals experiencing BKV associated diseases. The new structures give scientists a better-quality research tool to work with.

Sarah Harwood, patient involvement coordinator at Kidney Research UK said: “Losing a donor kidney soon after transplantation is one of the most difficult things a kidney patient can go through – so much hope followed by crushing disappointment. Seeing this amount of detail about the BK virus will hopefully speed up our ability to protect precious donated kidneys.”

The structures were created using the cryo-electron microscopy method, which won a Nobel Prize in 2017, by freezing infectious BKV particles and taking thousands of images using the microscopes. These two-dimensional images were then combined computationally to produce a high-resolution, three-dimensional view of the virus.

Professor Neil Ranson, Director of Cryo-Electron Microscopy at the University of Leeds, said: “Cryo-electron microscopy has been around for 30 years and has been incredibly useful, but until recently the technology lacked the ability to routinely look at molecules at the level of detail needed.

“Without that detail, scientists sometimes struggled to understand the structure of biological molecules and how they function, especially when they are in their normal workplace: inside our cells.

“However, the Titan Krios microscopes we have installed in Leeds are absolutely state-of-the-art, and mean that these limitations have been shattered. Researchers and industry users who work with us can now image biological molecules with an incredible resolution. Crucially, we’ll also be able to see how these molecules interact with each other.”

The BK Polyomavirus structure research was funded by Kidney Research UK, Wellcome and Kidney Research Yorkshire and leads on from previous research funded by Kidney Research UK.

A research paper announcing the new structures has been published in the journal Structure. The level of detail in the image allows us to see features on the virus as tiny as ~3 Ångströms wide. One Ångström is equivalent to one ten-billionth of a metre or 0.1 nanometre. The structure is so small it cannot be seen by the naked eye.

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