̽��ֱ�� of Cambridge - Ian Groves

Llama ‘nanobodies’ could hold key to preventing deadly post-transplant infection

sc604 — Thu, 22 Jul 2021 09:07:34 +0000

Around four out of five people in the UK are thought to be infected with HCMV, and in developing countries this can be as high as 95%. For the majority of people, the virus remains dormant, hidden away inside white blood cells, where it can remain undisturbed and undetected for decades. If the virus reactivates in a healthy individual, it does not usually cause symptoms. However, for people who are immunocompromised – for example, transplant recipients who need to take immunosuppressant drugs to prevent organ rejection – HCMV reactivation can be devastating.

At present, there is no effective vaccine against HCMV, and anti-viral drugs often prove ineffective or have very serious side-effects.

Now, in a study published in Nature Communications, researchers at Vrije Universiteit Amsterdam in the Netherlands and at the ̽��ֱ�� of Cambridge have found a way to chase the virus from its hiding place using a special type of antibody known as a nanobody.

Nanobodies were first identified in camels and exist in all camelids – a family of animals that also includes dromedary, llamas and alpacas. Human antibodies consist of two heavy and two light chains of molecules, which together recognise and bind to markers on the surface of a cell or virus known as antigens. For this special class of camelid antibodies, however, only a single fragment of the antibody – often referred to as single domain antibody or nanobody – is sufficient to properly recognize antigens.

Dr Timo De Groof from Vrije Universiteit Amsterdam, the study’s joint first author, said: “As the name suggests, nanobodies are much smaller than regular antibodies, which make them perfectly suited for particular types of antigens and relatively easy to manufacture and adjust. That’s why they’re being hailed as having the potential to revolutionise antibody therapies.”

̽��ֱ��first nanobody has been approved and introduced onto the market by biopharmaceutical company Ablynx, while other nanobodies are already in clinical trials for diseases like rheumatoid arthritis and certain cancers. Now, the team in ̽��ֱ��Netherlands and the UK have developed nanobodies that target a specific virus protein (US28), one of the few elements detectable on the surface of a HCMV latently infected cell and a main driver of this latent state.

Dr Ian Groves from the Department of Medicine at the ̽��ֱ�� of Cambridge said: “Our team has shown that nanobodies derived from llamas have the potential to outwit human cytomegalovirus. This could be very important as the virus can cause life-threatening complications in people whose immune systems are not functioning properly.”

In laboratory experiments using blood infected with the virus, the team showed that the nanobody binds to the US28 protein and interrupts the signals established through the protein that help keep the virus in its dormant state. Once this control is broken, the local immune cells are able to 'see' that the cell is infected, enabling the host’s immune cells to hunt down and kill the virus, purging the latent reservoir and clearing the blood of the virus.

Dr Elizabeth Elder, joint first author, who carried out her work while at the ̽��ֱ�� of Cambridge, said: “ ̽��ֱ��beauty of this approach is that it reactivates the virus just enough to make it visible to the immune system, but not enough for it to do what a virus normally does – replicating and spreading. ̽��ֱ��virus is forced to put its head above the parapet where it can then be killed by the immune system.”

Professor Martine Smit, also from from the Vrije Universiteit Amsterdam, added: “We believe our approach could lead to a much-needed new type of treatment for reducing – and potentially even preventing – CMV infectious in patients eligible for organ and stem cell transplants.”

̽��ֱ��research was funded by the Dutch Research Council (NWO), Wellcome and the Medical Research Council, with support from the NIHR Cambridge Biomedical Research Centre.

Reference
De Groof TWM, Elder E, et al. Targeting the latent human cytomegalovirus reservoir for T-cell mediated killing with virus specific nanobodies. Nature Communications (2021). DOI: 10.1038/s41467-021-24608-5

Scientists have developed a ‘nanobody’ – a small fragment of a llama antibody – that is capable of chasing out human cytomegalovirus (HCMV) as it hides away from the immune system. This then enables immune cells to seek out and destroy this potentially deadly virus.

Our team has shown that nanobodies derived from llamas have the potential to outwit human cytomegalovirus

Ian Groves

Jessica Knowlden on Unsplash

Llamas

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Scientists launch a pre-emptive strike on deadly post-transplant infection

ta385 — Tue, 23 Feb 2021 12:45:00 +0000

Around 80% of the UK population is currently infected with human cytomegalovirus (HCMV) and in developing countries this can be as high as 95%. ̽��ֱ��virus can remain dormant in our white blood cells for decades and, if it reactivates in a healthy individual, does not usually cause symptoms. But, for people who are immunocompromised, HCMV reactivation can be devastating.

HCMV reactivation has been identified in COVID-19 patients, though scientists do not yet understand the relationship between the two viruses. Reactivation or re-infection in transplant recipients can lead to severe illness, including organ rejection and, in some cases, death.

More than 200,000 kidney, lung and stem cell transplants take place globally every year and HCMV reactivation occurs in more than half of these cases. For reasons scientists don’t yet fully understand, immunosuppressants appear to encourage the virus to reactivate as well as compromising the patient’s ability to fight it. There remains no effective vaccine against HCMV and anti-viral therapies often prove ineffective or detrimental.

Now, a team from the ̽��ֱ�� of Cambridge’s School of Clinical Medicine has identified a drug type and treatment strategy that could dramatically reduce these devastating reactivation events. ̽��ֱ��study, published in the journal PNAS, describes how scientists exposed HCMV-infected blood samples to a wide-range of ‘epigenetic inhibitors’ – drugs widely used in cancer treatment – hoping to prompt the latent virus to produce proteins or targetable antigen that are visible to our immune system.

They discovered that a particular group of these drugs, ‘bromodomain inhibitors’, successfully reactivated the virus by forcing it to convert its hidden genetic instructions into protein. This then enabled T-cells in the blood samples to target and kill these previously undetectable infected cells.

̽��ֱ��study is the first to identify the involvement of human host bromodomain (BRD) proteins in the regulation of HCMV latency and reactivation but also proposes a novel ‘shock and kill’ treatment strategy to protect transplant patients.

Lead author Dr Ian Groves said: “We’re looking to purge the patient’s viral reservoir before they go into the operating theatre and before they start taking immunosuppressants, when they would become extremely vulnerable to the virus reactivating. In other words, we’re proposing a pre-emptive strike.

“Prior to transplantation, many patients will have a relatively healthy immune system, so when the virus puts its head above the parapet, its cover is blown, and the immune system will see it and kill the cells it’s been hiding in. Ideally, donors would also be treated to avoid re-infecting recipients.”

There are similar drugs in Phase 1–3 clinical trials around the world for other intended uses, mainly in the treatment of cancers but also Type 2 diabetes-related cardiovascular disease.

Dr Groves said: “This would be the first type of treatment to reduce HCMV infection levels pre-transplant in order to lower the chances of virus reactivation during immune suppression after transplantation. Our findings could lead to thousands of lives being saved every year.”

“In addition to the terrible human suffering this virus causes, treating its effects adds enormously to the high costs already incurred by transplantation. It’s a really serious issue for health services in wealthy nations and a desperate one in developing countries. Our findings offer an opportunity to transform this horrible situation.”

̽��ֱ��study builds on over 25 years of extensive research into the molecular biology of HCMV and its immune evasion tactics (funded by the Medical Research Council). ̽��ֱ��researchers hope their study could eventually help doctors fight HCMV on other fronts, including in maternity and neo-natal care. HCMV affects at least 1% of all live births in developed countries, and many more in developing countries. These children can be left with brain damage and hearing loss, but congenital infection during pregnancy can also lead to miscarriage.

Reference

I. J. Groves et al., ‘Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention’. PNAS (2021). DOI: 10.1073/pnas.2023025118

A potential new treatment to protect immunosuppressed patients from human cytomegalovirus (HCMV) has been discovered by scientists at the ̽��ֱ�� of Cambridge. Their study shows that certain epigenetic inhibitors expose and help to destroy dormant HCMV infections, which often reactivate to cause serious illness and death in these vulnerable groups. Subject to clinical trials, their proposed ‘shock and kill’ treatment strategy offers hope to transplant patients across the world.

Our findings could lead to thousands of lives being saved every year

Ian Groves

Sasin Tipchai via Pixabay

Surgeons at work in an operating theatre

Funding

This research was supported by GlaxoSmithKline and the Medical Research Council.

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