̽��ֱ�� of Cambridge - John Sinclair

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.

̽��ֱ��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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Silent killer

lw355 — Fri, 13 Sep 2013 13:14:24 +0000

To catch the herpes virus human cytomegalovirus (HCMV) you must be exposed to someone who has it. This isn’t difficult: it is carried by around 65% of the population. Once in the body, HCMV persists for life owing to its clever ability to avoid our immune system and to go into hiding inside our cells in a latent state. Now, research is identifying changes in these cells that could lead to a new route to eradicating the virus.

“HCMV can be acquired very early in childhood, and the number of people infected gradually rises throughout life,” said Professor John Sinclair, a molecular virologist in the Department of Medicine. “ ̽��ֱ��active virus can not only be passed from an infected mother to her child in breast milk but can easily be transferred from child to child in saliva – one child puts a toy in their mouth, then it’s passed to another child who does the same, and the virus is passed on. It’s also a sexually transmitted disease, so there’s another increase in infections when people become sexually mature.”

Once acquired, the virus goes into a latent state in the body. If it reactivates in healthy people, their immune responses prevent it from causing disease. But when the immune system is suppressed, active HCMV becomes dangerous. It is a major cause of illness and death in organ and bone marrow transplant patients, who are given drugs to deliberately suppress their immune system and prevent their body rejecting the transplant. With an increasing demand for transplants in the UK, HCMV is set to become a growing problem.

“If it’s not treated well, or it develops resistance to antiviral drugs, HCMV can lead to pneumonitis – inflammation of the lung tissue – and, in the most extreme case, it replicates all over the body and the patient ends up with multiple organ failure,” said Dr Mark Wills, a viral immunologist working alongside Sinclair in the Department of Medicine.

“Tissue from donors carrying the virus often has to be used for transplants because there are so few donors and so many people carrying the virus,” said Sinclair. “By transplanting bone marrow, or an organ from someone with the infection, you’re giving the patient the virus and you’re immune-suppressing them. That’s the worst of both worlds.”

And HCMV is not a worry just for transplant patients. “HCMV is now the leading cause of infectious congenital disease – that is, disease present at birth,” said Sinclair. Women in early pregnancy who are newly infected with HCMV or whose HCMV reactivates are at real risk, and this can lead to disease in their unborn baby. HCMV also targets HIV-AIDS patients, where a progressive failure of the immune system allows this opportunistic infection to thrive.

There is no vaccine to prevent HCMV infection, and the antiviral drugs available to treat it have significant toxicity and only limited effectiveness. In addition to the problem of viral resistance, drugs can only target HCMV in its active state, which means the virus can never be fully eradicated. “You can suppress the virus down to a very low level, but you can never get rid of the latent reservoir with the currently available antiviral drugs,” said Wills.

Sinclair and Wills, who have just received their fifth consecutive five-year grant from the Medical Research Council (MRC), have focused on understanding how the virus maintains this latent infection in specialised cells of the immune system and how the immune system is prevented from eliminating the virus from the body.

“ ̽��ֱ��belief has always been that, in its latent state, HCMV was just sitting there doing nothing, waiting to reactivate,” said Sinclair. “But we’ve started to identify major changes in latently infected cells, and we think these are targetable with novel drugs and immunotherapies.

“One change is in a transporter protein normally used by the cell to pump out things it needs to get rid of,” he added. “If you put the chemotherapy drug vincristine on a healthy cell, the cell will pump it out and survive. Working with Paul Lehner at the Cambridge Institute for Medical Research we found that, during latent infection, this transporter protein is less effective, making the cell more prone to killing by vincristine.” Their results were published in Science in April 2013.

“In addition to treatment with drugs, we’re looking into immunotherapies – treatments based on using the patient’s immune system,” said Wills. “Clearly, the difficulty is that all healthy people have very good immune responses to the virus, yet we all still carry it and can never get rid of it. There must be a problem here – the virus is deliberately trying to evade the immune system by manipulating it.”

Sinclair and Wills are trying to understand how the virus does this while in its latent state. Their findings show that HCMV disrupts the proper activation of the immune system by manipulating small signalling molecules called cytokines and chemokines, which normally help to kick-start the process of removing a foreign invader. “Now we know this, we can start to think about intervening,” said Wills.

“We’ve also found that latently infected cells are producing a number of viral proteins,” added Wills. “That’s a dangerous strategy for the virus, because these proteins could be presented on the surface of the cells they’re hiding in, which would attract immune cells like T cells to kill them. Our initial research showed that there are T-cell responses – so why aren’t the viral cells being eliminated? It’s paradoxical.” In further investigations, they uncovered another mechanism in which the virus was promoting a certain subtype of T cell that suppresses the immune system. “So now we’re working to remove the immunosuppressive component of that immune response by either removing or neutralising the function of the immunosuppressive T-cell subtype, to enable the other components of the body’s immune response to target the infected cells,” added Wills.

By targeting latent infection, this work holds great promise for developing better methods of treatment for HCMV and for the design of a vaccine. “If you intervene just before a transplant, and use this immunotherapeutic technique to target the latently infected cells, in combination with the drugs, you can purge the infected cells,” said Sinclair. “This massively reduces the potential that HCMV will reactivate in the person receiving the transplant, because effectively you’re not giving them the virus,” he added.

They have proved this concept in the laboratory and their new MRC grant will enable them to trial its effectiveness in a model system as a stepping stone to human clinical trials. “A decade ago we couldn’t have even contemplated doing this type of work,” said Sinclair, “but now we have worked out what’s going on during latent infection, we can try to target these changes. Being able to clear the latent infection is key to eradicating much of the disease caused by HCMV that we see in the clinic.”

Many of us are infected with a virus we’ll never clear. While we’re healthy, it’s nothing to worry about, but when our immune system is suppressed it could kill us.

̽��ֱ��virus is deliberately trying to evade the immune system by manipulating it

Mark Wills

̽��ֱ��District

HCMV

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Search and rescue: scientists identify a novel therapy with potential for treating Parkinson’s disease

ns480 — Thu, 22 Dec 2011 11:29:41 +0000

Scientists at the ̽��ֱ�� of Cambridge have made a significant step in the development of a novel therapy that could one day help to slow down, or even halt, the damage caused by Parkinson’s disease (PD), one of the most common neurodegenerative disorders. ̽��ֱ��therapy, which has been shown to be effective in rat models of the condition, involves exploiting the natural process by which common viruses protect mitochondria (the energy-producing power house of cells) in order to keep cells alive while they replicate.

̽��ֱ��research, published this week in the Journal of Experimental Medicine, involved molecular virologists working in collaboration with neuroscientists to share their expertise across disciplines. Building on an earlier study published in 2007, the researchers have now shown proof of principle for their methodology which offers a potential novel disease -modifying approach to treating PD. ̽��ֱ��researchers’ work in harnessing the behaviour of viruses may have wider applications for the treatment of other neurodegenerative diseases - including Alzheimer’s and Huntington’s disease.

Although the age of onset varies considerably, PD is strongly associated with the elderly, with an average age of onset of around 70 years. Around 120,000 people in the UK are directly affected by the disorder with the numbers diagnosed likely to rise as the average age of the population increases. ̽��ֱ��disease results from a loss of many different types of nerve cells in the brain but especially a population that produces dopamine, a chemical that relays signals from one neuron to another. It is not known why these cells die, but when they do the people affected experience problems with walking and moving quickly.

Current treatments for PD centre on symptomatic drugs which, though they help treat some of the motor features of PD, are not able to stop the disease from progressing. Indeed, over time these drugs can produce their own side-effects.

̽��ֱ��novel methodology developed by the Cambridge researchers stemmed from the work of Professor John Sinclair and colleagues at the Department of Medicine in studying the ways in which common viruses – such as herpes - seek to survive and replicate in cells in the body. When these viruses invade a cell, a tiny component of the virus called the Beta2.7 gene guards the mitochondria from damage for an interval of time – typically five days - so that the virus can replicate and spread from cell to cell.

In looking at how the virus gene functions, Professor Sinclair spotted the potential for harnessing this protective function to help cells survive attack by neurological disorders such as PD. ̽��ֱ��component of the virus that protects the cells’ mitochondria is a section of RNA (ribonucleic acid) which, like DNA, is essential for life. ̽��ֱ��molecular virologists led by Professor Sinclair used a method of complexing (mixing) the RNA derived from a human cytomegalovirus to a protein of a rabies virus. This protein was selected as it enables the beta2.7 to cross into the brain when the whole complex is given into the circulation, and, as only of a portion of the rabies and herpes viruses are used, there is no danger of contracting any disease from either virus.

Having identified the potential offered by the virus as an agent for ‘search and rescue’, Professor Sinclair collaborated with Professor Roger Barker and colleagues at the Cambridge Centre for Brain Repair to see whether this novel protein/RNA complex could protect neurons from cell death associated with PD. Using rat models, the results have been promising and resulted in a further tranche of research funding from the Michael J Fox Foundation to take work in the laboratory forward to help develop the novel therapeutic for eventual clinical use.

̽��ֱ��researchers emphasise that much work remains to be done in taking the therapy to the point at which clinical trials can be undertaken. “Our results with rat models are tremendously encouraging, but we need to do a lot more in terms of refining and optimising the therapy before it could be used in patients. For example, we don’t know what the dosages or frequency of treatment might need to be in treating humans,” said Professor Sinclair.

“What we have established is proof of principle – essentially showing that this is a truly novel and highly promising pathway for treating not just the dopamine cell loss in Parkinson’s but also all cell losses in this condition, as well as other chronic neurodegenerative disorders.”

̽��ֱ��novel therapy offers a number of significant advantages over all currently used surgical and drug therapies. Professor Barker explained: “In many ways the therapy we’ve developed is a beautiful treatment. It can be delivered through an injection direct into the bloodstream, for example into the arm of the patient. This makes it much easier to use than many other putative disease-modifying therapies such as growth factors which have to be injected directly into the brain. This new agent also appears to be non-immunogenic – in other words it does not trigger an immune response so it can be used repeatedly and should still maintain its potency. Finally, it appears to go only into the brain and nowhere else in the body and then to target only cells that are unwell.”

̽��ֱ��next stage of the research will be to test the novel therapy in other models of PD to help define the dosage and time course of delivery.

A collaboration between virologists and neuroscientists at Cambridge ̽��ֱ�� has demonstrated how viruses that cross the blood/brain barrier could be exploited to slow down, or even halt, the progress of Parkinson’s and other neurodegenerative diseases.

What we have established is proof of principle – essentially showing that this is a truly novel and highly promising pathway for treating not just the dopamine cell loss in Parkinson’s but also all cell losses in this condition, as well as other chronic neurodegenerative disorders.

Professor John Sinclair

Jez atkinson from Flickr Creative Commons

Pensive parent

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