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Preventing Deadly Post-Transplant Infection With Llama Nanobodies

Researchers have developed virus-specific nanobodies from llamas that can target the latent reservoir of cytomegalovirus in humans.

A small fragment of a llama antibody, known as a “nanobody,” has been engineered to drive out the human cytomegalovirus, a virus that, once infected, causes lifelong infection. Usually, the human cytomegalovirus remains undetected in the human body by laying low and hiding away from the immune system. But with this new virus-specific nanobody, latently infected cells can be reactivated, thereby enabling immune cells to seek out and destroy this pathogen.

Despite being widely prevalent, plaguing four out of five people in the UK, and nearly 95 per cent of people in developing countries, the majority of cytomegalovirus infections go undetected. This is because the virus remains dormant, hidden away inside white blood cells, where it can remain undisturbed and unnoticed for decades. Even if the virus reactivates, it usually causes little to no symptoms in healthy individuals.

However, the same cannot be said for immunocompromised individuals like transplant recipients who need to consume immunosuppressant drugs to prevent organ rejection. The effects of human cytomegalovirus reactivation in these individuals can be devastating. Moreover, because there has yet to be an effective vaccine against the virus and most anti-viral drugs available are either ineffective or pose very serious side effects, treating infections can be challenging.

In a new study published in Nature Communications, researchers at Vrije Universiteit Amsterdam in the Netherlands have joined hands with scientists at the University of Cambridge to develop a new method to chase out the virus from its hiding spot. By engineering llama nanobodies to target and inhibit a viral receptor US28 that is responsible for maintaining their latent state, it allows the detection of the virus by immune cells, enabling the purge of the virus from the body.

“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 threat[en]ing complications in people whose immune systems are not functioning properly,” said Dr. Ian Groves from the Department of Medicine at the University of Cambridge.

Although it was first identified in camels, nanobodies have been found to exist in all camelids, which is a family of animals that consists of dromedaries, llamas, and alpacas. Like human antibodies, nanobodies help to identify foreign substances and activate complement systems to destroy the invader. However, unlike human antibodies, which normally consist of two heavy and two light chains to recognise and bind to foreign antigens, this special class of camelid antibodies require only a single fragment or domain to properly recognise antigens, thus often referred to as a single domain antibody or nanobody.

“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,” explained Dr. Timo De Groof from Vrije Universiteit Amsterdam, the study’s joint first author.

To demonstrate the efficacy of their nanobody, the team performed a series of laboratory experiments using a blood sample infected with the virus. Their findings revealed that the nanobodies could bind to the US28 protein and partially inhibit the signalling of the viral receptor, which normally helps the virus remain dormant, thereby effectively reactivating latently infected cells. This would mean that local immune cells can start recognising and purging the latent reservoir, clearing the blood of the virus.

Additionally, because reactivating latently infected cells would not induce virus production, this method has become an attractive alternative to clear human cytomegalovirus out of immunocompromised individuals without causing lethal complications.

“The 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. The virus is forced to put its head above the parapet where it can then be killed by the immune system,” commented Dr. Elizabeth Elder, joint first author, who carried out her work while at the University of Cambridge.

With this new nanobody, scientists hope to not only reduce future human cytomegalovirus infections but also bring in the long-awaited and much-needed treatment for infected patients who are also in line for organ and stem cell transplants. [APBN]

Source: De Groof et al. (2021). Targeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies. Nature Communications, 12, 4436.