Study employs llama nanobodies to hunt human cytomegalovirus

Researchers created a “nanobody”, a small fragment of a llama antibody, that can evade human cytomegalovirus (HCMV) as it hides away from the immune system. The nanobody enables the immune cells to find and destroy this potentially deadly virus.

Study employs llama nanobodies to hunt human cytomegalovirus
Image Credit: University of Cambridge.

In the United Kingdom, nearly four out of five people are infected with HCMV, and in developing countries, this can be as high as 95%. In most people, the virus remains dormant. The virus remains hidden inside white blood cells, where it remains undisturbed and undetected for decades.

When the virus reactivates in a healthy individual, it does not generally cause symptoms. However, in the case of immunocompromised people—for instance, transplant recipients who are on immunosuppressant drugs to prevent organ rejection—HCMV reactivation can be disastrous.

Currently, there is no effective vaccine against HCMV, and anti-viral drugs usually prove ineffective or exhibit very drastic side effects.

Scientists from the Vrije Universiteit Amsterdam in the Netherlands and the University of Cambridge identified a way to bring out the virus from its hiding place by employing a unique type of antibody known as a nanobody. The research findings are published in Nature Communications journal.

Nanobodies were first recognized in camels, and they exist in all camelids—a class of animals that also includes llamas, dromedary, and alpacas. Human antibodies contain two heavy and two light chains of molecules, which together identify and attach to markers on the cell surface or virus called antigens.

However, in the case of this special class of camelid antibodies, only a single fragment of the antibody—commonly referred to as single domain antibody or nanobody—is adequate to accurately identify antigens.

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 revolutionize antibody therapies.”

Dr Timo De Groof, Study Joint First Author, Vrije Universiteit Amsterdam

The biopharmaceutical company Ablynx introduced the first approved nanobody into the market, and other nanobodies are also in clinical trials for diseases like rheumatoid arthritis and some cancer types.

Researchers from the Netherlands and the United Kingdom created nanobodies that target a particular virus protein (US28), one of the few elements that can be detected on the surface of an HCMV latently infected cell and the key driver of this latent state.

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.”

Dr Ian Groves, Department of Medicine, University of Cambridge

The researchers used blood infected with the virus in their laboratory experiments and demonstrated that the nanobody attaches to the US28 protein and hinders the signals established through the protein that helps keep the virus in its dormant state.

When this control is lost, the local immune cells can “see” that the cell is infected, which allows the host’s immune cells to identify and kill the virus, purifying the latent reservoir, thereby clearing the blood of the virus.

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.”

Dr Elizabeth Elder, Study Joint First Author, University of Cambridge

Dr. Elder pursued her work while at the University of Cambridge.

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

Source:
Journal reference:

De Groof, T. W. M., et al. (2021) Targeting the latent human cytomegalovirus reservoir for T-cell-mediated killing with virus-specific nanobodies. Nature Communications. doi.org/10.1038/s41467-021-24608-5.

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