One step closer to taming Epstein-Barr virus

Disease and treatment 2. okt 2021 3 min Professor Mette Rosenkilde Written by Kristian Sjøgren

The Epstein-Barr virus causes mononucleosis and many other diseases. Researchers have now mapped the structure of a protein this virus uses to evade the immune system.

For many years, researchers and doctors have dreamed of being able to develop drugs that target Epstein-Barr virus, which causes mononucleosis.

This virus can also be especially harmful to people who are already seriously ill or are immunosuppressed after transplantation. In this situation, the virus can even lead to cancer of the blood and blood-forming organs or serious infections that doctors have difficulty treating.

The dream of discovering a drug that can stop Epstein-Barr virus is now a step closer after researchers in Denmark and at Stanford University successful mapped a G protein–coupled receptor called BILF1 that the virus uses to evade our immune system.

The mapping revealed why some types of drugs will probably never defeat the virus. However, the research also identified opportunities for therapeutic targeting.

“Research on other viruses shows that this protein as a G protein–coupled receptor is a suitable target for drug intervention. Our research aims to determine how we can target this protein and thus Epstein-Barr virus. So far, various types of drugs have been developed to help people survive serious infection with Epstein-Barr virus, but we do not yet have drugs that specifically targets the virus itself. We can finally start designing drugs to target the virus based on these results,” explains a researcher behind the study, Mette M. Rosenkilde, Professor, Department of Biomedicine, University of Copenhagen.

The research results have been published in Immunity.

Protein structure finally mapped

The researchers froze samples of the protein at minus 200°C and then used cryogenic electron microscopy to map its structure, firing electrons at the protein while capturing hundreds of images and assembling them into a three-dimensional representation of the protein structure.

However, determining the structure is even more complicated, which is why it took so long to map the relevant protein.

One problem has been that BILF1 is not like other receptors, which is why predicting its three-dimensional structure in a model based on other receptors has been difficult. In particular, researchers have had difficulty in predicting the structure of the parts of the protein to be targeted with drugs.

“Epstein-Barr virus has likely obtained this protein from people, since we have similar proteins in our bodies. Although we know a lot about these human proteins, we were not able to identify the structure of this protein in the membrane until now,” says Mette M. Rosenkilde.

Traditional types of drugs do not work

The mapping has revealed interesting results, and the researchers now realise why developing traditional drugs against this kind of virus has been so problematic.

According to Mette M. Rosenkilde, this means that developing drugs from classical small molecules and making them interact with the receptor will not work. BILF1 does not have a structure to which the small molecules can bind. Instead, the receptor has an extracellular loop that is markedly different from what researchers had previously seen.

“The structure is too fluffy for small molecules, and this extracellular loop also blocks the binding site. This is exciting news, but it also means that we have to use other types of drugs to target this receptor,” explains Mette M. Rosenkilde.

Mette M. Rosenkilde also says that the protein is much more stable and robust in its signalling than anticipated, because its signalling remains very active regardless of how many mutations the researchers insert into it.

According to Mette M. Rosenkilde, this indicates that the receptor being active is a definite advantage for the virus. Inactivating the protein may be a way to tame the virus.

Active form of the protein can also lead to cancer

Researchers can use the mapping of the protein structure to discover how to develop various drugs to target the vulnerable parts of this key protein required by Epstein-Barr virus.

Further, the sites against which the researchers target their drugs must not be present at the human equivalent of this receptor class.

However, there may be several possible target mechanisms because the virus seems to have modified so much of the protein.

“We are currently considering various ways to use this protein to combat the virus,” says Mette M. Rosenkilde.

Another interesting aspect of activated BILF1 is that it helps to downregulate the body’s ability to recognise viruses. The receptor thus helps the virus to evade the immune system.

However, activated BILF1 is also linked to an increased risk of developing cancer.

“BILF1 has several roles. Viruses are not supposed to cause cancer. They try to evade the immune system while manipulating the cellular signalling system. The problem is that this can lead to the development of cancer, although this only happens when the receptor is very active. There are therefore many factors involved in understanding this receptor and how we can target it with drugs. This applies not only to active Epstein-Barr virus infection but also to cancer treatment,” concludes Mette M. Rosenkilde.

Structural basis for the constitutive activity and immunomodulatory properties of the Epstein-Barr virus–encoded G protein–coupled receptor BILF1” has been published in Immunity. In 2020, the Novo Nordisk Foundation awarded a grant to Mette M. Rosenkilde for the project "Turning virus survival & defense mechanisms into offensive antiviral therapy".

Mette Rosenkilde is professor at the Department of Biomedical Sciences (BMI). She is head of the Molecular Pharmacology Laboratory (MolPharm) where th...

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