Metabolic Inhibition Offers a New Approach To Combat Epstein-Barr Virus - Technology Networks

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The Epstein-Barr virus (EBV) has been associated with a range of diseases including cancer and most recently the development of autoimmune diseases such as multiple sclerosis. Ninety percent of adults are infected with EBV. Despite its high prevalence and link to disease, no drug or approved vaccination can specifically target the virus within the body.

A new study, published in the journal Science, has shown that inhibition of a specific metabolic pathway in infected B cells can diminish infection and therefore reduce the risk of downstream disease.

When EBV breaches the immune system

EBV is often contracted when we are young and is asymptomatic. However, individuals who contract the virus as adults are much more likely to develop glandular fever, otherwise known as infectious mononucleosis.

Sixty years on from the groundbreaking discovery of EBV by Anthony Epstein and Yvonne Barr, the virus continues to be a hot topic of research, as it was the first virus to be directly associated with the development of cancer. It is now estimated that cancer-causing viruses are responsible for approximately 30% of cancer cases in low- and lower-middle–income countries and around 15% of cancers worldwide.

Studies investigating the role of viruses in cancer development have led to the authorization of vaccines, as with the human papillomavirus. Similarly, a vaccine against hepatitis B has been used to help prevent the development of liver cancer for quite some time.

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To better understand how EBV infection can become chronic and cause subsequent comorbidities, researchers from the University of Basel and the University Hospital Basel looked at how B cells infected with EBV engage host pathways that mediate cell proliferation and transformation. In the study, they focused on a group of patients who had developed EBV-triggered blood cancer following organ transplantation.

It is necessary to weaken the immune system using medications to prevent a transplanted organ from being rejected. However, this makes it easier for EBV to proliferate and cause blood cancer, referred to as post-transplant lymphoma.

"In transplant patients, it's standard practice to use drugs against various viruses. Until now, there's been nothing specific for preventing or treating EBV-associated disease," said Professor Christoph Hess, research group leader at the University of Basel.

Repurposing IDO1 inhibitors to prevent EBV-related blood cancers

The research team discovered that the EBV protein EBNA2 initiates nicotinamide adenine dinucleotide (NAD) de novo biosynthesis, by driving the expression of the metabolic enzyme IDO1. This ultimately leads to greater energy production by the mitochondria of infected cells to match adenosine triphosphate (ATP)-production with the bioenergetic requirements of proliferation and transformation.

Subsequently, the researchers found that EBV upregulates the enzyme IDO1 months before post-transplant lymphoma is diagnosed, which may help develop biomarkers for the disease.

In experiments with mice infected with EBV, IDO1 inhibition reduced the transformation of B cells and therefore the viral load and the development of lymphoma.

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The researchers concluded, "Virus-orchestrated NAD biosynthesis is, thus, a druggable metabolic vulnerability of EBV-driven B cell transformation—opening therapeutic possibilities for EBV-related diseases."

IDO1 inhibitors have been previously developed in the hope that they could treat established cancer with mixed results. This class of drugs may now receive a second chance in applications aimed at dampening EBV infection and thereby tackling EBV-associated diseases.

Reference: Müller-Durovic B, Jäger J, Engelmann C, et al. A metabolic dependency of EBV can be targeted to hinder B cell transformation. Science. 2024. doi: 10.1126/science.adk4898

This article is a rework of a press release. Material has been edited for length and content.

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