Mono, Multiple Sclerosis, and Cells That Live Forever: Wistar’s Dr. Paul Lieberman on Progress in EBV Research

Paul M. Lieberman, Ph.D., is leader of the Genome Regulation and Cell Signaling Program at the Ellen and Ronald Caplan Cancer Center. He studies how certain viruses, such as Epstein-Barr virus, establish a long-term latent infection that can lead to cancer or autoimmune disorders.

Why did you choose to focus your research on EBV?

I became interested in EBV during my graduate student introduction to virology. Someone explained that this virus is very good at immortalizing cells, and I became intrigued by the concept of immortalization.

EBV is very good at immortalizing otherwise-mortal B lymphocytes, or B-cells, which are a type of white blood cell. If you take a person’s blood and put it in culture, those B-cells will die in a few days. But if you infect the B-cells with EBV, they can live forever. It’s basically what an oncogene can do to a cell — it can take a cell from being normal and short lived to growing forever. I wanted to know: What can make a cell live forever?

Your research works on understanding how cancer-associated viruses persist in a latent state and increase the risk of cancer and autoimmune disorders. What does it mean for a virus to persist in a latent state? Do all viruses do this?

The viruses we study, like EBV, are unique in how they establish a long-term latent infection in cells that will both be long-lived and also can divide. Most viruses do not do this. The majority of viruses, like SARS CoV 2 and flu, don’t stick around. But with all herpesviruses — and EBV is a herpesvirus — the virus finds a place to live in the body for the life of the host. Chickenpox is a good example. You get infected as a child, but the virus lingers in a long-lived neuron and then can reactivate much later and cause shingles.

The viruses we study persist in blood cells, in particular B lymphocytes. The lymphocytes have what are called memory cells, which can live for decades, and the virus finds a place to survive in those long-lived cells. EBV, like other herpesviruses, goes through periodic reactivations. In most healthy individuals, EBV reactivation is asymptomatic because other immune cells like T-cells and natural killer cells do a great job at getting rid of those virally infected cells. Unfortunately, the virus is very good at playing cat and mouse so that the immune system manages to eliminate most of the virus, but not all of it. Then, the virus waits until the immune system is compromised to reemerge or in some cases, cause cancer.

How did scientists connect EBV to multiple sclerosis? And is your lab working on anything regarding this connection?

EBV was originally identified as a “tumor virus” because it was discovered in tumor samples of a rare childhood lymphoma called Burkitt lymphoma that occurred in Central Africa. Sir Tony Epstein, who recently passed away, was responsible for that discovery.

EBV’s ability to immortalize and induce tumors associated with a number of lymphomas has been fairly easy to prove because you can isolate the cancer cells and show that the virus is in those cancer cells. However, the plot thickened when scientists found that EBV also causes mono and many people who are infected with EBV never get cancer.

EBV is now suspected to be associated with autoimmune disease — multiple sclerosis (MS) being one of those. In 2022, Alberto Ascherio, an epidemiologist at Harvard, published a longitudinal study in Science that looked at 10 million blood samples of EBV-positive and EBV-negative individuals over 20 years and found that EBV infection preceded symptoms of MS. Thanks to his work, most scientists are convinced that EBV infection along with complications of mono create something like a 32-fold increase in risk of developing MS. That’s very significant — more than smoking cigarettes increases risk of getting cancer.

The trouble is that, unlike with EBV-infected tumors, sometimes we can find the virus in a patient with MS, but in a lot of cases we can’t. One hypothesis my lab is pursuing is that very few cells are infected with EBV, but it’s enough to cause sufficient inflammation to trigger the disease. However, right now, it’s difficult to definitively show exactly where EBV is in autoimmune disease and what it’s doing. This research is important because it will determine what the best therapeutic will be.

You’re also leading an NCI-funded team of scientists to explore the role of EBV in epithelial cancers. Why study epithelial cancers?

We understand a lot about how EBV infects lymphocytes, but EBV causes on the order of about 150,000 cases of epithelial cancer — meaning nasopharyngeal carcinomas and stomach cancer — every year. And we have very little understanding of why that happens, what the virus is doing in those cancers, or the best ways to treat EBV in that context.

For this program we built a multidisciplinary team that is well-situated to invent new small-molecule drugs and identify the right combination of drugs to treat EBV-epithelial cancers. EBV-infected cancer has allowed us to be very precise because we can target the virus. With this sort of precision medicine, you can reduce a lot of the off-target side effects and resistance issues that you see with other treatments like some of the more severe chemotherapeutics.

What excites you most about where EBV research is headed?

I think we are in the chase for a cure. This opportunity to target EBV across a number of different diseases is what keeps me wanting to get back to work, day after day. If we can eliminate the virus or eliminate the activity of the virus, we can cure a lot of disease.

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