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EBV

Unraveling the Ties That Bind: Epstein-Barr Virus and Multiple Sclerosis

A conversation with the Lieberman Lab delves into how EBV can trigger MS and potential therapeutic solutions that can be developed with this knowledge.

Epstein-Barr virus (EBV) is ubiquitous, establishing lifelong infection found throughout the world. It targets the immune system’s B cells and typically remains silent in immune system memory cells. Though infection with the virus is largely asymptomatic, specific biological and environmental conditions can enable the virus to cause more serious diseases. For instance, the virus can cause rare cancers that occur at much higher rates in immunosuppressed individuals. More recent research has found a connection between EBV and the neurodegenerative disease, multiple sclerosis (MS).

In a recent article published in Nature Reviews Microbiology, Paul Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor; program leader, Gene Expression & Regulation Program, Ellen and Ronald Caplan Cancer Center; and director, Center for Chemical Biology & Translational Medicine; and Samantha Soldan, Ph.D., staff scientist in the Lieberman laboratory, review evidence of EBV as a cause of MS and the implications of this knowledge in research and clinical spheres.

“Eliminating EBV latent infection should be a safe and effective way to treat EBV cancers and autoimmune disease, especially multiple sclerosis,” Lieberman says.

We spoke with Soldan about the link between EBV and MS as well as how this knowledge can be harnessed into potential therapeutics for the disease.

Q: What is some of the background linking EBV to cancer?

A: EBV was the first virus to be implicated as a causative agent of human cancer. EBV has been linked to nasopharyngeal cancers, stomach cancers, primary CNS lymphomas, Hodgkin’s and non-Hodgkin’s lymphomas, NK/T-cell lymphomas, and leiomyosarcomas, as well as several autoimmune disorders, including MS. It is currently estimated that 1.5-2% of all human cancers are attributable to EBV infection. All EBV-related cancers are associated with latent infection, where no infectious virus is produced by the tumor cells. Different types of EBV-associated cancers express different EBV latency genes. Notably, all EBV cancers express the viral protein EBNA1—required to maintain the EBV genome in latently infected cells and a primary interest of the Lieberman lab.

Q: What inspired this review to investigate evidence behind EBV as a cause of MS?

A: The case for EBV as a causative agent in MS has been mounting over the last 40 years. This year, two landmark studies were published: one providing a strong epidemiologic link to MS and the other suggesting a mechanism by which EBV may drive disease pathogenesis. These two studies have intensified the MS community’s interest in the link between EBV and MS, both as a disease trigger and as a potential driver of disease pathogenesis.

Dr. Paul Lieberman is a leading expert in EBV and in the study of EBV EBNA1 specifically, and he was invited to write a review article focused on the role of EBV in MS for Nature Reviews Microbiology. Paul asked me to be a co-author for this manuscript and I was delighted to have this opportunity. My background is in neurovirology, and I have been involved in research investigating the relationship between viruses and neuroinflammatory diseases, including MS, since graduate school. I am deeply invested in trying to better understand the role that EBV plays in MS.

Q: Why is multiple sclerosis a complex disease to study?

A: Multiple sclerosis is the most common demyelinating disorder of young adults, effecting more than one million individuals in the U.S. alone. MS is a heterogenous and often disabling disease that develops because of the interplay between the immune system and the environment in genetically susceptible individuals. The clinical progression of MS is variable and unpredictable with several distinct disease courses. In addition, MS patients often transition from a relapsing-remitting to a progressive disease course over time and the mechanism of the disease and central nervous system damage also evolve, which are a hallmark of MS.

Further complicating matters, epidemiological studies have shown that environmental factors (including EBV infection) that contribute to one’s risk of developing MS often occur many years before clinical onset. Collectively, these complex interactions between genetic, immunologic, and environmental risk factors makes attributing disease-contributing agents and designing preventative measures and effective therapies for MS very challenging.

Q: How does EBV trigger MS? Can you explain these processes?

A: How a ubiquitous agent like EBV triggers disease in a small percentage of those who are infected is an enigma. We face this challenge in understanding the role of EBV in cancer as well as MS. For MS and many autoimmune diseases, we can identify inflammatory and autoreactive immune responses and characterize immune responses to infectious agents and antigens that trigger immune response in patients. However, understanding what set immune cells on an autoreactive and inflammatory path before the patient is symptomatic is a difficult task.

Nevertheless, there are several theories as to how EBV may be both a trigger and a driver of MS and we discuss these in the review. We believe that it is likely that EBV is involved in the pathogenesis of MS at many levels and in different anatomic compartments.

Q: What are some potential therapies that could arise out of understanding the role of EBV in MS?

A: In recent years, therapies depleting B-cells have proven to be tremendously beneficial in MS. While EBV primarily infects B-cells, these B-cell depletion therapies eliminate cells regardless of whether they are infected by EBV, making it difficult to determine if any of the clinical benefit derived from these drugs is related to their effects on the virus.

There are several EBV specific therapies in development that have the potential to present new, effective options for patients with MS. In addition, they may also help us better understand the role of EBV as a trigger and driver of disease pathogenesis. These include vaccines to prevent the development of infectious mononucleosis, MS, and EBV-associated cancers; cell-based immunotherapies, including EBV-specific cytotoxic T cell lines; and EBV specific antivirals.

Q: Why is it important to review existing literature and reveal new directions for research?

A: I find review articles to be incredibly helpful, both to the writer and the reader. When writing a review, you must commit time and energy to refamiliarizing yourself with the latest literature as well as the history of the field.  The process helps you take the proverbial 30,000-foot view and see the whole picture, forcing you to get your head out of the specific aspect of research that you are generally focused on and enabling you to generate new ideas and consider new approaches to your work. Reviews are also very important for colleagues and especially trainees to get perspective on where the field is headed and where there are gaps in our knowledge.

Q: What do you currently work on with Dr. Lieberman regarding MS and EBV and where is your research headed?

A: We are working in several directions to better understand the role that that EBV plays in the pathogenesis of MS. Our current work focuses on characterizing virus-host interactions and maintenance of EBV latency in EBV infected B-cells from MS patients compared to healthy controls. Dr. Chenhe Su, a postdoctoral fellow in the Lieberman lab, is also working very hard on these studies. 

I am especially interested in developing better animal models to understand how host factors like age of exposure, genetic background, metabolism, and sex influence host-virus interactions and EBV reprogramming of B-cells. We are also testing EBV-specific antiviral therapies, including the EBNA1 inhibitor developed in the Lieberman lab, to determine its potential as a therapeutic agent for use in MS.