By IDSE News Staff

There may be a causal link between Epstein-Barr virus (EBV) and multiple sclerosis (MS), according to new research out of the Harvard T.H. Chan School of Public Health (Science 2022 Jan 13. doi:10.1126/science.abj8222).

The researchers suggest that someday MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system that attacks the myelin sheaths protecting neurons in the brain and spinal cord. Its cause is unknown, yet one of the top suspects is EBV, a herpesvirus that can cause infectious mononucleosis and establishes a latent, lifelong infection in B lymphocytes. 

Establishing a causal relationship between the virus and disease has been difficult because EBV infects approximately 95% of adults; MS is a relatively rare disease; and the onset of MS symptoms begins about 10 years after EBV infection, according to Alberto Ascherio, MD, DrPH, a professor of epidemiology and nutrition at the Harvard Chan School, in Boston, and senior author of the study.

To determine the connection between EBV and MS, the researchers conducted a study among more than 10 million young adults on active duty in the U.S. military and identified 955 who were diagnosed with MS during their period of service.

The team analyzed serum samples taken biennially by the military and determined the soldiers’ EBV status at the time of first sample and the relationship between EBV infection and MS onset during the period of active duty. In this cohort, the risk for MS increased 32-fold after infection with EBV but was unchanged after infection with other viruses, including cytomegalovirus, which had a similar infection rate among the group as EBV. 

Serum levels of neurofilament light chain, a biomarker of the nerve degeneration typical in MS, increased only after EBV infection, they said. The findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS, according to the study.

“The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” Dr. Ascherio said. “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.”

Dr. Ascherio added that the delay between EBV infection and onset of MS may be partially due the symptoms of MS being undetected during the earliest stages, and partially due to the evolving relationship between EBV and the host’s immune system, which is repeatedly stimulated whenever latent virus reactivates.

“Currently, there is no way to effectively prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral drugs could ultimately prevent or cure MS,” Dr. Ascherio said.

This is not the only disease linked to latent EBV infections. Several studies have linked the disease to the development of cancers, including Burkitt lymphoma, nasopharyngeal carcinoma and Hodgkin lymphoma.

Researchers at the Wistar Institute, in Philadelphia, reported a new enzymatic function of the EBV protein, Epstein-Barr nuclear antigen 1 (EBNA1), which may be a critical factor in EBV’s ability to contribute to the development of different cancer types (Cell 2021;185[3]:643-654.e13).

EBNA1 serves as an attractive therapeutic target for these cancers because it is expressed in all EBV-associated tumors, performs essential activities for tumorigenesis, and there are no similar proteins in the human body.

“We discovered an enzymatic activity of EBNA1 that was never described before, despite the intense research efforts to characterize this protein,” said Paul M. Lieberman, PhD, the Hilary Koprowski, M.D., Endowed Professor, and leader of the Gene Expression and Regulation Program at Wistar, and corresponding author of the study. “We found that EBNA1 has the cryptic ability to cross-link and nick a single strand of DNA at the terminal stage of DNA replication. This may have important implications for other viral and cellular DNA-binding proteins that have similar cryptic enzyme-like activities.”

Dr. Lieberman and his colleagues also found that one specific EBNA1 amino acid called Y518 is essential for this process to occur and, consequently, for viral DNA persistence in the infected cells.

They created a mutant EBNA1 protein in which the critical amino acid was substituted with another and showed that this mutant could not form covalent binding with DNA and perform the endonuclease activity responsible for generating single-strand cuts.

In latently infected cells, the EBV genome is maintained as an episome, which is replicated by cellular enzymes along with the cell’s chromosomes. When the cell divides, the two episomal genomes segregate into the two daughter cells.

While it was known that EBNA1 mediates replication and partitioning of the episome during division of the host cell, the exact mechanism was not clear. The new study sheds light on the process and describes how the newly discovered enzymatic activity of EBNA1 is required to complete replication of the viral genome and maintenance of the episomal form.

“Our findings suggest that one could create small molecules to ‘trap’ the protein bound to DNA and potentially block replication termination and episome maintenance, similar to known inhibitors of topoisomerases,” said Jayaraju Dheekollu, PhD, the first author on the study and staff scientist in the Lieberman Lab. “Such inhibitors may be used to inhibit EBV-induced transformation and treat EBV-associated malignancies.”