Future Therapies Targeting Epstein-Barr Virus Could Help Combat MS

It is difficult to pinpoint a single cause of multiple sclerosis (MS), but for years, researchers have suspected a link between the condition and the Epstein-Barr virus (EBV), the common herpesvirus responsible for mononucleosis.¹ A recent review of a growing body of evidence from a team of researchers in London provided a compelling case for moving forward with therapies that directly target EBV to treat or prevent MS.²

The Case for a Causal Role

Researchers have known for some time that EBV is strongly associated with MS.¹ People who have never been infected with EBV have a near-zero risk of developing the disease, and studies have shown that individuals who go on to develop MS were exposed to the virus before their diagnosis.² These epidemiological findings suggest that while EBV may not be the sole cause of MS, it is a necessary trigger for the disease.

Despite the strong connection, a precise understanding of how the virus contributes to the disease has been elusive. Several theories have been proposed, including:

• Molecular mimicry: The virus produces antigens that resemble proteins found in the body, prompting the immune system to mistakenly attack its own cells
• Immune dysregulation: EBV infection alters the immune system, priming it to develop autoimmunity in the future
• The "driver hypothesis": The virus continues to drive disease activity through cycles of latent and lytic infection

The review supported the driver hypothesis, suggesting that ongoing viral replication or latent-lytic cycling continuously exposes the immune system to EBV antigens, which may be needed to drive the inflammatory disease activity seen in MS. The article also noted that people with MS appear to control EBV infection less effectively than others.

A key finding that supported the idea of targeting EBV came from observations in people with HIV. Consistent epidemiological findings from multiple countries, including England, Denmark, and Sweden, showed that people who were HIV positive had a lower risk of developing MS. These observations were made during the era of highly active antiretroviral therapy (HAART), suggesting that the therapy itself—and not the HIV infection—was responsible for the protective effect. As some of the antivirals in HAART are also active against EBV, this finding bolstered the rationale for testing antiretrovirals in MS.

A Focus on Therapeutics

The review highlighted that many existing MS disease-modifying therapies, particularly those that deplete B-cells, may already work by targeting EBV either directly or indirectly. The researchers called for a new wave of drug development to target EBV as a therapeutic strategy. They also suggested that it is appropriate to re-evaluate the mechanisms of currently licensed therapies and those in late-stage development to see how they impact EBV biology.

Strategies that were highlighted included:

1. CNS-penetrant small molecule anti-viral agents to target both latent and lytic EBV infection
2. Immunotherapies, such as therapeutic EBV vaccines or cytotoxic T cells, to boost the body’s natural immune response against the virus
3. Higher-dose B-cell depleting therapies to target B-cells in the central nervous system

Limitations and a Look Ahead

The review acknowledged several limitations, primarily that it is a summary of existing research and not a new clinical study. The document did not provide specific patient demographics, as it was a review of multiple studies, but it did highlight the challenges of conducting future research. The authors explained that the long lag between initial EBV infection and the onset of MS, coupled with the near-ubiquity of EBV in the general population, makes it difficult to conduct high-quality prospective studies. The review also noted that some studies on EBV-targeted therapies, such as the phase 2 EMBOLD trial for ATA188, have failed.

The authors recommended that “future directions for proving EBV's causal role in MS [should] include conducting large-scale, long-term studies that initially follow EBV-negative individuals and monitor their immunological health over time to see what happens after asymptomatic or symptomatic EBV seroconversion. This will uncover the mechanisms by which EBV might trigger MS and autoimmunity in general. Working out what happens during infectious mononucleosis and how it might affect the CNS is critical for identifying new therapeutic strategies.”

References

1. Aloisi F, Giovannoni G, Salvetti M. Epstein-Barr virus as a cause of multiple sclerosis: Opportunities for prevention and therapy. Lancet Neurol. 2023;22:338-349. doi:10.1016/S1474-4422(22)00471-9

2. Giovannoni G, James L, Adeniran AA, et al. The case for targeting latent and lytic Epstein-Barr virus infection in multiple sclerosis. Brain. 2025;148(9):3057-3071. doi:10.1093/brain/awaf170