Epstein–Barr virus and multiple sclerosis: Mechanistic insights and clinical implications

Dr Micah Luftig discusses the implications for clinical risk stratification and early intervention, and how EBV-targeted strategies may shape future therapeutic approaches

Growing evidence has positioned Epstein–Barr virus (EBV) as a central factor in the development of multiple sclerosis (MS), transforming how researchers and clinicians understand disease susceptibility and progression. Advances in epidemiology, immunology and molecular biology are now revealing how EBV infection may influence immune dysregulation, autoreactive B-cell expansion and central nervous system inflammation in MS.

In this interview, Dr Micah Luftig (Duke University, Durham, NC, USA) discusses emerging mechanistic insights linking EBV to MS pathogenesis. Presented at ACTRIMS 2026, Dr Luftig discusses the implications for clinical risk stratification and early intervention, and how EBV-targeted strategies may shape future therapeutic approaches. He also reflects on key scientific and therapeutic developments presented at ACTRIMS 2026.

Q. Could you give an overview of the role of Epstein–Barr virus in MS susceptibility, and how our understanding of this relationship has evolved in recent years?

EBV is now widely regarded as an essential trigger for MS, rather than a background infection that happens to co-occur. Early epidemiologic work showed higher EBV seroprevalence and elevated anti-EBNA1 titres in people who later developed MS, but causality remained debated. Over the last two decades, several lines of evidence have converged. A landmark longitudinal study in US military personnel demonstrated that virtually all individuals who developed MS after being EBV-seronegative at baseline seroconverted to EBV before MS onset, with a roughly 32-fold increase in risk following infection. No other infectious or environmental exposure examined in that cohort showed a comparable effect size on MS risk.^[1]

At the same time, clinical observations clarified that infectious mononucleosis (IM), typically reflecting delayed primary EBV infection in adolescence or early adulthood, confers an additional two- to threefold risk of MS beyond EBV seropositivity alone.^[2,3]

Genetic data have also reshaped our understanding: the strongest inherited MS risk factor, HLA-DRB1*15:01 (DR15), not only increases overall susceptibility but appears to specifically alter immune control of EBV-infected B cells and their capacity to present myelin antigens. Experimental work in DR15-humanised mice indicates that EBV infection produces a >10-fold higher EBV-infected B-cell burden than in non-DR15 controls, and DR15-positive EBV-infected B cells are particularly efficient at loading myelin basic protein peptides.^[4,5]

Finally, molecular mimicry studies have shown that EBNA1-specific T- and B-cell responses frequently cross-react with central nervous system (CNS) antigens, such as GlialCAM and Anoctamin-2, in a substantial subset of MS patients.^[6,7,8]

Collectively, these epidemiologic, genetic and mechanistic data have shifted the field from “EBV as a risk correlate” to “EBV as a necessary but not sufficient trigger”, integrated with age at infection, host genetics and immune regulation in determining who ultimately develops MS.

Q. What do current mechanistic insights tell us about how EBV may contribute to the transition from susceptibility to clinical disease, rather than being a coincidental association?

Mechanistic data now provide a coherent framework for how EBV can drive the transition from a susceptible state to overt MS, arguing strongly against a purely coincidental association.

First, EBV fundamentally reprogrammes B cells. During latency, viral proteins such as EBNA transcription factors and latent membrane proteins mimic and subvert germinal centre pathways, rendering infected B cells less dependent on classical B-cell receptor signalling and more resistant to apoptosis. This allows survival and expansion of autoreactive B-cell clones that would normally be deleted or anergised.

Single-cell multiomic analyses of de novo EBV infection of human B cells reveal diverse fates, including germinal-centre-like, memory-like and plasma-cell-like cells, and critically, a subset resembling age-associated B cells (ABCs) characterised by T-bet and CXCR3 expression. These ABC-like cells are enriched in multiple autoimmune diseases, including MS, and respond to innate cues, providing a plausible link between chronic viral latency, innate activation and autoreactivity.^[9,10,11,12]

Recent work from our group shows that EBV can directly induce this T-bet+CXCR3+ phenotype from naïve B cells in vitro, in a manner that is transient and independent of interferon-gamma, and that EBNA2 is the key viral transcriptional regulator driving this programme. Chromatin accessibility and three-dimensional chromatin interaction data identify EBNA2 binding at regulatory elements controlling T-bet, and CRISPR perturbation of these elements selectively abrogates EBV-induced T-bet expression without affecting cytokine-driven ABC induction. (unpublished data)

Importantly, peripheral blood from treatment-naïve relapsing–remitting MS patients shows an increased frequency of EBV-infected B cells, and EBV-encoded RNA-positive cells are disproportionately enriched within the T-bet+CXCR3+ ABC-like compartment. These EBV-infected ABCs express chemokine receptors that favour CNS homing and are poised for lytic reactivation, providing a route for EBV-programmed B cells to traffic into the CNS and participate directly in local inflammation.^[13]

Overlaying this with independent mechanisms further strengthens causality. EBV-infected B cells in DR15-positive individuals efficiently present myelin antigens to autoreactive T cells (“mistaken self”), while molecular mimicry between EBNA1 and CNS antigens expands cross-reactive CD4 T cells that can both target EBV and myelin. Pender’s model posits that EBV persistence in autoreactive B cells offers survival niches for pathogenic T cells, sustaining chronic demyelinating immunity.

Thus, EBV does not merely coexist with MS; it shapes the B-cell and T-cell compartments, promotes CNS-homing autoreactive B cells and provides multiple non-mutually exclusive routes by which a susceptible host progresses to clinical disease.

Q. From a clinical perspective, how should emerging EBV data influence how healthcare professionals think about MS risk stratification, early disease monitoring or intervention timing?

From a clinical standpoint, emerging EBV data should refine how healthcare professionals conceptualise MS risk and early intervention, even though practice-changing tools are still under development. First, EBV seronegativity in adulthood is now rare but informative; the near-universal seroconversion before MS onset in longitudinal cohorts suggests that individuals who remain EBV-seronegative are at extremely low risk for classic MS, a point that may become relevant once EBV vaccines are available.

More practically, a history of infectious mononucleosis, particularly when combined with high EBV antibody titres and HLA-DRB1*15:01 positivity, identifies a subgroup with substantially elevated lifetime risk. While we are not yet at the point of formal “EBV-based” risk scores, it is reasonable for clinicians to weigh IM history and EBV serologic profiles alongside family history, sex, smoking and vitamin D status when discussing risk with high-concern individuals.

In early disease, EBV biology may also inform monitoring strategies. Longitudinal studies correlating EBV-specific immune responses, EBV-infected B-cell phenotypes (such as ABC-like cells) and viral load with MRI activity and clinical relapses are ongoing and should clarify whether EBV-linked biomarkers can flag impending disease activity. If specific EBV-infected B-cell subsets correlate tightly with subclinical MRI lesions, clinicians could eventually use these as adjunctive markers to refine decisions about when to escalate therapy in radiologically isolated syndrome or very early relapsing disease.

The strong efficacy of anti-CD20 therapies, which deplete EBV-harbouring B cells, already supports the notion that targeting the EBV-conditioned B-cell compartment is particularly impactful in MS. For timing, a growing conceptual shift is to intervene earlier against EBV-driven mechanisms, whether with broad B-cell depleters or, in the future, more EBV-specific approaches, before chronic CNS-resident immune networks and neurodegeneration become entrenched.

While current clinical diagnostic practice (McDonald criteria) does not yet include EBV-focused testing, it is increasingly appropriate for clinicians to view EBV as a central component of the pathobiology, shaping their threshold for early high-efficacy therapy in patients with strong EBV-linked risk features.^[14,15,16]

Q. Looking ahead, how might EBV-targeted strategies reshape MS intervention models across the disease course, and what key questions must still be answered before this can meaningfully change practice?

Looking ahead, EBV-targeted strategies have the potential to reshape MS intervention across the disease course, from primary prevention to late-stage disease modification.

On the preventive side, EBV vaccines could be deployed in adolescence or in genetically high-risk individuals (for example, DR15-positive persons with a family history of MS) to prevent primary EBV infection or at least attenuate infectious mononucleosis. If vaccine-induced immunity can reduce or delay EBV infection, the 32-fold risk gradient observed after seroconversion suggests that a profound impact on MS incidence could be achievable.^[17,18] However, the long latency between infection and MS onset means that demonstration of true prevention will require large, long-term trials.

In established MS, more targeted approaches are being explored, including adoptive transfer of autologous EBV-specific T cells, CAR-T cells engineered against EBV antigens on B cells and antivirals that preferentially target lytic reactivation or latent programmes. Another conceptual avenue is blocking CNS entry or retention of EBV-infected ABC-like cells by targeting chemokine receptors such as CXCR3 or other subset-specific markers.

For these strategies to meaningfully change practice, several key questions must be answered. We need precise mapping of where EBV-infected cells reside in MS, for example peripheral blood versus cervical lymph nodes versus CNS meningeal follicles, and which cell subsets (ABCs, memory B cells, plasma cells) are actually pathogenic at different disease stages. It is also unclear whether all MS is “EBV-dominant” or whether there are biologically distinct subtypes where EBV plays a lesser role; if so, EBV-targeted therapies may show differential benefit and will require robust stratification biomarkers.

Longitudinal studies must determine whether changes in EBV-infected B-cell phenotypes or EBV-specific immune responses track treatment response and progression closely enough to guide therapy in real time.^[19,20]

Finally, the safety of long-term EBV suppression, especially in individuals with pre-existing EBV-driven immunity, needs careful evaluation, as EBV also shapes normal immune memory. Over the next five years, priorities include deep single-cell and spatial profiling of EBV-infected cells in blood and CNS, biomarker-linked prevention and interventional trials and systematic efforts to define EBV-dominant versus non-dominant MS endotypes.

Q. What were the most important therapeutic and treatment updates at ACTRIMS 2026?

ACTRIMS Forum 2026 was framed around “MS at a Crossroads”, emphasising how mechanistic advances, including EBV biology, should redirect therapeutic strategies over the next decade. Within that context, one of the most important themes was the convergence of virology, immunology and neuroimaging in redefining treatment priorities. Presentations in the session “From Susceptibility to Symptoms: Rethinking MS Intervention” highlighted the central role of EBV-conditioned B cells in MS and underscored why B-cell-directed therapies, such as anti-CD20 monoclonal antibodies, have become foundational across the relapsing and progressive spectrum.

Emerging data on EBV-infected age-associated B-cell-like subsets in treatment-naïve patients reinforced the rationale for early, high-efficacy B-cell targeting to interrupt EBV-driven immune networks before irreversible CNS injury occurs.

In parallel, the meeting emphasised future-facing therapeutic avenues rather than only incremental drug comparisons. Talks and discussions called for moving beyond “one-size-fits-all” escalation models toward mechanism-based stratification, identifying patients whose disease is particularly EBV-dominant, microglia-dominated or neurodegeneration-driven and aligning therapies accordingly. There was strong interest in EBV-specific approaches, including vaccines, adoptive T-cell therapies and antivirals, as potential adjuncts to existing disease-modifying therapies, especially in high-risk or early-stage patients, though these remain largely in preclinical or early clinical phases.

The programme also highlighted the need for longitudinal biomarker platforms that integrate peripheral immune phenotyping, EBV-related measures and advanced imaging to guide treatment sequencing and de-escalation decisions. Overall, the most important “therapeutic update” was conceptual: the field is actively reconsidering when and how to intervene, with EBV biology increasingly central to arguments for earlier, more targeted and more individualised MS therapy across the disease course.

References

1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296–301. DOI: 10.1126/science.abj8222
2. Handel AE, Williamson AJ, Disanto G, et al. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS ONE. 2010;5(9):e12496. DOI: 10.1371/journal.pone.0012496
3. Thacker EL, Mirzaei F, Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol. 2006;59(3):499–503. DOI: 10.1002/ana.20820
4. Zdimerova H, Murer A, Engelmann C, et al. Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15. Eur J Immunol. 2021;51(1):64–75. DOI: 10.1002/eji.202048655
5. Wang J, Jelcic I, Mühlenbruch L, et al. EBV infection and HLA-DR15 jointly drive multiple sclerosis by myelin peptide presentation. Cell. 2026;189(2):569–584. DOI: 10.1016/j.cell.2025.12.046
6. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603:321–327. DOI: 10.1038/s41586-022-04432-7
7. Tengvall K, Huang J, Hellström C, et al. Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proc Natl Acad Sci USA. 2019;116(33):16512–16517. DOI: 10.1073/pnas.1902623116
8. Thomas OG, Olsson T, et al. Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Sci Adv. 2023;9(20):eadg3032. DOI: 10.1126/sciadv.adg3032
9. SoRelle ED, Dai J, Reinoso-Vizcaino NM, et al. Time-resolved transcriptomes reveal diverse B cell fate trajectories in the early response to Epstein-Barr virus infection. Cell Rep. 2022;40(9):111286. DOI: 10.1016/j.celrep.2022.111286
10. SoRelle ED, Reinoso-Vizcaino NM, Horn GQ, Luftig MA. Epstein-Barr virus perpetuates B cell germinal center dynamics and generation of autoimmune-associated phenotypes in vitro. Front Immunol. 2022;13:1001145. DOI: 10.3389/fimmu.2022.1001145
11. Ramesh A, Schubert RD, Greenfield AL, et al. A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis. Proc Natl Acad Sci USA. 2020;117(37):22932–22943. DOI: 10.1073/pnas.2008523117
12. van Langelaar J, Wierenga-Wolf AF, Samijn JPA, et al. The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies. Eur J Immunol. 2021;51(3):626–633. DOI: 10.1002/eji.202048739
13. Läderach F, Piteros I, Fennell É, et al. EBV induces CNS homing of B cells attracting inflammatory T cells. Nature. 2025;646(8083):171–179. DOI: 10.1038/s41586-025-09378-0
14. SoRelle ED, Luftig MA. Multiple sclerosis and infection: history, EBV, and the search for mechanism. Microbiol Mol Biol Rev. 2025. DOI: 10.1128/mmbr.00119-23
15. Läderach F, Münz C. Latent, Lytic, and Linked to Multiple Sclerosis—How EBV Drives Autoimmunity. Eur J Immunol. 2026;56(2):e70153. DOI: 10.1002/eji.70153
16. Montalban X, Leray E, Oh J, et al. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol. 2025;24(10):850–865. DOI: 10.1016/S1474-4422(25)00270-4
17. Moderna mRNA-1189 EBV vaccine. Phase 2 clinical trial. ClinicalTrials.gov Identifier: NCT05164094. Available at: https://clinicaltrials.gov/study/NCT05164094 (accessed 23 March 2026).
18. Yea C, et al. Epstein–Barr virus and multiple sclerosis: lesson learned to develop new vaccines and therapies. Exp Mol Med. 2025. DOI: 10.1038/s12276-025-01482-5

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