Epstein-Barr Virus and Multiple Sclerosis

Reviews
Epstein–Barr virus and multiple

sclerosis
Samantha S. Soldan and Paul M. Lieberman ✉
Abstract | Epstein–Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus with a well-
established causal role in several cancers. Recent studies have provided compelling epidemio
logical and mechanistic evidence for a causal role of EBV in multiple sclerosis (MS). MS is the most
prevalent chronic inflammatory and neurodegenerative disease of the central nervous system
and is thought to be triggered in genetically predisposed individuals by an infectious agent, with
EBV as the lead candidate. How a ubiquitous virus that typically leads to benign latent infections
can promote cancer and autoimmune disease in at-risk populations is not fully understood. Here
we review the evidence that EBV is a causal agent for MS and how various risk factors may affect
EBV infection and immune control. We focus on EBV contributing to MS through reprogramming
of latently infected B lymphocytes and the chronic presentation of viral antigens as a potential
source of autoreactivity through molecular mimicry. We consider how knowledge of EBV-
associated cancers may be instructive for understanding the role of EBV in MS and discuss
the potential for therapies that target EBV to treat MS.
Burkitt lymphoma
Epstein–Barr virus (EBV) was the first human tumour (SPMS) and (3) primary progressive MS (PPMS)12,13. In
An aggressive form of virus identified, after its discovery in tumour cells of addition, clinically isolated syndrome often progresses
non-Hodgkin lymphoma paediatric Burkitt lymphoma1,2. We now know that EBV is to MS, especially when symptoms are accompanied by
endemic to sub-Saharan Africa, ubiquitous, establishing lifelong infection in more than CNS lesions.
where it is associated with
90% of adults worldwide3,4. Despite its typically subclin- The aetiology of MS is complex and multifactorial,
Epstein–Barr virus infection.
ical persistence, EBV is consistently detected in numer- involving the interplay of known genetic susceptibility
Relapsing–remitting MS ous cancers, including nasopharyngeal carcinoma, factors, predominantly in genes directing the immune
(RRMS). A form of multiple subtypes of Hodgkin and non-Hodgkin lymphomas, system, and environmental factors, including infectious
sclerosis (MS) where disease a subtype of gastric carcinomas (EBV-associated gas- agents, lack of sun exposure and vitamin D, smoking
exacerbations are interspersed
with periods of disease inactivity.
tric carcinoma), natural killer (NK)/T cell lymphomas and obesity14. Infectious agents were first suspected
and leiomyosarcomas. In addition, EBV has a profound in the aetiology of MS soon after its classification as a
Secondary progressive MS effect on the immune system, and is the most common discrete clinical entity in the late 1800s15. The hetero-
(SPMS). A form of multiple causal agent of infectious mononucleosis5 as well as fatal geneity and the evolution of the disease throughout a
sclerosis (MS) that follows
lymphoproliferative disorders in various immunosup- patient’s lifetime and within the MS lesion itself have
relapsing–remitting MS
where progressive disability pressive conditions6. Increasingly, it is appreciated that further obscured the identification of a single infectious
accumulates with or without EBV is also a major risk factor for several autoimmune agent as a consistent disease trigger. Nevertheless, epi-
discernible relapse. disorders, notably multiple sclerosis (MS)7,8. demiological, serological and virological evidence has
MS is the most prevalent chronic inflamma- accumulated to support the role of EBV in the aetiol-
Primary progressive MS
(PPMS). A form of multiple
tory and neurodegenerative disease of the central ogy of MS, with recent large population-based studies
sclerosis (MS) that lacks nervous system (CNS). Approximately 2.8 million demonstrating that EBV infection is likely a prerequi-
distinct periods of disease (35.9/100,000) people have MS worldwide9. MS inci- site for disease (reviewed in refs.7,16–18; Table 1). In the
exacerbations. dence is also increasing in developing countries9 and most definitive epidemiology study on viruses and MS
among children10. The neurological signs and symp- to date, more than ten million US army personnel were
toms of MS include impaired motor function; visual followed up over 20 years, and a 32-fold increased risk
symptoms; fatigue; eye movement disorders; blad- of MS diagnosis was shown in individuals who con-
The Wistar Institute,
Philadelphia, PA, USA.
der symptoms; sensory symptoms; sexual dysfunction; verted to EBV seropositivity compared with those who
✉e-mail: lieberman@ ataxia; deafness; spasticity; dementia; and cognitive remained seronegative; this is the largest and most com-
wistar.org impairment11. The clinical progression of MS is variable prehensive study strongly suggesting that EBV infec-
https://doi.org/10.1038/ and unpredictable, with three distinct clinical courses: tion is required for subsequent development of MS18,19.
s41579-022-00770-5 relapsing–remitting MS (RRMS), (2) secondary progressive MS However, determining the precise mechanisms for EBV
naTure RevieWS | MiCRoBiology volume 21 | January 2023 | 51
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Table 1 | Selected studies providing evidence for a role of EBV in MS Specific strains of EBV may be associated with MS, but
conclusive MS genotypes have not been identified25–27.
Evidence Result Study Refs. EBV is typically acquired through oral secretory
Epidemiological Low rates of MS in areas with more Review 230
transmission before the age of 5–8 years in resource-poor
childhood infections regions, whereas in resource-rich environments, infec-
Increased risk of MS with a history Review 231
tion is frequently delayed until adolescence or young
of infectious mononucleosis adulthood5,28,29. During primary infection, the virus
Increased risk of MS with EBV Human serum 18 enters squamous epithelial cells and replicates within
seroconversion them, subsequently crossing the mucosal epithelial cell
Decreased risk of MS in seronegative Human serum 7,18 barrier via transcytosis and infecting local infiltrating
individuals B lymphocytes of Waldeyer’s tonsillar ring30. EBV infection
Immunological Increased levels of EBV-specific Review 121,122 of naive B lymphocytes initiates a developmental process
antibodies in MS and reprogramming similar to the germinal centre (GC)
MS-risk alleles enriched for transcription Computational 176,178 that results in long-lived memory B cells harbouring
control by EBNA2 GWAS EBV episomes23,31. Lifelong persistence occurs through
the establishment of latent reservoirs in these cells and
Deficient cytotoxic T lymphocyte control MS CD8+ 216
of EBV in MS T cells periodic reactivation primarily in the oropharynx32, but

other sites of EBV persistence, such as the gut mucosa
EBV-reactive OCBs MS CSF 85
or meninges, have been reported but not extensively
Molecular mimicry between EBNA1 MS B cells 17,116
characterized33,34.
and CNS antigens
EBV can enter various cell types through differ-
Virological Increased shedding of EBV in saliva Paediatric MS 55
ent mechanisms. The viral proteins gp350/gp220 and
of paediatric patients with MS gp42 are required for EBV entry into B lymphocytes.
EBV BZLF1 in MS lesions MS brain 166
Engagement of gp350 with CD21 (also known as com-
Prosurvival influence of EBV latency In vitro 232 plement receptor type 2) is followed by endocytosis of
genes on memory B cells the virus into a low-pH component, where fusion is
EBV loads correlate with T-bet+CXCR3+ MS B cells 171 facilitated by the virus’s core fusion machinery (gB, gH
memory cells and IFNγ production and gL)35. gp42 subsequently binds to gH and interacts
CNS, central nervous system; CSF, cerebrospinal fluid; EBV, Epstein–Barr virus; GWAS, genome-wide with HLA class II, which functions as a co-receptor35.
association study; IFNγ, interferon-γ; MS, multiple sclerosis; OCBs, oligoclonal bands. Entry into epithelial cells occurs via a CD21-independent
pathway. The EBV protein BMRF2 interacts with β1
in the development of MS remains challenging because integrin to trigger fusion and subsequent interactions
the virus is not always found in MS lesions. Related between EBV gH/gL and αVβ6/8 integrins, thereby
issues arise in the analysis of some EBV-associated mediating endothelial cell fusion and entry36,37. More
cancers, in which EBV is present in only a subtype or recently, ephrin receptor A2 (EphA2) was identified as
subpopulation of cancer cells and oncogenesis depends an important entry factor for EBV in epithelial cells38.
on additional mutations or environmental cofactors20. EphA2 genetic knockouts and inhibitors reduce infec-
Because most EBV infections do not cause disease, tion of endothelial cells, and EphA2 interacts with gH/gL
understanding the role of cofactors and aberrations in and gB38. In addition to B cells and epithelial cells, EBV
the normal infection process is key. One common cofac- can infect T cells, smooth muscle cells and NK cells,
tor in EBV disease is the disruption of normal immune where the mechanism of entry is unclear39. EBV infec-
Clinically isolated syndrome
An initial episode of neurologi-
control of EBV infection. Furthermore, as EBV infects tion of T cells and NK cells is thought to be a rare event
cal symptoms associated with and transforms B cells, we consider the intrinsic relation that can lead to the development of highly aggressive
inflammation and demyelina- ship of EBV with its host cells as a potential source of NK/T cell lymphomas and chronic active EBV infection40.
tion with symptoms character- immune dysfunction. EBV can also infect neuroblastoma cell lines and pri-
istic of multiple sclerosis that
mary fetal astrocytes in vitro, although latent infection
frequently, although not
always, progresses to multiple EBV biology and life cycle of neurons has not been unequivocally demonstrated in
sclerosis. EBV (human herpesvirus 4) is one of eight known human clinical specimens41,42.
herpesviruses, with a large (173-kb) double-stranded
Waldeyer’s tonsillar ring DNA genome with approximately 100 protein-coding EBV latent infection and B cell reprogramming. EBV
A ring of lymphoid tissue
surrounding the nasopharynx
genes and numerous non-coding RNAs and micro infection efficiently reprogrammes naive B cells towards
and oropharynx that includes RNAs (miRNAs)21,22. Like all herpesviruses, EBV has a developmental path recapitulating GC reaction, clonal
the tonsils and adenoids. both a productive (lytic) cycle and a non-productive expansion and differentiation towards a memory B cell
(latent) phase. EBV establishes long-term latent infec- phenotype23,31. These developmental stages correspond
Germinal centre
tion of B lymphocytes and productive infection in the to different viral gene programmes termed ‘latency
(GC). An area within lymph
nodes and other secondary oral mucosal epithelium23. EBV DNA is packaged as a types’. During the hyperproliferative phase, EBV adopts
lymphoid organs, including the linear genome in the infectious viral particle, but per- a type III latency in which most latency-associated
spleen, where T cell-dependent sists in the nucleus of latently infected cells as a closed, genes (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C,
B cell activation, differentiation circular chromatinized genome, referred to as an ‘epi- EBNA-LP, LMP1, LMP2 and multiple non-coding RNAs)
and proliferation occur. Germinal
centres are concentrated areas
some’. Although only two distinct EBV strains have are expressed43. Five latent genes (EBNA1, EBNA2,
of B cell somatic mutation and been delineated, the impact of genetic variation on the EBNA3A, EBNA3C and LMP1) are required for effi-
selection. pathobiology of EBV infection is poorly understood22,24. cient B cell immortalization in vitro44. Different degrees
52 | January 2023 | volume 21 www.nature.com/nrmicro
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Chronic active EBV infection

of transcriptional silencing result in latency types II, I and R), which coordinately activate many of the EBV
A rare condition marked by and 0, in which few or no viral genes are expressed. lytic genes22. Although EBV-related malignancies are
poor control of Epstein–Barr Importantly, all EBV-related cancers are associated with associated with specific latency types, lytic gene expres-
virus (EBV) infection, resulting latent infection, and the different latency types correlate sion has been shown in some tumour cells, and serol-
in high EBV plasma viral loads
with different EBV-associated malignancies45. However, ogy studies suggest that lytic antigen immunity precedes
and systemic infiltration by EBV-
positive B cells or EBV-positive there can be considerable variation in viral gene expres- EBV-associated malignancies, particularly nasopharyn-
T cells. sion among tumour cells and stages, including sporadic geal carcinoma, non-Hodgkin lymphoma and post-
and abortive lytic reactivation. At present, it is unclear transplant lymphoproliferative disease49,50. In addition,
Oral hairy leukoplakia whether any specific latency type or lytic infection is highly sensitive genome-wide RNA sequencing methods
A white lesion on the tongue
with a ‘hairy’ appearance that
associated with MS pathogenesis. have demonstrated expression of a subset of lytic genes
is caused by Epstein–Barr virus in EBV-positive tumour cells51, suggesting that aberrant
lytic infection and that can Viral reactivation and lytic gene expression. EBV lytic lytic gene expression and abortive lytic replication may
occur in immunocompromised cycle reactivation occurs in healthy individuals, and is occur more frequently in EBV-associated cancers and
individuals, especially those
required for transmission and potentially for replen- autoimmune disorders52. Defects in the control of EBV
with HIV/AIDS.
ishing the latent reservoir. However, aberrant lytic lytic reactivation have been suggested for MS, but the
Infectious mononucleosis activity is associated with several diseases, including findings remain controversial53–55.
A self-limiting disorder oral hairy leukoplakia46 and chronic active EBV infection.
characterized by fever, extreme
EBV reactivation occurs through regulated stages with Immune control of EBV. Immune responses to EBV
fatigue, sore throat and highly
swollen lymph nodes; most
immediate-early genes controlling the expression of infection differ widely and are influenced by genet-
frequently caused by immune late genes and viral DNA replication, followed by virus ics, the environment and age56 (Fig. 1). While primary
response to primary Epstein– assembly and egress22. Numerous cell signalling path- infection before the age of 5 years is often asympto-
Barr virus infection, although ways can trigger the switch to lytic infection, depending matic, primary infection in adolescence can result in
milder forms are associated
on the host cell type. Many of these pathways are related infectious mononucleosis. During mononucleosis, CD8+
with cytomegalovirus infection.
to immune cell signalling, such as activation of B cell T cells and NK cells rapidly expand in number. Most
receptor (BCR) signalling with anti-immunoglobulin or individuals maintain lifelong, effective immune con-
activation of protein kinase C by phorbol esters47,48. In trol of the virus, where reactivation occasionally occurs
latently infected memory B cells, the switch requires two but is quickly suppressed. This effective immune con-
EBV-encoded transcription factors, BZLF1 (also known trol is dominated by CD8+ T cells that target latently
as ZTA, ZEBRA and Z) and BRLF1 (also known as RTA infected cells and early lytic replication57. Various EBV
Early EBV infection ↓

infectious mononucleosis
CMV infection ↓
MS
Average age at MS onset (years after
Late EBV infection ↑ elevated EBV antibody reponses)
infectious mononucleosis
and multiple sclerosis Risk of infectious mononucleosis
with first EBV infection is negligible
Migration before 15
years can ↑ or ↓ risk EBV-seronegative individuals ↓ risk MS
0 5 10 15 20 30 40 50 60 70 80 90
Age (years)
Magnitude of response
0 5 10 15 20 30 40 50 60 70 80 90
Age (years)
Size of thymic EBV cytotoxic EBV antibodies TH2 cells TH1 cells MS onset
medulla T lymphocytes
Fig. 1 | The maturation of the immune system, EBV infection and the development of MS. The consequences of
Epstein–Barr virus (EBV) infection are influenced by the age and genetic background of an individual. The risk of both infec-
tious mononucleosis and multiple sclerosis (MS) increases when primary EBV infection occurs after the age of 10 years, when
thymic negative selection of autoreactive T cells slows and T helper 1 (TH1) cell-mediated responses approach their peak.
Most individuals receive a diagnosis of MS between the ages of 20 years and 50 years, years after EBV exposure. EBV infec-
tion increases the survival of memory B cells and causes lasting changes in the host cytokine response. There are many gaps
in our understanding of how the maturation of the immune system triggers an evolving process of EBV-driven autoimmune
reactivity leading to the development of MS. CMV, cytomegalovirus.
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latency proteins, including EBNA2, EBNA3A, EBNA3B, to EBV within the CNS, while others have not replicated
EBNA3C and LMP2, are recognized by CD8+ T cells these findings. The presence of EBV-reactive and human
through major histocompatibility complex (MHC) herpesvirus 6-reactive oligoclonal bands and antibody
class I presentation58. By contrast, immune response to reactivity to EBNA1 and EBNA2 epitopes have been
EBNA1 peptides is mediated predominantly by T helper 1 reported in MS CSF85,87. In addition, cytotoxic T lym-
(TH1)-polarized CD4+ T cells59,60. In addition, NK cells phocytes (CTLs) reactive to EBV lytic proteins have been
play a supportive role in controlling primary and lytic detected in the CSF of patients with MS88. The presence
infection, while NK T cells and γδ T cells restrict latency of serum antibodies to EBNA1 has been correlated with
types I and II (refs.5,61–63). These cytotoxic lymphocytes elevated intrathecal IgG levels in patients with early MS,
also successfully restrict EBV in preclinical models, indi- suggesting a role for EBV at the onset of MS symptoms.
cating that the cytolytic arm of the immune system must Cytokine production is highly perturbed in MS, with a
be engaged for efficient control of EBV infection45,64–66. characteristic upregulation of several pro-inflammatory
Study of primary genetic immunodeficiencies that are cytokines, including IL-12, TNF, IFNγ, lymphotoxin-α
associated with an increased risk of EBV-associated dis- and osteopontin89. Before disease relapse, IL-10 secre-
ease has identified key immunoregulatory factors for tion is downregulated and both IL-10 and TGFβ levels
controlling infection, such as the co-stimulatory proteins increase with disease remission89. Inflammatory B cells
CD27, SLAM family members, magnesium transporter secreting higher levels of IL-10 and GM-CSF have also
and the co-inhibitory CTLA-4 receptor67,68. been identified in peripheral blood from patients with
MS90–92. The effects of immunomodulatory therapies
EBV deregulation of immune control. Despite a robust in MS further underscore the role of the immune control.
immune response to primary infection, EBV estab- For example, IFNβ (type I interferon) treatment is thera-
lishes a long-term latent infection in B lymphocytes, peutic, while IFNγ (type II interferon) treatment exacer-
through a combination of viral reprogramming of bates disease progression93, and functional studies have
B lymphocytes and disarming many innate and adaptive confirmed that the IFNα/β pathway is downregulated
immune responses. EBV encodes numerous proteins in the peripheral blood mononuclear cells of untreated
that modulate the immune response. Some of these patients with MS94. More recently, the important role of
are expressed during the lytic or prelatent phase, while B cells in MS pathogenesis was revealed by the success
others are more consistently expressed during the latent of B cell depletion therapy targeting B cells, including
infection. For example, EBNA1 can induce CXCL12 anti-CD20 (see later)90.
to recruit regulatory T cells69 and suppress NK cell Ultimately, the immune abnormalities in MS are
responses by downregulating NKG2D ligands70. EBNA2 associated with the development of focal demyelinat-
transcriptionally activates numerous genes involved in ing lesions (also known as plaques) in CNS white and
immune regulation, such as those encoding tumour grey matter and can be visualized by MRI. These lesions
necrosis factor (TNF)71, lymphotoxin-α72, IL-18R73 and differ in size, distribution and cellular composition95.
PDL1 (refs.74,75). EBNA2 also suppresses interferon The neuropathological findings suggest that within the
responses76 and HLA class II gene expression77. Virally active lesion, inflammatory T cells, B cells, plasma cells,
encoded IL-10 (also known as BCRF1) suppresses pro- activated microglia and macrophages are associated
inflammatory cytokine secretion, such as secretion with oligodendrocyte loss, demyelination and astrocyte
of IL-2 and interferon-γ (IFNγ), while viral BNLF2a activation as the lesion forms around veins and venules,
inhibits the transporter associated with antigen process- expands into normal-appearing white matter and leads
ing (TAP)78. Multiple viral miRNAs target type I inter- to the formation of gliotic scars96–99. Within the active
feron pathways, such as IRF9, JAK1, JAK2 and RIG-I lesion, macrophages contain both early and late mye-
(ref.79). Functionally, EBV miRNAs suppress CD8+ T cell lin degradation products. Inflammation is greatest in
response and are required for the establishment of latent active lesions, but is also observed in other stages of
infection in humanized mice80. Thus, EBV encodes MS plaques. Interestingly, relatively little inflammation
numerous genes that deregulate innate and adaptive is observed in the initial stages of white matter lesions,
immunity, and it is not yet clear which, if any, of these leading to debate as to whether lesions are initiated by a
pathways are most involved in the pathobiology of MS. neurodegenerative or an inflammatory process and rais-
ing the possibility that initial tissue injury is initiated by
Pathobiology of MS lymphocyte-derived soluble factors that induce damage
The pathobiology of MS is notable for several immune directly or via activation of microglia97. Inactive MS
abnormalities, which have been described extensively lesions are hypocellular, with loss of oligodendrocytes
elsewhere. Briefly, oligoclonal bands in the cerebrospi- and myelin, astrocytosis, fewer myelin degradation pro
nal fluid (CSF) and elevated IgG concentrations in the ducts within macrophages and loss of axonal density96.
CNS are hallmarks of MS, and can be used for diagnosis. In addition to demyelination, axonal loss occurs in both
Notably, oligoclonal bands are found in several neuroin- white matter and grey matter and, over time, there is
flammatory disorders, and are typically directed against atrophy of the brain100. Remyelination may occur as new
the pathogen implicated in the disease. By contrast, the oligodendrocytes regenerate; the extent of remyelination
oligoclonal bands in MS are reactive against multiple depends on many factors, including the location in the
antigens, including viral antigens, bacterial antigens brain. Circumstances that determine whether inflam-
and self-antigens81–86. Several studies have provided evi- mation within a lesion resolves and remyelinates or if it
dence of EBV infection or elevated immune responses ‘smoulders’ are incompletely understood.
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Box 1 | Critical questions and knowledge gaps Ongoing clinical studies using antivirals, vaccines and
cell-based approaches targeting EBV in patients with
• How do developmental changes in the human immune system impact the long-term MS (discussed later) are likely to elucidate the role
control of Epstein–Barr virus (EBV) with respect to T cell responsiveness and latent of EBV as a driver of disease activity. The risk of MS
B cell reservoir? And how does this inform our understanding of the timing of EBV increases approximately 32-fold with EBV infection,
infection and its subsequent lifetime latency and immune control?
and more with symptomatic to severe infectious mon-
• What, if any, are the pathogenic roles of EBV in the central nervous system (CNS)? Do onucleosis and HLA-DR2b (HLA-DRB1*1501b and
CNS-infiltrating immune cells harbour EBV or EBV-reactive immune cells, especially
HLA-DRA1*0101a)18. How these genetic and environ-
in multiple sclerosis (MS)? What are the specific dynamics of EBV infection in the
CNS? Which cells are involved, and does this differ in patients with MS compared mental factors compound risk in MS is not fully under-
with healthy controls? stood, and there remain many plausible mechanisms.
• How does EBV reprogramming of B cells contribute to MS risk? Does EBV alter B cell
Determining which of these are the most frequent driv-
antigen presentation and T cell miscommunication to drive autoimmunity? Does EBV ers and how best to therapeutically intervene remain
rescue autoreactive B cells? challenges. In this section, we discuss the evidence for
• How do MS-risk alleles compound the effects of EBV latent infection in B cells? Is EBV as a trigger and/or a driver in MS pathogenesis, and
enhanced EBNA2 binding at MS-risk alleles sufficient to drive B cell autoimmunity? highlight critical questions that may elucidate the role
• How do EBV infection and the HLA-DR15 allele compound the risk of MS? Is there an of EBV as a trigger and potential driver of MS (Box 1).
altered presentation of EBV antigens or EBV-induced factors in this HLA haplotype?
• Which EBV factors are most consistently associated with MS pathogenesis, and can Molecular mimicry and mistaken self. Latent and per-
this inform more selective drug design and immunotherapies? sistent infection is a chronic source of viral antigenic
• How do effective MS therapies (for example, CD20 depletion, cladribine and stimulation. Several EBV antigens are the target of
CD52 depletion) affect EBV-positive cells, EBV infection cycle, the frequency of cross-reactive autoantibodies found in MS. This cross-
EBV-positive cells and EBV loads? Does deficient cytotoxic T lymphocyte control reactivity between self-antigens and EBV antigens
in MS lead to EBV reactivation and increased EBV antibody responses and CNS involves both cellular and humoral immune responses.
inflammation? Early studies found that patient-derived T cells autore-
active to myelin basic protein (MBP) were also cross-
reactive to a wide range of viral peptides, including
Immune cell composition within the lesion differs peptides from EBV115. Subsequent studies identified
with respect to the type of MS and the stage of the lesion. MBP-reactive T cells in patients with MS that cross-
T cell and B cell infiltration is greatest in active lesions react with EBNA1 (ref.116). Similar cross-reactivities with
in patients with RRMS. CD8+ T cells consistently out- EBNA1 were found for T cells autoreactive to anoctamin 2
number CD4+ T cells in all sites of the MS lesion except (ref.117), α-crystallin B chain (CRYAB)88,118 and most
for the perivascular and meningeal cuffs, where CD4+ recently glial cell adhesion molecule17. Mimicry has been
T cells, CD20+ B cells and plasma cells predominate98,99, reported for the lytic proteins BHRF1 and BPLF1 (ref.119).
suggesting that CD8+ T cells are more important effec- Peptides from these viral lytic proteins were found bound
tors in the immunopathogenesis of MS than previously to the HLA-DR15 haplotype and were cross-reactive
appreciated. Notably, fewer brain lesions, fewer inflam- with the self-protein RASGRP2 as a target autoantigen,
matory cells and more spinal cord lesions are found in which is expressed in the brain and B cells and is targeted
PPMS than in RRMS. by brain-homing, autoreactive CD4+ T cells119.
Autoreactive antibodies in MS also cross-react with
Immunogenetics of MS viral proteins, especially EBNA1 (ref.120). Higher levels
The genetic contribution to MS susceptibility is complex of antibodies to EBNA1 are typically observed in both
and is extensively reviewed elsewhere101,102. The strongest serum and CSF of patients with MS121,122. Elevated titres
genetic risk factor for MS is a specific haplotype of the of antibodies to EBNA1 were found to have a genetic
highly polymorphic MHC103. Specifically, an increased component beyond just HLA type123, and high titres of
risk of MS exists in individuals with the MHC class II antibodies to EBNA1 are associated with an increased
alleles HLA-DR2 and HLA-DQw1 (ref.104), with the pri- risk of MS124. Many of these EBNA1-specific antibodies
mary risk allele being HLA-DRB1*1501. Genome-wide are polyreactive, and it is not clear which antigen initi-
studies have identified more than 200 MS-associated ates the immunogenicity. In addition to viral mimicry,
loci across the human genome, and approximately 30 virus infection in peripheral tissue induces cellular stress
are associated with the MHC locus105–109. Most of these proteins, such as CRYAB, that can mimic CNS tissues
loci have well-ascribed functions in the immune system, and elicit an autoimmune reaction to proteins such
while some are associated with myelin structure or mito- as myelin125. Interestingly, CRYAB-specific antibodies
chondrial function110–113. Importantly, these studies also from patients with MS cross-react with EBNA1 (ref.126).
reveal shared genetic risk factors with other autoimmune Despite these correlations, the pathogenic role of auto-
conditions. reactive and EBV-cross-reactive antibodies in MS is not
well established.
How does EBV increase the risk of MS? Why then do so many self-reactive immune responses
MS has a complex aetiology, with multiple causative in MS cross-react with EBV peptides and EBNA1 in
factors that can be further defined as either drivers or particular? Peptide library analyses have identified sev-
triggers114. EBV is a trigger (that is, it must be acquired eral domains of EBNA1 that are recognized by autore-
before the onset of disease); however, its role as puta- active immune responses (Fig. 2). EBNA1 amino acids
tive ‘driver’ of disease progression is poorly defined. 391–410 peptide mimics CRYAB amino acids 1–15
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EBNA1–DNA complex
aa 350–459
NTD
NTD
DBD
DNA
NTD NTD
aa 350–459
DBD
EBNA1 (aa) Sequence Mimic Immune response
386–405 SQSSSSGSPPRRPPPGRRPF GlialCAM IgG
411–426 EADYFEYHQEGGPDGE MBP IgG
504–518 VAGGRVYGGSKTSLY β-SYN HLA-DR2b
431–440 PGAIEQGPAD ANO2 IgG
473–593 HLA-DRB1*15
385–420 PPPGRRPFFHPVGEA CRYAB IgG + HLA-DRB*1501
407–418 HPVGEADYFEY CD8 + HLA-B35
90–330(GA)n GAGGGAGAGG IgG
Fig. 2 | EBNA1 sequences and their potential role in molecular mimicry and autoreactivity. Computational model of
EBNA1 full-length protein233 indicating the most frequent peptide epitopes associated with multiple sclerosis autoimmun-
ity. DNA is shown as solid, protein as ribbon. Epitopes are highlighted in magenta and boxed. A partial list of EBNA1 pep-
tides and their autoimmune properties, including immune response type and cellular protein mimic. aa, amino acids;
ANO2, anoctamin 2; β-SYN, β-synuclein; CRYAB, α-crystallin B chain; DBD, DNA-binding domain; (GA)n, glycine-alanine
repeats; glialCAM, glial cell adhesion molecule; MBP, myelin basic protein; NTD, amino-terminal domain.
with an overlapping sequence of RRPFF126. A simi- EBV immortalization of a ‘forbidden’ autoreactive B cell
lar domain of EBNA1 (amino acids 386–405) mimics clone has been proposed as a potential mechanism trig-
glial cell adhesion molecule17. In the case of glial cell gering MS137. EBV transformation could bypass the nor-
adhesion molecule, post-translational modification of mal process of elimination of autoreactive B cells, although
the host protein increased cross-reactivity, providing most of this selection occurs in the bone marrow at early
a mechanism for epitope evolution and spreading in stages of B cell development138. Similar mechanisms
response to environmental signals. Some reactivity to of immune evasion are proposed for EBV-associated
EBNA1 was associated with germ line, unmutated BCR, cancers139 (Box 2). EBV immortalization bypasses many
suggesting that early antibodies have innate affinity for of the requirements for T cell help through the virally
a region of EBNA1 (ref.17). Other studies have pointed encoded CD40-like receptor LMP1 and BCR-like recep-
to the glycine-rich regions of EBNA1, which generate tor LMP2 (refs.23,31). Their combined expression is suffi-
repetitive, low-complexity peptides127. Autoreactive cient to drive lymphomagenesis in transgenic mice140, and
antibodies also react with peptides derived from the it is likely that these ligand-independent receptors provide
exposed surface of the EBNA1 DNA-binding domain, signals that can rescue autoreactive B cells. EBV-infected
but not the DNA-binding interface itself, suggesting B cells also express mature BCR and IgG without neces-
that the intact EBNA1–DNA complex is an impor- sarily passing through GC selection, further enabling the
tant antigenic stimulus128. Paradoxically, EBNA1 also survival of B cell clones reactive to self 141. EBV-infected
has immune-evasive properties. The internal Gly-Ala B cells alter T cell interactions mediated by CD70–CD27
repeats (amino acids 90–303) suppress HLA presenta- and OX40L that disable T cell control and enable B cell
tion through multiple mechanisms, including inhibition lymphomagenesis142,143. Whether these forbidden B cells
of peptide processing129–131, suppression of autophagy132 are antigen-presenting cells or antibody-producing
and translational suppression133,134 owing to the mRNA cells is not yet known. However, recent B cell depletion
structure134–136. How these activities are related to the studies suggest that B cell subtypes, and not plasma
high exposure of EBNA1 in autoimmune disease and cell numbers or overall circulating antibody levels, best
what aspects of EBNA1 peptide presentation differ in correlate with CNS pathogenesis in patients with MS90.
patients with MS are unclear.
EBV infiltrating the CNS. EBV-infected B cells migrate
Rescue of autoreactive and inflammatory B cells. EBV to the CNS, where they may have altered immune reac-
is highly efficient at immortalizing naive and resting tivities and are associated with EBV-associated diseases,
B cells (Fig. 3). However, it is not fully established which including primary CNS lymphoma (Fig. 4). EBV-positive
B cell subtypes may or may not be susceptible to EBV. B cells and plasma cells have been identified after death
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in MS lesions in the CNS of patients with MS, but Deficient CTL control of EBV infection. T cell control
not in controls144–146. EBV gene expression was a vari of EBV infection is required for homeostatic viral per-
able mixture of both latent transcripts (EBV-encoded sistence, and immune dysregulation is observed in all
small RNAs (EBERs), EBNA3A, LMP2A and LMP2B) EBV-associated disease. In healthy carriers of latent EBV
and lytic transcripts (BZLF1 and gp350) in these brain infection (more than 90% of the adult population),
lesions33,144,146–148. In situ hybridization experiments nearly 1% of all T cells are reactive to EBV latent or
revealed a significant number of EBER+ B cells and a lytic antigens159,160. Immune response to EBV is fre-
small number of BZLF1+ cells, although some EBV- quently skewed in patients with MS. Higher titres of
positive B cells were also found in the brains of controls148. EBNA1-reactive IgG are found several years before
EBV-infected plasma cells in the CNS have been found the onset of MS symptoms and correlate with MS
synapsed with cytotoxic CD8+ T cells, suggesting a local risk8,161,162. EBNA1-specific T cell frequencies increase
inflammatory interaction initiated by EBV-p ositive and specificities broaden in MS. CD4+ T cells show TH1
B cells in the CNS149. There is evidence that EBV estab- polarization and CD8+ T cell responses correlate with
lishes an extralymphatic viral sanctuary in the CNS150, disease activity163–166. MS progression correlates with a
especially in vulnerable individuals during infectious decreased functionality of EBV-specific CD4+ T cells
mononucleosis, in which approximately 50% of memory and CD8+ T cells, as measured by IFNγ production and
B cells can be EBV positive151. However, several studies cytotoxic activity167–169. T cell exhaustion may partly
failed to find evidence of EBV-positive B cells in the CSF of account for the failure to control chronic EBV infec-
patients with MS or MS lesions in the CNS152–157. Some tion. Developmental changes in the immune system are
of these conflicting findings may be due to technical also critical for control of EBV infection. Childhood
challenges of detecting transient EBV gene expression experience (time of exposure to EBV and geographical
in migratory B cells in the CNS of patients with MS and risk) indicate that immune system maturation, expo-
post-mortem samples158. sure and education are important components of MS
HLA
EBNA1 peptide mimicry
LMP2
BCR
HLA-DR15
PI3K
PDK1 LMP1
AKT MEKK
Survival
EBNA1 MKK4 P
MKK7 P
P
B cell JNK
P
EBNA2
EBV episomes Proliferation
RBPJ Ligand
IL-6, GM-CSF, TNF, OPN • CD4+ cell

• CD8+ cell
MSrisk • NK cell
allelles Receptor
EBF1 HLA-DR15
Inflammatory exosomes
Fig. 3 | EBV latency drives B cell survival of inflammatory B cells. Epstein– direct interaction with T cells or natural killer (NK) cells, as well as through
Barr virus (EBV) infection promotes the proliferation and survival of memory soluble factors, including exosomes. EBNA1 is frequently processed as an
B cells that may alter T cell control of EBV infection and autoimmune reac antigenic epitope that can stimulate autoreactive B cell and T cell
tive B cells and T cells. EBV LMP1 and LMP2 function as CD40-like and B cell development. Although EBV-positive cells are shown as antigen-presenting
receptor (BCR)-like mimics to bypass T cell-dependent germinal centre cells, it is not known whether they actually present EBNA1 peptides or
reactions. EBNA1 and EBNA2 drive gene regulatory changes that may affect whether these are presented by uninfected antigen-presenting cells,
preferentially multiple sclerosis (MS)-risk alleles. EBV-induced viral and including uninfected dendritic cells and macrophages that captured
cellular factors may promote inflammation, driving autoreactivity through infected cell debris. OPN, osteopontin; TNF, tumour necrosis factor.
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aetiology8. Poorly defined, idiosyncratic CTL deficien- induce autoreactive T cells through modification of their
cies may also enable EBV-positive B cells to proliferate, antigen presentation8,90.
migrate to the CNS and express inflammatory viral and
host factors169. Deregulation of B cell gene expression and autoimmune
control. EBV encodes several transcriptional regulators
EBV-associated inflammation. Both B cells and T cells and signalling molecules that reprogramme B cell gene
from patients with MS have atypical inflammatory networks implicated in cancer and autoimmunity. The
features. Patients with MS with high EBV loads have latency nuclear regulatory factor EBNA2 is essential for
T-bet+CXCR3+ memory B cells induced by IFNγ and TLR9 EBV immortalization and drives B cell proliferation175.
signals and EBV-reactive CTLs autoreactive to neuronal EBNA2 interacts with several host transcription fac-
tissue170. EBV load correlated with the early emergence of tors, and studies involving chromatin immunoprecip-
CXCR3+ class-switched memory B cells, GC-like B cell itation followed by sequencing revealed that EBNA2
development and trafficking of these cells to the CNS binds to almost half of the risk alleles for seven auto-
in mice170. These CXCR3+ B cells had enhanced ability immune disorders176. Genome-wide chromatin acces-
to secrete anti-EBNA1 IgG171. It is important to note sibility (assay for transposase-accessible chromatin
that EBV-negative B cells from patients with MS also using sequencing) and DNA looping (HiC) further
have inflammatory features, and memory B cell subsets, demonstrated the role of EBNA2 in altering chromatin
in particular, were found to secrete higher levels of GM- structure at many autoimmune genetic risk alleles177.
CSF in patients with MS relative to healthy controls92. Risk alleles were enriched for EBNA2 binding relative
EBV-infected B cells produce high levels of inflamma- to non-risk alleles, as demonstrated for a few specific
tory cytokines and exosomes that contain inflammatory examples, such as ZMIZ1 (ref.177).
components, including small viral nucleic acids, such as Genome-wide linkage studies have further impli-
EBERs and miRNAs172. Exosomes containing EBERs cated EBV as a regulator of MS-risk alleles178. Expression
with 5′-triphosphate pathogen-associated molecular quantitative trait locus analysis found that genes located
patterns stimulated dendritic cell antiviral inflamma- near MS-risk SNPs were linked with EBV type III
tory activity, similar to systemic lupus erythematosus172. latency. These genes include BATF, IRF5, IRF7 and
EBV miRNAs, which can be transported in exosomes, STAT genes. In a related study, EBNA2 bound prefer-
can target MS risk-associated genes, such as ZC3HAV1 entially to five of six MS-risk alleles, relative to non-risk
regulating interferon response173. Exosomes may cross alleles, and a peptide inhibitor that disrupts EBNA2
the blood–brain barrier, and are endocytosed by brain interaction with the cellular transcription factor RBPJ
microvascular endothelial cells174. Therefore, it is possi- altered high-r isk allele expression71. Thus, MS-r isk
ble that EBV-positive B cells in the periphery produce alleles could increase the efficiency of EBNA2 to pro-
exosomes that cross into the CNS and/or that EBV- mote B cell survival and immortalization71. EBNA2 tar-
positive B cells in the CNS are a source of these inflam- gets also overlap with those of vitamin D receptor, which
matory exosomes (Fig. 4). EBV-positive B cells may also is another risk factor for MS179. Furthermore, poly
morphisms in EBNA2 correlate with MS risk, suggest
Box 2 | Common themes of EBV-associated cancers and MS
ing that the virus strain may also be a risk factor180. The
precise mechanism of gene deregulation in MS may be
There are several common features of Epstein–Barr virus (EBV) infection as an aetiolog- further nuanced and influenced by epigenetic control.
ical agent in both cancer and multiple sclerosis (MS). Most EBV-associated cancers DNA methylation and genomic imprinting of alleles
result from EBV prolonging the survival of a cell that acquires additional oncogenic associated with MS have been implicated in MS181,182.
mutations or epigenetic changes that drive cancer cell evolution. Cancer may also arise
For example, HLA-DRB*1501 is hypomethylated and
from EBV entering a cell with precancerous mutations that may enable EBV to establish
an oncogenic infection, such as a type II latency in an epithelial cell. It is also possible
expressed at high levels in antigen-presenting cells in
that EBV acquires mutations and induces epigenetic changes in the host cell that drive patients with MS183,184. Alternative splicing has been seen
oncogenesis. These rare events amount to a significant incidence of cancer cases in MS B cells, and may be related to EBV transcriptional
owing to the high prevalence and persistence of EBV. Similar types of aberrations may reprogramming185.
need to be considered for MS. Does EBV infect a rare ‘forbidden’ B cell? If so, what EBV encodes several other transcription regulatory
are the B cells that are infected in patients with MS, and how may these differ from factors that can influence B cell biology. The EBV lytic
non-pathogenic EBV-positive B cells that do not drive MS? Could EBV have acquired activator BZLF1 is a potent transcriptional regulator of
rare mutations or polymorphisms that drive MS? Because EBV is so ubiquitous and numerous viral and cellular genes. BZLF1 expression has
because it is usually acquired early in life, the question of how the virus may be toler- been identified in plasma B cells in post-mortem brain
ated as ‘self’ versus chronically rejected as ‘non-self’ may depend on the age at primary
samples from patients with MS and has been associ-
infection. Antigens acquired before a certain stage of immune development and pre-
sented in the appropriate HLA context may be considered self-antigens and acquire
ated with reactive cytotoxic CD8+ T cell infiltration166.
tolerance. Similarly, foreign antigens that mimic self-antigens may escape immune rec- EBV-induced G protein-coupled receptor 2 (EBI2; also
ognition by posing as self or exhausting T cells. EBV modulation of many B cell immuno known as GPR183) is a G protein receptor for dihydroxy
regulatory genes is also likely to contribute to pathogenesis in both cancer and MS. cholesterol, which is overexpressed in MS lesions and
Indeed, similarly to MS, infectious mononucleosis in adolescence increases the risk of involved in migration of CD4+ T cells186.
developing Hodgkin lymphoma (an approximately fourfold increase). In Hodgkin lym- EBV genomes are also regulated by epigenetic modi-
phoma, EBV rescues defective germinal centre B cells from apoptosis and initiates early fication, especially DNA methylation, which can impact
events in lymphomagenesis by altering normal B cell gene expression programmes139. viral gene expression and latency type187,188. Epigenetic
Therefore, it is possible that an analogous EBV-mediated rescue of autoreactive B cells control of EBV is an important component of EBV
or other B cell subsets may set the stage for the development of MS.
cancer aetiology, but its role in autoimmune disease is
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Periphery IL6, OPN, CNS

CXCR4 Neuron
• Uncontrolled latency
• Inflammatory cascade
Inflammatory B cell
EBNA1 peptides
• CNS trafficking
EBVpositive type I • Autoreactivity
EBNA1 • Molecular mimicry
memorylike Astrocyte reactive
MBP glialCAM
Episome
Autoreactive T cell Inflamed

EBNA1 only astrocyte
Immune
evasive
T cell
Primary infection
EBV
• Cytokines
• Exosomes
CD21 CD19
Exosomes
CD20
LMP1
Microglia
Lytic
Inflammatory cytokine
LMP2
Naive B cell EBVpositive type III
Germinal centrelike reaction
• Deficient
Defective CTL T cell control
• Aberrant EBV
tropism
EBV lytic reaction
Fig. 4 | Mechanisms of EBV-mediated inflammatory cascades in periphery and CNS. Epstein–Barr virus (EBV) may drive
inflammatory events in both the periphery and the central nervous system (CNS), leading to the development of the multi-
ple sclerosis lesion in the CNS. EBV immune-evasive features and risk-associated immune deficiencies promote EBV inflam-
matory cascades in the periphery. CNS pathogenesis may be initiated through multiple mechanisms, including natural and
EBV-driven CNS trafficking of autoreactive B cells and T cells, molecular mimicry driven by chronic EBV infection, EBV-driven
inflammatory cytokines and exosomes, and aberrant EBV lytic infection and tropisms owing to deficient immune control.
CTL, cytotoxic T lymphocyte; glialCAM, glial cell adhesion molecule; MBP, myelin basic protein; OPN, osteopontin.
not well described. Studies in MS patients and animal higher levels of MBP-specific T cells in patients with
models have identified gene variants, miRNAs and MS than in controls81. Related studies implicate variant
viral co-factors that exert epigenetic control to increase peptide binding of the high-risk HLA-DRB1*15 allele
inflammation, immune cell differentiation and myelin in the presentation of various autoreactive peptides.
breakdown189. Epigenetic modification of genes that pro- Some of these peptides may be derived from EBV pro-
mote neuroinvasion of EBV-positive B cells, including teins, providing a potential mechanism to explain the
the genes encoding osteopontin and CXCR4, has been combined risk of EBV infection and HLA-DRB1*15.
described in some experimental models, suggesting that For example, humanized mice reconstituted with HLA-
EBV may affect epigenetic mechanisms driving MS190. DR15 had elevated CD8+ T cell responses and CD4+
T cells cross-reacting with MBP192. In addition, some
EBV interactions with HLA. HLA alleles have different studies have found that HLA-DR15 and HLA-DRB*07
binding affinities and specificities for antigenic peptides patients with MS have higher EBV viral loads, whereas
that impact T cell immunogenicity and functionality191. HLA-A*02 individuals have lower viral loads, suggest-
Antigenic peptides derived from MBP have been identi- ing that class I and class II MHC molecules modulate
fied from B cells from patients with MS and correlate with EBV latency control193,194. However, other studies did not
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find increased EBV viral loads in MS or changes that improvement after autologous EBV-specific T cell therapy
immediately precede or coincide with relapses195–197. targeting EBNA1, LMP1 and LMP2A214. Early results sug-
Nevertheless, HLA-A*02 correlates with a decreased gest that ATA188 is safe and well tolerated, with a decrease
risk of MS (reviewed in ref.198). Alternatively, but per- in Expanded Disability Status Scale (EDSS) score217.
haps related, MS-associated risk alleles, including HLA-
DRB5, are also correlated with differentially regulated Antivirals, vaccines and their potential to target EBV in
gene expression199,200. Higher expression levels of HLA MS pathogenesis. Specific antivirals for treating EBV
alleles may also affect peptide selection and presentation infection have not, to date, been approved for treatment
that contribute to peptide mimicry and autoreactivity. of MS. Moreover, several clinical trials testing the effi-
Another intriguing finding is that the HLA-DR15 allele cacy of antivirals, specifically those with broad antiher-
can serve as a co-receptor for EBV entry into B cells, pesvirus activity, including acyclovir and valacyclovir,
raising the possibility that viral entry pathways may also did not demonstrate a clear benefit in MS218–220. IFNβ,
contribute to MS risk201. a cytokine with broad antiviral, antiproliferative and anti-
inflammatory effects, was the first immunomodulatory
Opportunities for therapeutic intervention therapy to successfully modify the disease course of MS,
Existing immunomodulatory therapies and their poten- and is still one of the most frequently used therapeu-
tial effect on EBV. The effectiveness of immunosuppres- tic options for MS; it is considered a first-line therapy
sive and anti-inflammatory therapies in MS supports with modest efficacy in controlling ongoing disease221.
the autoimmune component in disease pathogenesis. The exact mode of action of IFNβ in MS is only partly
Corticosteroids effectively treat MS flares202, but are too understood. IFNβ has potent antiviral activity and is
immunosuppressive for long-term use. Several immuno known to counteract many immunomodulatory actions
suppressive and chemotherapeutic drugs that dramati of EBV222,223. Antiviral nucleoside analogues may also
cally decrease the levels of circulating immune cells, be effective for treating EBV infection in MS. Recent
including cyclophosphamide, cladribine, mitoxantrone, studies have shown that the non-cyclic nucleoside ana-
methotrexate and teriflunomide, have been used with logue tenofovir alafenamide (TAF), which was devel-
variable success203,204. It is now appreciated that B cells oped as a specific inhibitor for the HIV and hepatitis
play an essential role in MS pathogenesis, on the basis B virus reverse transcriptases and is frequently used in
of the success of CD20-specific depletion. Monoclonal HIV pre-exposure prophylaxis, also inhibits the EBV
antibodies to the B cell antigen CD20 (ocrelizumab DNA polymerase224. Notably, TAF was twice as potent
and ofatumumab) reduce MS relapse and lesion for- as ganciclovir in direct inhibition of EBV replication
mation, while a monoclonal antibody (anti-IL-12 p40 and DNA polymerase activity225. In addition, anecdotal
and anti-IL-23 p40, ustekinumab) that targets both TH1 reports and case studies have suggested that there may
cells and TH17 cells did not show similar efficacy205–207. be a clinical benefit and decreased relapses in patients
Importantly, additional therapeutics that broadly tar- with RRMS receiving TAF regimens226. A clinical trial
get B cells, including anti-CD52 monoclonal antibody (NCT04880577) has been initiated to test the ability
and cladribine act as B cell-depleting drugs and are of TAF as an add-on therapy to ocrelizumab to reduce
of therapeutic use in MS. By contrast, treatments that symptoms and promote neuroprotection in RRMS.
target naive and plasma B cells (for example, atacicept) There are distinct challenges for EBV vaccine devel-
or boost memory B cells (for example, infliximab) opment. Sterilizing immunity to EBV may not be
further aggravate MS via TNF blockade208. The effects possible given the efficiency of EBV transmission and
of these treatments on EBV load is not yet known. persistence, and merely delaying the time of infection
Interestingly, teriflunomide has been shown to reduce is undesirable, because it increases the risk of mono-
both EBV-induced lymphoproliferation and lytic viral nucleosis and MS. Furthermore, identification of the
replication209. most appropriate viral antigens is complex for both
prevention of infection and treatment of existing dis-
EBV-specific CTL therapy. Cell-based immunotherapies, ease. Vaccine approaches to block early events in EBV
including EBV-specific CTL lines, have proven success- primary infection would require neutralizing antibodies
ful in the treatment of post-transplantation lymphopro- that target components of viral entry proteins (includ-
liferative disorder and EBV-associated lymphomas and ing gp350, gp42, gH, gL and gB). Therapeutic vaccines
nasopharyngeal carcinoma, with low rates of graft-versus- for various EBV-associated cancers or autoimmune
host disease210–212. Therefore, the use of autologous T cell disease may need to target multiple viral proteins, as
therapy has been expanded to clinical trials in MS213–216. both latent and lytic viral genes have been implicated
These therapies attempt to compensate for deficient in disease pathogenesis. In addition to careful consid-
CTL control of EBV-infected B cells. Phase I trials using eration of the viral antigens included in the vaccine,
ATA188, an allogenic T cell therapy using T cells from a successful vaccine strategy for EBV must stimulate both
healthy donors, have been initiated to evaluate allogenic the humoral arm and the cell-mediated arm of the adap-
EBV CTL therapy in PPMS and SPMS (NCT03283826), tive immune system and induce production of effector
and the first clinical episode highly suggestive of MS and long-lived memory cells. The development of a
Graft-versus-host disease (NCT02912897). Initial reports have demonstrated vaccine targeted at preventing the development of mono
A condition in which the
donor’s immune system (the
increased circulation of LMP-reactive and lymphoblastoid nucleosis in EBV-seronegative children could poten
graft) rejects the recipient cell line (LCL)-reactive effector CD8+ memory cell popu- tially reduce the likelihood that these individuals will
(the host) as non-self. lations. Notably, patients with PPMS have reported clinical later develop MS. A small trial examining the efficacy
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of vaccination with the HLA-B*0801-restricted CD8+ control this primary infection may lead to colonization
T cell epitope FLRGRAYGL demonstrated a reduced of resident memory B cell and T cell follicles in CNS
likelihood of developing mononucleosis in those chil- accessible sites, such as tertiary lymphoid structures,
dren who seroconverted227. Similarly, vaccination of that are uniquely prone to inducing immune pathol-
EBV-seronegative young adults with a recombinant ogy in the CNS. The time of infection likely contributes
gp350 subunit vaccine prevented the development to immune system elimination of viral, autoreactive
of mononucleosis, although it did not decrease rates of T cells and antibodies that target CNS components.
asymptomatic EBV infection228. Phase I/II trials demon These events must be further exacerbated by numerous
strated that this gp350 subunit vaccine was well tol- genetic risk alleles, especially HLA-DRB1*1501, that
erated and immunogenic, inducing robust gp350 may compound the effects of EBV infection through
antibody responses as well as EBV-neutralizing antibody aberrant presentation of autoreactive peptides. Other
responses229. Following the success of its severe acute alleles can cooperate with EBV transcription regulatory
respiratory syndrome coronavirus 2 vaccine, Moderna factors, such as EBNA2, through altered binding spec-
launched a vaccine trial (NCT05164094) using mRNA ificity and gene programmes promoting inflammatory
encoding EBV gp350, gB, gH/gL and gp42 in seronega- B cell proliferation. Whether there are any special fea-
tive 18–30-year-old adults. Further studies are required tures of EBV antigens, such as EBNA1, that induce high
to determine whether this approach or other vaccine rates of polyreactivity and self-mimicry needs to be fur-
approaches could ultimately decrease the likelihood of ther investigated. Among the most pressing questions is
developing mononucleosis and, subsequently, MS. whether EBV-infected cells or viral products act within
the CNS or indirectly through inflammatory events in the
Conclusions periphery. Ultimately, how autoreactive immune cells
Despite years of controversy, the role of EBV infection and antibodies form and accumulate in the CNS remain
and seropositivity as essential co-factors for most forms high-priority questions. Knowing that EBV is a likely
of MS may now be settled. As the severity of EBV pri- driver of inflammatory autoimmune disease provides a
mary infection strongly correlates with the development target for future therapies.
of MS many years later, it is likely that MS depends on
the initial immune response to EBV infection. Failure to Published online 5 August 2022
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Epstein–Barr virus and multiple

naTure RevieWS | MiCRoBiology volume 21 | January 2023 | 51

of EBV in MS T cells periodic reactivation primarily in the oropharynx32, but

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Chronic active EBV infection

Early EBV infection ↓

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IL-6, GM-CSF, TNF, OPN • CD4+ cell

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Periphery IL­6, OPN, CNS

Autoreactive T cell Inﬂamed

EBV lytic reaction

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Periphery IL6, OPN, CNS