Epstein-Barr Virus (EBV) and autoimmune diseases: Pathogenic Mechanisms and Therapeutic Insights

Epstein-Barr Virus (EBV) and autoimmune diseases: Pathogenic Mechanisms and Therapeutic Insights | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Journal of Medical Virology This is a preprint and has not been peer reviewed. Data may be preliminary. 10 September 2025 V1 Latest version Share on Epstein-Barr Virus (EBV) and autoimmune diseases: Pathogenic Mechanisms and Therapeutic Insights Authors : Shipra Gupta , Vijayalakshmi Reddy , Lonika Lodha , and Ashwini Anand 0000-0002-2018-7066 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175748801.17440913/v1 Published Journal of Medical Virology Version of record Peer review timeline 1478 views 231 downloads Contents Abstract Virus structure Life cycle Mechanisms of Epstein Barr Virus induced autoimmunity Implications for Prevention and Therapy Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Epstein-Barr virus (EBV), a ubiquitous human γ-herpesvirus infecting over 90% of the global population, has been increasingly implicated as a key environmental trigger in the development of various autoimmune diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and others. EBV latent proteins (e.g., EBNA1, EBNA2, LMP1) mimic host antigens and dysregulate B and T cell responses, promoting autoreactivity. Novel therapeutics, including small-molecule latency disruptors, EBV-specific T cell therapies, and advanced B-cell depletion strategies, show promise in addressing EBV-driven autoimmunity. Understanding its pathogenic mechanisms and therapeutic implications is critical for improving disease management. This review summarises EBV’s roles in autoimmunity through mechanisms including molecular mimicry, B-cell transformation, and immune dysregulation. It also examines emerging antiviral and immune-modulating strategies targeting EBV infection and latency. Introduction Epstein-Barr virus (EBV), a DNA virus, was discovered by electron microscopy in a biopsy of a patient with Burkitt’s lymphoma in 1964 by scientists Anthony Epstein, Yvonne Barr, and Burt Achong. 1 EBV is a member of the Herpesviridae family and the Gammaherpesvirinae subfamily, and is also known as Human Herpesvirus 4 (HHV-4). 2 EBV is classified into two genotypes —type 1/type A and type 2/typeB, which are distinguished based on the variation in the EBNA2 and EBNA3 genes. Type 1 EBV has increased lymphocyte transformation capacity compared to Type 2 EBV. Coinfections with both type 1 and type 2 genotypes have been reported. 2–4 EBV is the most common human virus infecting 90% of the population globally. 5,6 The major route of transmission is through contact with the oral secretions, but it can also be transmitted through contact with other body fluids, blood transfusion and organ transplantation. Primary infections are typically acquired in childhood, but in developed countries, the age at which primary infection occurs has been rising over time. This trend is linked to higher socioeconomic status, which is associated with a lower prevalence of age-specific antibodies. 6 EBV infection in adolescents and young adults leads to infectious mononucleosis. Clinical symptoms include fever, fatigue, sore throat, and lymphadenopathy, with characteristic increase in the number of atypical lymphocytes. 7 While EBV is best known for its role in various malignancies—such as Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma—it has also been increasingly recognized for its role in the development of autoimmune diseases in EBV infected individuals. Numerous well designed studies have been carried out which suggest that EBV infection may act as a key environmental trigger in the development of autoimmune conditions, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren’s syndrome, autoimmune thyroiditis, autoimmune hepatitis, cryptogenic fibrosing alveolitis and pure red cell aplasia (Pender M, 2003;). 2,7 The major mechanisms proposed include molecular mimicry, disruption of immune regulations, among others, although the precise causal relationships remain under investigation. The article aims to provide a comprehensive review of the EBV associated autoimmune conditions, with emphasis on mechanisms leading to the development of these conditions. Understanding the underlying mechanisms, though they have not been established conclusively, will be important for the management of these conditions. The article also reviews potential therapeutic agents and vaccine candidates being developed for the management of autoimmune diseases associated with EBV. Virus structure Epstein-Barr virus (EBV), a member of the Herpesviridae family, has a complex virion structure characteristic of herpesviruses. The EBV virion is an enveloped particle approximately 120–180 nm in diameter. It consists of four main components: a linear double-stranded DNA genome, an icosahedral capsid, a proteinaceous tegument layer, and a lipid envelope embedded with viral glycoproteins. 3 The capsid, composed of capsomere proteins (n=162), encases the viral genome and acts as a protecting layer. The capsid proteins also play a critical role in virus assembly, egress and immune evasion. 8 Surrounding the capsid is the tegument, which contains proteins important for initiating viral replication upon entry into the host cell. The outer envelope contains external glycoprotein spikes (gp350, gH, gB, gp42, gM, gN, gL), which facilitate viral entry and determine host cell tropism. The EBV genome is a linear double-stranded DNA molecule approximately 170 kb in size. After infecting a host cell, it circularizes and encodes more than 85 genes. Among the open reading frames (ORFs) that regulate the viral life cycle are six EBV nuclear antigens (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, and EBNA-leader protein) and three latent membrane proteins (LMP1, LMP2A, and LMP2B). 5 EBNA3A, EBNA3B, and EBNA3C are closely located in the EBV genome and encode transcription factors that play key roles in viral regulation. 6 Life cycle The Epstein-Barr virus (EBV) has a biphasic life cycle consisting of latent and lytic phases, which enable the virus to persist in the host and contribute to its pathogenic potential. Following primary infection, usually through the oral route, EBV infects B lymphocytes and establishes latency, during which the viral genome persists as an episome in the host cell nucleus without producing new virions. In this latent phase, EBV expresses a restricted set of viral genes depending on the type of latency program—latency I, II, or III—each associated with different diseases. For example, latency I, expressing only EBNA1 and non-coding RNAs, is commonly found in Burkitt lymphoma, while latency II and III, which express additional latent proteins such as LMP1 and EBNA2, are observed in Hodgkin lymphoma and lymphoproliferative disorders. The latent phase allows the virus to evade immune detection and maintain lifelong persistence. Under certain conditions such as immune suppression or cellular stress, EBV can reactivate into the lytic phase. This phase is marked by the expression of immediate early genes, such as BZLF1 and BRLF1, which activate early lytic genes necessary for viral DNA replication. Subsequently, late genes are expressed, encoding structural proteins for virion assembly. The newly formed virions are assembled in the nucleus and released from the cell, allowing the virus to infect new cells. While the lytic phase is essential for viral spread and transmission, both phases of the EBV life cycle contribute to its ability to cause disease, including various cancers and chronic infections. Figure 1. Schematic overview of Epstein–Barr virus (EBV) entry, latency, and reactivation. EBV infects both epithelial cells and B lymphocytes via receptor-mediated attachment and fusion. On epithelial cells, viral glycoproteins such as gH/gL, gB, and BMRF2 interact with integrins, EphA2, and HLA class II. On B cells, gp350/220 binds to CR2/CD21 to mediate entry. Once internalized, the capsid is transported along microtubules to the nucleus, where the viral genome circularizes to form episomes. Once inside the host nucleus, EBV establishes latency in one of four forms. Latency 0 is characterized by the absence of protein expression. Latency I involves expression of EBNA1 only. Latency II includes expression of EBNA1, LMP1, LMP2a, and non-coding RNAs. Latency III is marked by the expression of EBNA1, EBNA2, EBNA3A-C, EBNA-LP, LMP1, LMP2a, EBERs, and BART transcripts. Under specific stimuli, EBV undergoes lytic reactivation marked by expression of immediate-early genes such as BZLF1 and BRLF1, leading to viral replication, assembly, and release of new infectious virions. This dynamic latency–lytic switch plays a central role in viral persistence and immune evasion. (Image created at https://BioRender.com). Mechanisms of Epstein Barr Virus induced autoimmunity The association between EBV infection and autoimmune diseases has been a subject of extensive research. EBV is considered to play a key role in the development of certain autoimmune disorders, likely through mechanisms involving molecular mimicry, aberrant immune responses, chronic immune activation and persistent viral infection. These diseases include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease. EBV and Multiple Sclerosis Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in which the immune system attacks the protective myelin sheath around nerve fibres. The first study that reported the presence of EBV antibodies in MS patients was published more than 40 years ago, when researchers found that individuals with MS had significantly higher levels of EBV antibodies in MS patients compared to the control subjects. 9 Numerous epidemiological studies have been carried out which suggest strong evidence linking EBV infection to MS, where individuals with a history of EBV infection are at a higher risk for developing the disease. A largest longitudinal study involving 10 million young adults revealed a 32-fold increased risk of MS after EBV seroconversion. 10 Odds ratio for sero-positivity to anti-EBNA IgG in MS cases was found to be 4.5 [95% confidence interval (CI) 3.3 to 6.6, p<0.00001] in a meta-analysis study. 11 Various mechanisms have been proposed to explain the development of multiple sclerosis by EBV, and widely studied mechanisms include molecular mimicry, B cell transformation by EBV and immune dysregulation in EBV infected individuals. All these mechanisms lead to the development of autoantibodies. Several studies have proposed that molecular mimicry between EBV proteins, Epstein-Barr nuclear antigen1 (EBNA1) and myelin proteins might contribute to the autoimmune attack on myelin. It has been reported that antibodies from the patient’s sera react with viral proteins particularly EBNA-1. Analyses using peptide libraries have identified several domains within EBNA1 that are specifically recognized by autoreactive immune responses. One such peptide, consisting of amino acids 391–410 of EBNA1, closely resembles a sequence found in the host protein CRYAB (alpha-crystallin B chain), a protein that helps prevent protein aggregation, specifically amino acids 1–15, with an overlapping sequence of RRPFF. 12 Additionally, another study demonstrated molecular mimicry between the EBNA1 region spanning amino acids at position 386–405 and the glial cell adhesion molecule (Glial-CAM), a protein in the CNS involved in maintaining the integrity and function of the myelin sheath. Cross-reactive antibodies targeting both EBNA1 and Glial-CAM are commonly found in patients with MS. 13 Lang et al., 2007 explored the role of HLA class II alleles (DRB11501 and DRB50101) in MS susceptibility, demonstrating that a T cell receptor from an MS patient recognizes both myelin basic protein and EBV peptides. Further, analysis of the crystalline structures revealed a similarity between DRB50101-EBV peptide complex and DRB11501-restricted myelin basic protein (MBP), both of these were recognised by the patient derived autoreactive TCR. 14 Holmoy et al., 2004, reported the presence of CD4+ T cells specific for the EBV DNA polymerase peptide, EBV 627-641 in the CSF from MS patients, and that a high proportion of these CD4+ T cells cross-recognized an immunodominant myelin basic protein peptide. 15 Molecular mimicry has also been observed for the viral lytic proteins BamHI H Rightward Frame 1 (BHRF1) and BamHI P Leftward Frame 1 (BPLF1). Peptides derived from these proteins were found to bind to the HLA-DR15 haplotype and cross-react with the self-protein RASGRP2, which is expressed in the brain and B cells. This self-protein is targeted by brain-homing, autoreactive CD4+ T cells. 16 Further, Pender M, 2003 hypothesised that EBV induces B cell transformation leading to the development of auto-reactive B cells that might be responsible for development of multiple sclerosis. EBV drives aberrant activation of B cells by expressing latent proteins such as LMP1 and LMP2A, which mimic CD40 and B cell receptor signalling, respectively. This bypasses normal tolerance checkpoints, resulting in the survival and expansion of autoreactive B cells which resemble memory B cells. These EBV infected B cells can act as antigen-presenting cells, presenting CNS-derived autoantigens to T cells and contributing to a chronic inflammation. Upon entering the central nervous system, these autoreactive cells lead to the sustained immune responses to myelin antigens leading to demyelination characteristic of MS. 17 Several studies have explored the contribution of immune dysregulation by EBV as a factor leading to the development of MS. Studies have shown that CD8+ T-cell responses to EBV lytic antigens at the start of MS and throughout the disease are reduced, while in contrast responses to CMV lytic antigens remain normal in the same individuals. Further, there is an increase in the number of CD8+ T cells targeting EBV latent antigens in these individuals, however, these cells show signs of exhaustion with reduced cytokine function. Additionally, it has been shown that during MS relapse, both EBV specific CD4+ and CD8+ T cells tend to increase with latent-specific CD8+ T cells becoming more functional. However, over time, this response appears to decrease, suggesting functional exhaustion. Elevated levels of anti-EBNA1 IgG have been linked to lower levels of EBV-specific CD8+ T cells . Taken together, these findings support the hypothesis that impaired CD8⁺ T-cell control of EBV reactivation allows the accumulation of latently infected cells, including potentially autoreactive B cells. 18 EBV and Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder marked by the presence of autoantibodies against nuclear antigens (ANAs) in nearly all patients. Predominant symptoms reported in SLE patients are inflammation, rash, and vascular lesions, while some patients present with complaints of systemic pain and fatigue. 19 The exact cause of SLE remains unclear, but it is believed to result from a complex interplay of genetic predisposition and environmental triggers. Among the environmental factors, EBV infection has emerged as a potential contributor to the development and exacerbation of SLE. The association between EBV and SLE was first reported in 1969. Research studies suggest that EBV may contribute to SLE through various mechanisms, including viral reactivation, molecular mimicry, and alterations in immune responses. Immunological studies have been carried out to study the prevalence of EBV antibodies and DNA in the general population and its correlation to development of SLE. Studies have detected high level of EBV IgG antibodies in children and adult compared to respective control groups, while the IgG responses towards other herpes viruses such as cytomegalovirus (CMV) and herpes simplex virus (HSV) were similar between SLE patients and controls. 20,21 These antibodies are directed against viral capsid antigen (VCA) and EBV Early antigen (EA) antigens. Further, increased EBV viral loads have also been reported in SLE patients suggesting reactivation of the virus due to the dysregulated EBV latent cycle. Increased levels of BZLF1 (BamHI Z fragment leftward open reading frame 1), an immediate-early gene responsible for initiating the lytic cycle, have been detected in SLE patients, suggesting enhanced viral reactivation. Additionally, the latent genes LMP1 (Latent Membrane Protein 1) and LMP2A (Latent Membrane Protein 2A), typically expressed in latency II, are also found in SLE patients, indicating potential dysregulation of EBV latency. This suggests that SLE patients may exhibit a hybrid latency pattern, between latency II and III. The presence of both lytic and latent genes in these individuals, which is not seen in healthy seropositive individuals, points to a potential link between EBV reactivation and the immune dysregulation observed in SLE. 22 It is observed that SLE patients have higher IFNγ-secreting CD4+ T cells while exhibiting lower frequencies of EBV-specific CD8+ T cells, which are also functionally impaired. These impaired CD8+ T cells show upregulation of PD1, which leads to suppressed responses to EBV as blocking PD1 restores IFNγ production. These findings suggest that EBV-specific T cells in SLE have an exhausted phenotype, though CMV-specific T cell responses remain unaffected by PD1 blockade. This suggests that while general immune surveillance remains intact, SLE patients have a defect in regulating EBV infection. 23 Further, both CD4+ and CD8+ T cells specific to EBV lytic and latent antigens are reduced in SLE patients. A negative correlation exists between EBV-specific T cell responses and SLE disease activity index (SLEDAI), with fewer EBV-specific T cells observed in patients with higher disease activity. There is also an inverse relationship between EBV-specific T cells and anti-EBV antibodies, implying a dysfunctional immune response to EBV in SLE. 24 Additionally, Th17 and Treg cells are reduced in SLE patients having EBV or CMV viremia. 25 The decrease in these immune cells seems to be a result of the dysregulated immune responses in SLE, rather than being driven solely by the viral infection, in spite of viremia correlating with SLEDAI. Finally, EBV can transactivate HERV-K18, a superantigen, which may lead to excessive T cell activation. 26 Interestingly, the first detected autoantibodies specific to lupus were found to target EBNA1. In B cells infected with EBV, nearly half of the genetic variants associated with an increased risk of SLE can be influenced by EBNA-2, another protein produced by EBV. EBNA-2 helps form complexes that regulate gene activity at the genetic sites linked to SLE risk. The transcription factors that control these genes can bind to the SLE-risk associated loci only when EBV is present. This suggests that EBV may act both as an environmental factor that creates favourable conditions for the development of SLE and as a genetic factor that influences the risk of the disease. 27 Another mechanism widely implicated to explain EBV’s role in SLE pathogenesis is molecular mimicry. 7 EBNA-1 has been shown to cross-react with SLE-associated autoantigens resulting in cross-reactive antibodies followed by epitope spreading, which eventually can result in development of SLE. 27–29 In SLE, the most common autoantibodies target nuclear antigens, but other antibodies, such as anti-Sm, anti-Ro, and anti-dsDNA, are also frequently present. Molecular mimicry between EBNA1 and several SLE antigens, including SmB/B’, SmD, and 60 kDa Ro, is implicated as a key mechanism in pathogenesis of SLE. EBNA1 shares structural similarities with SmB/B’ and SmD, and autoantibodies targeting these antigens can cross-react with EBNA1. Additionally, anti-Ro antibodies, which are among the earliest detectable in some lupus patients, also cross-react with EBNA1. 30 EBNA1 promotes the production of anti-dsDNA, anti-Sm, and anti-Ro antibodies, intensifying the autoimmune response. This immune activation is further amplified by epitope spreading, where B cells present additional cross-reactive peptides to T cells, enhancing antibody production against other SLE related antigens. EBV infection can facilitate this spreading, exacerbating the autoimmune response. 20,30,31 Moreover, the viral protein vIL-10, a homolog of human IL-10, competes with hIL-10 for receptors, inhibiting hIL-10’s immune regulatory effects. vIL-10 also triggers a pro-inflammatory response in monocytes and impairs the clearance of apoptotic cells, leading to increased antigen presentation and autoantibody production, which further worsen SLE. 32 EBV and Rheumatoid Arthritis Rheumatoid arthritis (RA) is a complex autoimmune condition characterized by chronic joint inflammation, leading to progressive joint deterioration, loss of function and disability. The exact cause of rheumatoid arthritis (RA) remains unknown, but several factors, including environmental influences such as viral infections and host genetic composition have been implicated in pathogenesis. An important mechanism responsible for EBV’s role in RA is molecular mimicry between EBV antigens such as gp110, EBNA-6, and EBNA-1, and autoantigens reactive to RA autoantibodies. 33 EBV antigens undergo post-translation citrullination, thereby becoming targets for anti-citrullinated protein/peptide antibodies (ACPA), which is the most important class of RA-specific autoantibodies. 34 EBV-1 DNA is more likely to be detected in patients with RA compared with healthy controls and family history of RA also correlates with presence of EBV-1 DNA. 35,36 Association with EBV begins in the pre-clinical stage of RA, as evident by the higher levels of EA-IgG antibodies in this stage among patients who went on to develop RA in the future. 37 During the clinical stage, higher titres of anti-EBV-CA-IgM, anti-EBV-EA(D)-IgG and anti-EBNA-1 antibodies are seen in RA patients compared to healthy controls, 36–38 while decreased titres of anti-VCA-IgM and anti-EA(D)-IgM, anti-EA(D)-IgG indicate reduction in inflammation after therapy. 39 In general, patients with RA mount a stronger humoral immune response to EBV antigens compared to healthy controls. 40 Active EBV infection has been demonstrated in B cells and plasma cells present in RA-inflicted synovium, along with presence of differentiated ACPA-reactive B cells in this milieu. These plasma cells and B cells also exhibit immunoreactivity against EBV latent and lytic antigens. Further, evidence of EBV latent RNA transcripts in synovium has also been reported. 41 EBV and other autoimmune diseases Sjogren’s Syndrome Sjogren’s Syndrome (SS) is a chronically progressive and relapsing autoimmune condition principally affecting the salivary and lacrimal exocrine glands and resulting in drying of mucosal surfaces (for example, xerostomia and xerophthalmia) and an increased risk of lymphoma. EBV DNA has been isolated from salivary glands and peripheral blood mononuclear cells of patients with SS, 42 at a higher rate than from healthy salivary glands, 43 and EBV infection is known to induce SS-related autoantibodies such as anti-SS-A, anti-SS-B and anti-U1RNP, possibly due to molecular mimicry with the viral EBNA2, eBeR1 and eBeR2 proteins. 44 SS is significantly associated with higher levels of IgM-anti-VCA and IgG-anti-EA antibodies. 45 Other mechanisms suggested to be involved in EBV-related SS are increased IL-21 expression from T-cells, increased CD70 expression from B cells, and an increased CD4+ to CD8+ T cell ratio. 46 Inflammatory Bowel Disease Inflammatory Bowel Disease (IBD) encompasses Crohn’s Disease (CD) and Ulcerative Colitis (UC), two chronic inflammatory conditions of the gastrointestinal tract (GIT). EBV has been detected from the entire GIT mucosa in IBD patients, and mucosal CD4+ T-cell immune responses to EBV are deficient in UC patients. 47 EBV is associated with severe disease and requirement for surgery in IBD, 48 and latent EBV infection in these patients should be monitored. 49 Mucosal EBV viral loads are higher in treatment-refractory patients compared to treatment-responsive ones. 47 Some of the mechanisms by which EBV exacerbates UC are upregulation of macrophage pyroptosis, IL12-TH1 and IL23-TH17 cytokine axes. 50,51 Graves’ Disease Graves’ Disease (GD) is an immune-mediated cause of hyperthyroidism mediated by antibodies against the thyrotropin receptor (TRAbs). PBMCs from GD patients exhibit significantly higher incidence of EBV DNA than healthy controls, but EBV does not appear to affect the disease severity. 52 EBV-encoded RNA (EBER) has been detected in thyroid follicular cells, which represents EBV reactivation which in turn stimulates TRAb production by CD19+ B-cells. 53,54 Serological evidence, such as higher levels of anti-EBV IgG, 55 and anti-EA antibody, 56 along with anecdotal reports of antecedent infectious mononucleosis, 57 further indicate the association between EBV and GD. Although the functional TRAbs in GD are IgG, EBV reactivation-induced TRAb-IgM are also cytotoxic to thyroid follicular cells in-vitro and may play a role in the pathogenesis of GD. 58,59 Celiac Disease Celiac disease (CD) is a chronic enteropathy characterized by immune mediated damage to gut mucosa in response to dietary gluten. EBV DNA and proteins indicative of active infection have been detected in duodenal mucosa of patients with refractory CD, indicating some association between the two. 60 More specifically, a strong association between EBNA2 and CD has been described. EBNA2 binds to certain genetic loci associated with celiac disease, influencing gene regulation. 61 Another mechanism suggested is EBV-induced increased MHC class II expression in enterocytes leading to increased gluten antigen presentation and subsequent immune-mediated damage to the intestinal mucosa. 62 Type 1 Diabetes Mellitus Type 1 diabetes mellitus (T1DM) is a form of diabetes caused by autoimmune destruction of insulin-producing pancreatic beta cells, leading to a life-long dependency on insulin injections. EBV infection appears to play a variable role in the pathogenesis of T1DM, with both protective as well as triggering effects being reported. 63 While serologic evidence linking EBV with T1DM remains inconclusive, other mechanisms such as latent EBV-induced T cell cytotoxicity, molecular mimicry, and EBNA2 binding to T1DM-related genetic loci have been proposed. 61,64–67 However, no consensus currently exists to definitively explain the immunopathogenesis of EBV-induced T1DM. Implications for Prevention and Therapy Managing EBV-associated autoimmune diseases would require a multi-modal therapeutic approach that targets both virus and host immune dysregulation. However, since routine clinical detection of EBV in autoimmune conditions is not a standard practice, these diseases are typically managed using conventional immunosuppressive or immunomodulatory protocols without specific consideration of viral involvement. Since EBV possesses the unique ability to interact with and modulate the host cell molecular machinery, treatment of EBV must ideally meet three different objectives - inhibition of active viral replication; cure of latent viral infection; and interruption of EBV-induced cellular proliferation and transformation. In particular, the management of Epstein-Barr virus (EBV)-associated autoimmune diseases is still evolving, driven by advances in understanding EBV latency, immune evasion, and host-pathogen interactions. However, with numerous research studies unravelling the association between the EBV and development of autoimmune diseases, efforts have been directed towards development of drugs that address both the viral component and the dysregulated immune response. Current strategies encompass depletion of EBV-harboring cells, vaccine development, virus-specific cellular therapies, and small-molecule inhibitors aimed at viral replication or latency maintenance. Commonly used anti-herpes viral drugs, such as the nucleoside analogues ganciclovir (GCV) or acyclovir, have limited efficacy against EBV due to its latent state; novel small-molecule inhibitors are under investigation. Table 1: EBV-targeted approaches Class of Therapeutic agents Molecule Mechanism of action Role in Autoimmune Diseases Small-molecule antivirals / latency disruptors Suramin Inhibits the EBV-encoded deubiquitinating enzyme BPLF1, leading to ~90% reduction in viral infectivity in vitro. 68 Currently under preclinical investigation; potential for reducing EBV-driven immune activation. VK-1727 , VK-2019 Target the DNA-binding domain of E (EBNA1), disrupting viral genome replication and episomal maintenance. VK-2019 demonstrated safety in a Phase I/IIa clinical trial. 69 EBNA1 is implicated in the pathogenesis of MS and SLE; these agents may offer targeted antiviral intervention. BRACO-19 Stabilizes G-quadruplex DNA structures in the EBV genome, thereby preventing EBNA1 binding and inhibiting latent replication. 69 Potential candidate for latency-targeted therapy in EBV-associated autoimmune conditions; preclinical data only Pentamidine derivatives Disrupts the transmembrane domain of latent membrane protein 1 (LMP1), attenuating EBV-mediated signaling and infection. 70 Preclinical efficacy shown in EBV-infected cell models; no autoimmune application evaluated yet Lytic-induction + polymerase inhibition Romidepsin, Nanatinostat + Ganciclovir/ Valganciclovir Histone deacetylase inhibitors (HDACi) activate the EBV lytic cycle, increasing expression of viral kinases that phosphorylate antiviral prodrugs (e.g., ganciclovir), resulting in selective apoptosis of infected cells. 71,72 Evaluated in EBV-positive lymphomas; conceptually promising for purging latent EBV reservoirs in autoimmune diseases, though not yet studied in SLE or MS. Vaccination Moderna mRNA-1195 Induces both humoral and cellular immune responses targeting lytic and latent EBV antigens. mRNA-1195 encodes multiple viral glycoproteins, including gp350 and gH/gL. 73 EBV vaccination may prevent primary infection, which is a strong risk factor for MS; therapeutic use in seropositive autoimmune patients remains investigational. Table 2. Immune-modulating strategies B-cell depletion therapies Rituximab Obinutuzumab, Ocrelizumab, Ofatumumab CD19 CAR T cells Chimeric monoclonal antibody targeting CD20 on B cells; depletes circulating and memory B cells, which serve as EBV reservoirs. 74 Afucosylated humanized monoclonal antibodies targeting CD20; induce more effective B-cell depletion via antibody-dependent cytotoxicity. 75 Autologous T cells engineered with chimeric antigen receptors (CARs) targeting CD19; result in profound B-cell aplasia and immune reset. 76 Widely used in EBV-driven post-transplant lymphoproliferative disorder (PTLD) Ocrelizumab is approved for relapsing and primary progressive MS. Obinutuzumab showed improved renal outcomes in lupus nephritis. Demonstrated drug-free remission in pilot SLE trial; under evaluation for broader autoimmune use. EBV-Specific adoptive T cell therapies Allogeneic EBV-specific cytotoxic T lymphocytes (EBV-CTLs) Infusion of donor-derived T cells targeting EBV latent proteins (e.g., EBNA1, LMP2), restoring immune surveillance of infected B cells. 77 Approved in the EU for EBV associated PTLD. Being evaluated in MS (e.g., ATA188); preliminary results suggest correlation with functional improvement. Type I interferon blockade Anifrolumab Fully human monoclonal antibody targeting type I interferon receptor subunit IFNAR1; blocks IFN-α/β signaling and interferon-stimulated gene expression. 78 FDA-approved for moderate-to-severe SLE; reduces skin and musculoskeletal disease and enables steroid tapering. JAK-STAT Pathway Inhibitors Tofacitinib, Baricitinib Inhibit Janus kinases (JAK1/2/3), thereby blocking downstream interferon and cytokine signaling including IL-6 and IFN-α. 79 Baricitinib showed efficacy in Phase II SLE trial; ongoing studies in lupus nephritis. May reduce EBV-driven inflammation indirectly. Checkpoint Inhibitors Anti-PD-1 (e.g., Nivolumab), Anti-CTLA-4 (e.g., Ipilimumab) Block inhibitory receptors PD-1 and CTLA-4 on T cells, enhancing EBV-specific cytotoxicity in cancer. 80 Effective in EBV associated cancers (e.g., nasopharyngeal carcinoma), but may exacerbate or induce autoimmunity; generally avoided in SLE/MS. Bruton’s tyrosine-kinase (BTK) inhibitors Evobrutinib Oral small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), suppressing B-cell receptor signaling and pro-inflammatory cytokine release. 81,82 Demonstrated reduction in MRI lesions in MS; Phase II SLE trials failed to meet endpoints. NK-cell checkpoint blockade Monalizumab Anti-NKG2A monoclonal antibody; blocks inhibitory NK cell receptor to enhance cytotoxicity against EBV-infected B cells. 83 Preclinical data support NK-based clearance of EBV-infected cells; not yet tested in autoimmune disease trials. Toll-like receptor 7/8/9 blockade E6742 Small-molecule antagonist of toll-like receptors 7, 8, and 9; reduces plasmacytoid dendritic cell activation and type I interferon gene signature. 84 Early phase trials in SLE show downregulation of interferon-stimulated genes; may be beneficial in EBV-high lupus subsets. Future Perspectives Advancing our understanding of Epstein-Barr virus (EBV) in autoimmune diseases necessitates addressing several critical areas. While EBV infects over 95% of adults, only a subset develops autoimmune diseases, indicating that additional factors contribute to disease onset. Research should focus on elucidating how EBV interacts with host immune responses and genetic predispositions to trigger autoimmunity. 51 Investigating the roles of EBV-specific CD8+ T cells and natural killer (NK) cells in controlling EBV infection is crucial. Identifying genetic variants and epigenetic modifications that influence susceptibility to EBV-associated autoimmunity can provide insights into disease mechanisms. Recent studies have highlighted the role of histone modifications and non-coding RNAs in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). 85 These mechanisms may also serve as potential therapeutic targets in EBV-associated autoimmune diseases. Targeting EBV directly through antiviral therapies or vaccines holds promise for preventing or mitigating autoimmune diseases. The development of an EBV vaccine could potentially reduce the incidence of EBV-associated conditions, including certain autoimmune diseases. 86 To conclude, the association between EBV infection and autoimmune diseases highlights the complexity of immune system interactions with persistent viral infections. Future research aimed at unraveling these interactions will be instrumental in developing targeted therapies and preventive strategies to combat EBV-associated autoimmune diseases. Authorship Statement: Shipra Gupta: conceptualization, literature search, writing- original draft, writing- review and editing. Vijayalakshmi Reddy: literature search, writing- original draft, writing- review and editing. Lonika Lodha: literature search, writing- original draft. MA Ashwini : writing- original draft, writing- review and editing, visualization, supervision. All authors have read and approved the final manuscript. Conflict of interest : The authors declare no conflict of interests. References 1. Epstein MA, Achong BG, Barr YM. VIRUS PARTICLES IN CULTURED LYMPHOBLASTS FROM BURKITT’S LYMPHOMA. Lancet Lond Engl . 1964;1(7335):702-703. doi:10.1016/s0140-6736(64)91524-7 2. Damania B, Kenney SC, Raab-Traub N. Epstein-Barr virus: Biology and clinical disease. 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Collection Journal of Medical Virology Keywords antiviral agents b cell epstein-barr virus immune responses oncogenesis virus classification Authors Affiliations Shipra Gupta National Institute of Mental Health and Neurosciences Department of Neurovirology View all articles by this author Vijayalakshmi Reddy National Institute of Mental Health and Neurosciences Department of Neurovirology View all articles by this author Lonika Lodha National Institute of Mental Health and Neurosciences Department of Neurovirology View all articles by this author Ashwini Anand 0000-0002-2018-7066 [email protected] National Institute of Mental Health and Neurosciences Department of Neurovirology View all articles by this author Metrics & Citations Metrics Article Usage 1478 views 231 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shipra Gupta, Vijayalakshmi Reddy, Lonika Lodha, et al. 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