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Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.

Both myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) and long COVID (LC) are characterized by similar immunological alterations, persistence of chronic viral infection, autoimmunity, chronic inflammatory state, viral reactivation, hypocortisolism, and microclot formation. They also present with similar symptoms such as asthenia, exercise intolerance, sleep disorders, cognitive dysfunction, and neurological and gastrointestinal complaints. In addition, both pathologies present Epstein–Barr virus (EBV) reactivation, indicating the possibility of this virus being the link between both pathologies. Therefore, we propose that latency and recurrent EBV reactivation could generate an acquired immunodeficiency syndrome in three steps: first, an acquired EBV immunodeficiency develops in individuals with “weak” EBV HLA-II haplotypes, which prevents the control of latency I cells. Second, ectopic lymphoid structures with EBV latency form in different tissues (including the CNS), promoting inflammatory responses and further impairment of cell-mediated immunity. Finally, immune exhaustion occurs due to chronic exposure to viral antigens, with consolidation of the disease. In the case of LC, prior to the first step, there is the possibility of previous SARS-CoV-2 infection in individuals with “weak” HLA-II haplotypes against this virus and/or EBV.

Activated cytotoxic CD4 T cells (HLA-DR+) play an important role in the control of EBV infection, especially in cells with latency I (EBNA-1). One of the evasion mechanisms of these latency cells is generated by gp42, which, via peripherally binding to the β1 domain of the β chain of MHC class II (HLA-DQ, -DR, and -DP) of the infected B lymphocyte, can block/alter the HLA class II/T-cell receptor (TCR) interaction, and confer an increased level of susceptibility towards the development of EBV-associated autoimmune diseases or cancer in genetically predisposed individuals (HLA-DRB1* and DQB1* alleles). The main developments predisposing the factors of these diseases are: EBV infection; HLA class II risk alleles; sex; and tissue that is infiltrated with EBV-latent cells, forming ectopic lymphoid structures. Therefore, there is a need to identify treatments for eliminating cells with EBV latency, because the current treatments (e.g., antivirals and rituximab) are ineffective.

An association between Epstein-Barr virus (EBV) infection and systemic lupus erythematosus (SLE) has been suggested from previous serologic evidence. Since most adults in Taiwan are EBV-infected, seroepidemiologic studies based on standard assays for EBV are unlikely to dissociate SLE patients and control groups. We reexamine this question by using novel methodologies in which IgA anti-EBV-coded nuclear antigens-1 (EBNA-1) and IgG anti-EBV DNase antibodies were analysed by ELISA, and EBV viral loads were detected by real-time quantitative PCR for 93 adult SLE patients and 370 age-, sex- and living place-matched healthy controls in Taiwan. The specificities of antibodies for extractible nuclear antigens were determined by Western blot. Our results show that IgA anti-EBV EBNA1 antibodies were detectable in 31.2% SLE patients but only in 4.1% of controls (odds ratio [OR] = 10.72, 95% confidence interval [CI] = 5.19–22.35; P < 10-7), IgG anti-EBV DNase antibodies were detected in 53.8% SLE patients but only in 12.2% controls (OR = 8.40, 95% CI = 4.87–14.51; P < 10-7). EBV DNA was amplifiable from the sera of 41.9% SLE patients but from only 3.24% controls (P < 0.05). A significant association of IgG anti-EBV DNase antibodies with anti-Sm/RNP antibodies was observed (P < 0.005). The higher seroreactivity and higher copy numbers of EBV genome indicated association of EBV infection with SLE in Taiwan.

The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1) is essential for replication and maintenance of circular EBV genomes in latently infected B lymphocytes and is the only EBV protein expressed in nearly all cells carrying the virus. EBNA-1 is suggested to be oncogenic in vivo since its expression induces B-cell neoplasia in transgenic mice. EBV wild-type isolates from ten malignant tumors and from 15 children with various benign EBV-associated disorders were examined for the presence of EBNA-1 variant strains by PCR and sequencing. One isolate harbored both the B95-8-like and a variant sequence within the C-terminus of the EBNA-1 gene. All other isolates (n = 24) revealed clustered nucleic acid sequence alterations within the EBNA-1 gene, which led to amino acid exchanges at positions 524, 563, 574, 585, 594 and 595. Few isolates exhibited additional amino acid exchanges at positions 564, 571 or 588. The observed EBNA-1 sequence variation pattern seems not to be restricted to a certain EBV-associated disease or tumor type. The EBNA-1 variant strains reported here may reflect the most prevalent EBV strains in the exposed population. In none of all the cases studied so far did the sequence alteration affect any known functionally crucial amino acids in the core domain of EBNA-1. This suggests that strict conservation of most of the C-terminal portion of EBNA-1 sequence may be essential for survival of EBV in the infected host.

Primary effusion lymphoma (PEL) is a B cell lymphoma that is always associated with Kaposi’s sarcoma-associated herpesvirus (KSHV) and in many cases also with Epstein–Barr virus (EBV); however, the requirement for EBV coinfection is not clear. Here, we demonstrate that adding exogenous EBV to KSHV⁺ single-positive PEL leads to increased KSHV genome maintenance and KSHV latency-associated nuclear antigen (LANA) expression. To show that EBV was necessary for naturally coinfected PEL, we nucleofected KSHV⁺/EBV⁺ PEL cell lines with an EBV-specific CRISPR/Cas9 plasmid to delete EBV and observed a dramatic decrease in cell viability, KSHV genome copy number, and LANA expression. This phenotype was reversed by expressing Epstein–Barr nuclear antigen 1 (EBNA-1) in trans, even though EBNA-1 and LANA do not colocalize in infected cells. This work reveals that EBV EBNA-1 plays an essential role in the pathogenesis of PEL by increasing KSHV viral load and LANA expression.

Objectives Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infections in patients with Neuromyelitis optica spectrum disorder (NMOSD) remain unclear. The objective of this study was to investigate CMV and EBV infections in patients with NMOSD. Methods Serum immunoglobin (Ig) G antibodies against CMV and EBV were measured in patients with NMOSD and healthy controls (HCs), including anti-CMV, anti-EBV nuclear antigen-1 (EBNA-1), anti-EBV virus capsid antigen (VCA), and anti-EBV early antigen (EA) IgGs. The immune status ratio (ISR) was used to evaluate the serum anti-CMV and anti-EBV IgG levels and ISR ≧1.10 was defined as seropositivity. Results In total, 238 serum samples were collected from 94 patients with NMOSD and 144 HCs, and no significant difference of sex and age between NMOSD and HCs. Comparing to the HCs, patients with NMOSD exhibited significantly higher serum anti-CMV IgG level. In contrast, the serum anti-EBNA1 IgG level was significantly lower in patients with NMOSD than in HCs. The serum anti-VCA and anti-EA IgG levels did not differ between the two groups, but the anti-EA seropositivity was significantly higher in NMOSD group than that in HC group. We did not find associations between serum anti-CMV or anti-EBV IgG levels and NMOSD disease stage, immunotherapy, or disability score. Conclusions Our findings indicated that increased CMV infection and EBV recent infection, as well as reduced EBV latency infection were associated with the risk of NMOSD. Prospective cohort studies are needed to verify our findings and clarify the correlation between CMV and EBV infections and clinical characteristics of NMOSD.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease leading to inevitable disability and primarily affecting the young and middle-aged population. Recent studies have shown a direct correlation between the risk of MS development and Epstein–Barr virus (EBV) infection. Analysis of the titer of EBV-specific antibodies among patients with MS and healthy donors among Russian population confirmed that MS is characterized by an increased level of serum IgG binding EBNA-1 (EBV nuclear antigen 1). The number of patients with elevated levels of EBNA-1-specific antibodies does not differ statistically significantly between two groups with diametrically opposite courses of MS: benign MS or highly active MS. It can be assumed that the primary link between EBV and the development of MS is restricted to the initiation of the disease and does not impact its severity.

Nasopharyngeal carcinoma (NPC) is a multifactorial disease with genetic, viral, environmental and lifestyle-related risk factors. Epstein-Barr virus (EBV) can promote the oncogenic transformation of an infected cell into malignant. EBV encodes many stimulating products including Epstein-Barr virus nuclear antigen-1 (EBNA-1) which plays a key role in the regulation of gene expression and replication of the genome in the latent period of infection. EBNA-1 in serum and tumour tissue of NPC patients correlates with NPC prognosis. Moreover, the presence of EBV DNA in serum samples from NPC patients' blood circulation can be used as an early marker in the diagnosis of NPC. The objective of this study was to find effective methods for monitoring the progress of NPC patients undergoing radiotherapy and therapeutic efficacy by observing the changes in EBV DNA in serum and saliva. The pre-experimental design compared blood and saliva taken from a pre-test and post-test group of NPC patients before and after radiation therapy. The concentration of EBV DNA was measured in the serum and saliva after amplification using quantitative polymerase chain reaction (qPCR) with compatible primers for the EBNA-1 gene. The data were statistically analysed by paired -test. Highly significant ( = 0.0001) increase in qPCR and decrease in the mean concentration of EBV DNA (p = 0.0001) were observed in serum samples, but no significant changes were observed in saliva. The results suggest that EBV DNA in serum can be used as the gold standard and a marker for monitoring the response to radiation therapy in NPC patients, whereas the examination of EBV DNA from saliva samples is not accurate and thus, not appropriate.