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The acquisition or reactivation of Epstein-Barr virus (EBV) after allogeneic Hematopoietic Stem Cell Transplant (HSCT) can be associated with complications including the development of post-transplant lymphoproliferative disorder (PTLD), which is associated with significant morbidity and mortality. A number of risk factors for PTLD have been defined, including T-cell depletion, and approaches to monitoring EBV, especially in high-risk patients, with the use of preemptive therapy upon viral activation have been described. Newer therapies for the preemption or treatment of PTLD, such as EBV-specific cytotoxic T-cells, hold promise. Further studies to help define risks, diagnosis, and treatment of EBV-related complications are needed in this at-risk population.

BACKGROUND AND OBJECTIVE: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mothers education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p

The Epstein–Barr virus (EBV) is a ubiquitous gamma‐herpesvirus and a class 1 carcinogen that is closely associated with a series of malignant lymphomas and epithelial cell carcinomas. Although these EBV‐related cancers may exhibit different features in clinical symptoms and anatomical sites, they all have a characteristic immune‐suppressed tumor immune microenvironment (TIME) that is tightly correlated with an abundance of tumor‐infiltrating lymphocytes (TILs) that primarily result from the EBV infection. Overwhelming evidence indicates that an upregulation of immune‐checkpoint molecules is a powerful strategy employed by the EBV to escape immune surveillance. While previous studies have mainly focused on the therapeutic effects of PD‐1 and CTLA‐4 blockades in treating EBV‐associated tumors, several novel inhibitory receptors (e.g., CD47, LAG‐3, TIM‐3, VISTA, and DDR1) have recently been identified as potential targets for treating EBV‐associated malignancies (EBVaMs). This review retrospectively summarizes the biological mechanisms used for immune checkpoint evasion in EBV‐associated tumors. Its purpose is to update our current knowledge concerning the underlying mechanisms by which an immune checkpoint blockade triggers host antitumor immunity against EBVaMs. Additionally, this review may help investigators to more fully understand the correlation between EBV infection and tumor development and subsequently develop novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV‐based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti‐BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b‐IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913–0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced‐stage than in early‐stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1‐IgA and BNLF2b‐IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%–21.7%, p <.0001) compared with the two‐antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression. [ABSTRACT FROM AUTHOR]

Background: Kidney transplantation (KT) is the best treatment for patients with end-stage renal disease. However, postoperative complications remain the main issues faced during KT recovery period. Posttransplant lymphoproliferative disorders (PTLD) are one of the severe and life-threatening complications that occur after KT while the recipient is undergoing immunosuppressive therapy. PTLD risk factors include Epstein-Barr virus (EBV) infection, the cumulative degree of immunosuppression, as well as genetic aspects. PTLD is more common in the transplanted organ itself and its surroundings, and the central nervous system, while PTLD involving the pharyngeal soft tissue is relatively rare, with only a few reported case reports. Therefore, systematic experience is scarce regarding whether the treatment or the care. Case presentation: Herein, we report a 41-year-old male, underwent a reproductive KT due to chronic renal insufficiency. Recurrent fever, pharyngeal pain, and bilateral cervical lymph node enlargement were recurred during five years' follow-up after KT surgery. In this inpatient experience, the patient vomited a large amount of blood from the oropharynx, then the tonsil artery was ligated by emergency operation. EBV-associated T/NK cell monomorphic PTLD was eventually diagnosed by blood EBV DNA test, pharyngeal biopsy, and corresponding pathological examination. After six cycles of R-CHOP chemotherapy, the clinical symptoms and laboratory tests changed into normal. Subsequent three years' follow-up shows no tumor recurrence and good transplant kidney function. Conclusion: This rare case report describes a manifestation of PTLD with pharyngeal involvement. Early diagnosis using histopathological examination is crucial to prevent damage to the throat and airway, and even life-threatening conditions. Discontinuing immunosuppression and starting systemic treatment can help in disease regression. Since the low incidence of this disease, limited clinical experience, and limited data, our experience with a smooth recovery through efficacy treatment and nursing can provide a reference for the development of new clinical drugs and diagnostic and treatment plans of patients with PTLD in the future. [ABSTRACT FROM AUTHOR]

Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies. [ABSTRACT FROM AUTHOR]

Lung transplantation is an effective means of treating various end-stage lung diseases. However, compared with other solid organ transplants, the survival rate after lung transplantation is relatively low. The main reason is the numerous complications after lung transplantation, among which infection is one of the most common complications. Respiratory viral infections are an important type of infection after lung transplantation, which severely affect the survival time and quality of life of lung transplant recipients. Early identification, early prevention, and active diagnosis and treatment are of great significance in reducing the incidence and fatality of respiratory viral infections after lung transplantation. This article reviews the epidemiology, risk factors, prevention and treatment principles, and specific prevention and treatment progress of common viruses in respiratory viral infections after lung transplantation at home and abroad, in order to provide a reference for the prevention and treatment of respiratory viral infections after lung transplantation in clinical practice. [ABSTRACT FROM AUTHOR]

Birds, especially the chick and hen, have been important biomedical research models for centuries due to the accessibility of the avian embryo and the early discovery of avian viruses. Comprehension of avian tumor virology was a milestone in basic cancer research, as was that of non-viral genesis, as it enabled the discovery of oncogenes. Furthermore, studies on avian viruses provided initial insights into Kaposi's sarcoma and EBV-induced diseases. However, the role of birds in human carcinogenesis extends beyond the realm of virology research. Utilization of CAM, the chorioallantoic membrane, an easily accessible extraembryonic tissue with rich vasculature, has enabled studies on tumor-induced angiogenesis and metastasis and the efficient screening of potential anti-cancer compounds. Also, the chick embryo alone is an effective preclinical in vivo patient-derived xenograft model, which is important for the development of personalized therapies. Furthermore, adult birds may also closely resemble human oncogenesis, as evidenced by the laying hen, which is the only animal model of a spontaneous form of ovarian cancer. Avian models may create an interesting alternative compared with mammalian models, enabling the creation of a relatively cost-effective and easy-to-maintain platform to address key questions in cancer biology. [ABSTRACT FROM AUTHOR]

Background: Information related to herpes simplex virus 1 and 2 (HSV-1 and 2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) seroprevalence in France is either lacking, incomplete, or outdated, despite their public health burden. Method: We used routinely collected serological data between 2018 and 2022 to estimate HSV-1, HSV-2, VZV, EBV, and CMV seroprevalence in France. To account for demographic differences between our analytic samples and the French population and get estimates for sparsely sampled districts and age classes, we used a multilevel regression and poststratification approach combined with Bayesian model averaging via stacking weights. Results: The observed seroprevalence (number of positive tests/number of tests) were 64.6% (93,294/144,424), 16.9% (24,316/144,159), 93.0% (141,419/152,084), 83.4% (63,199/75, 781), and 49.0% (23,276/47,525), respectively, for HSV-1, HSV-2, VZV, EBV, and CMV. Between 2018 and 2022, France had a model-based average (equal-tailed interval at 95%) expected seroprevalence equal to 61.1% (60.7,61.5), 14.5% (14.2,14.81), 89.5% (89.3,89.8), 85.6% (85.2,86.0), and 50.5% (49.3,51.7), respectively, for HSV-1, HSV-2, VZV, EBV, and CMV infections. We found an almost certain lower expected seroprevalence in Metropolitan France than in overseas territories for all viruses but VZV, for which it was almost certainly greater. The expected seroprevalences were likely greater among females for all viruses. Limitations: Our results relied on the assumption that individuals were sampled at random conditionally to variables used to build the poststratification table. Implications: The analysis highlights spatial and demographic patterns in seroprevalence that should be considered for designing tailored public health policies. [ABSTRACT FROM AUTHOR]

A DNA tumor virus called Epstein-Barr virus (EBV) is the cause of 1-2% of human cancers. EBV-associated carcinogenesis is caused by a persistent latent infection. The shortage of antiviral medications or vaccinations to control the virus led to a significant percentage of critically sickness individuals needing to be hospitalized. In the absence of an effective vaccine and approved drug, there is an immediate need for treatments that can combat EBV infection. Epstein Barr nuclear antigen 1 (EBNA1) is continually expressed in all malignancies linked to EBV; it is a desirable target for curative interference. Herein, natural product compounds from the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database were mined to identify potent EBNA1 inhibitors. The performance of the molecular docking technique was initially assessed in expecting the ligand-target binding pose according to the available experimental data. On the basis of the estimated docking protocol, the NuBBE database was virtually screened toward the EBNA1 protein, and the natural compounds with binding scores less than KWG (calc. − 7. 8 kcal/mol) were subjected to molecular dynamics (MD) simulations followed by binding energy (Δ G binding ) calculation using MM/GBSA approach. Based on binding energy computations, NuBBE1460 revealed superior Δ G binding with a value of − 3 6. 2 kcal/mol, compared to KWG (calc. − 3 2. 4 kcal/mol). Post-MD analyses displayed a high steadiness of NuBBE1460 within the EBNA1 protein binding pocket. Furthermore, the physicochemical, pharmacokinetic and toxicity features of the identified compound were predicted, demonstrating high degrees of its oral bioavailability. The energetical and geometrical properties of NuBBE1460 were calculated using the DFT method. Conclusively, this study offers NuBBE1460 obtained from natural sources as a lead EBNA1 inhibitor for future investigation and development as a therapeutic for EBV. NuBBE database was virtually screened as potent EBNA1 inhibitors using in-silico calculations. Compared to KWG, a reference inhibitor, NuBBE1460 exhibited better binding affinity against EBNA1. NuBBE1460 demonstrated promising stability in complex with EBNA1 and unveiled good oral bioavailability. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) reactivation in COVID-19 patients has been reported, but studies on its clinical significance are lacking. We herein report the occurrence of infectious mononucleosis (IM) due to EBV reactivation in a 60-year-old man with rheumatoid arthritis being treated with methotrexate and tocilizumab. The patient presented with a fever and tested positive for COVID-19. Laboratory findings revealed an increased atypical lymphocyte count, decreased platelet count, and elevated liver enzyme levels. Flow cytometry showed predominant expansion of reactive T cells. EBV reactivation was confirmed using real-time polymerase chain reaction. The patient was treated with remdesivir, and clinical improvement was observed after 10 days of treatment. Follow-up showed a gradual decrease in the EBV-DNA load with no recurrence of atypical lymphocytes. These findings suggest that COVID-19 in immunocompromised patients may lead to unexpected EBV reactivation and IM, even for patients outside the age at which IM is likely to occur. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated a correlation between p53 overexpression and diminished survival in gastric cancer patients. However, conflicting findings exist, and we hypothesize that these discrepancies arise from the cancer's complexity and heterogeneity, coupled with a lack of consensus on aberrant p53 expression. We enrolled a cohort of 187 patients with surgically resected gastric cancer. Patient categorization was based on Epstein–Barr virus (EBV), microsatellite instability (MSI), and Lauren classification (intestinal, diffuse and mixed). Utilizing an incremental algorithm, we evaluated p53 immunohistochemical (IHC) patterns in all 187 cases, while next-generation sequencing was successfully performed on 152 cases to identify TP53 mutations (mutTP53). MutTP53 was identified in 32 % of the 152 cases, comprising 36 missense, 5 nonsense, and 7 frameshift alterations. Missense mutations predominantly correlated with p53 overexpression, while nonsense and frameshifting alterations related to null expression. Trial calculations indicated that null expression and a p53 IHC cutoff at >40 % offered the best prediction of mutTP53 (kappa coefficient, 0.427), with the highest agreement (0.524) observed in diffuse type and the lowest (0.269) in intestinal type. Null expression and a p53 IHC cutoff at >10 %, but not mutTP53 per se , provided the optimal prediction of survival outcome (p = 0.043), particularly in diffuse type (p = 0.044). Multivariate analysis showed that aberrant p53 IHC expression was not an independent prognostic factor. P53 IHC patterns are predictive biomarkers for mutTP53 and gastric cancer outcomes, where a prerequisite involves a nuanced approach considering cutoff values and molecular-histologic subtyping. [ABSTRACT FROM AUTHOR]

Purpose of Review: The aim is to elucidate the mechanisms of autoimmune dysregulation that contribute to the onset and course of Guillain–Barre Syndrome (GBS) and Myasthenia Gravis (MG), with an emphasis on the important role that the Epstein-Barr virus (EBV) plays as an exacerbator or trigger of these autoimmune reactions. It further explores diagnostic strategies and therapeutic approaches to improve patient outcomes. Recent Findings: Recent researches have underscored the challenging nature of EBV due to its insidious behavior and persistent latency, which make it difficult to create successful preventive and therapeutic approaches. These discoveries have revealed how EBV's ability to induce host immune dysfunction can exacerbate or spark inflammatory processes, leading to its association with various autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and Sjögren's syndrome. Moreover, this review will shed light on the intricate connections between EBV and autoimmune neuromuscular disorders like MG and GBS, emphasizing the urgent requirement for further investigation to devise effective strategies against EBV-related conditions. Summary: MG and GBS, while both autoimmune illnesses affecting the neuromuscular system, differ greatly in their pathogenesis and clinical presentation. Viral infections, notably EBV, are vital in causing or aggravating these diseases. Understanding the link between EBV and autoimmune dysregulation could enhance diagnostic accuracy, therapeutic approaches, and preventive options, such as antiviral medications or vaccinations. Continued research and interdisciplinary collaboration are crucial to clarify how EBV affects MG and GBS, potentially leading to tailored treatments. Identifying precise biomarkers and pathways will improve clinical protocols, public health standards, and education on the EBV-autoimmunity relationship. [ABSTRACT FROM AUTHOR]

Cancer cells show a dynamic metabolic landscape, requiring a sufficient supply of nucleotides to proliferate. They are highly dependent on de novo purine biosynthetic pathways for their nucleotide requirements. Phosphoribosyl pyrophosphate amidotransferase (PPAT), catalyzing the first step of de novo purine biosynthesis, is highly expressed in various cancers. We observed an increased expression of PPAT in nasopharyngeal carcinoma (NPC). Moreover, our ribonucleic acid sequencing analysis showed high PPAT expression in Epstein–Barr virus‐positive NPC, which was supported by in vitro analysis. Through a gene knockdown study, we showed that the suppression of PPAT expression reduced the proliferation and invasion of NPC cells. We also demonstrated the regulation of PPAT by glutamine, a cosubstrate for PPAT. A glutamine antagonist, 6‐diazo‐5‐oxo‐L‐norleucine, blocked glutamine‐mediated induction of PPAT and reduced NPC cell proliferation. Immunohistochemical analysis of PPAT in NPC tissues revealed increased expression of PPAT with disease progression, which was significantly associated with poor prognosis. In summary, this study highlighted the biological function of PPAT in NPC, establishing its potential as a novel prognostic biomarker for aggressive NPC and a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Inborn errors of immunity (IEI) are a group of genetically heterogeneous disorders with a wide-ranging clinical phenotype, varying from increased predisposition to infections to dysregulation of the immune system, including autoimmune phenomena, autoinflammatory disorders, lymphoproliferation, and malignancy. Lymphoproliferative disorder (LPD) in IEI refers to the nodal or extra-nodal and persistent or recurrent clonal or non-clonal proliferation of lymphoid cells in the clinical context of an inherited immunodeficiency or immune dysregulation. The Epstein-Barr virus (EBV) plays a significant role in the etiopathogenesis of LPD in IEIs. In patients with specific IEIs, lack of immune surveillance can lead to an uninhibited proliferation of EBV-infected cells that may result in chronic active EBV infection, hemophagocytic lymphohistiocytosis, and LPD, particularly lymphomas. Areas covered: We intend to discuss the pathogenesis, diagnosis, and treatment modalities directed toward EBV-associated LPD in patients with distinct IEIs. Expert opinion: EBV-driven lymphoproliferation in IEIs presents a diagnostic and therapeutic problem that necessitates a comprehensive understanding of host–pathogen interactions, immune dysregulation, and personalized treatment approaches. A multidisciplinary approach involving immunologists, hematologists, infectious disease specialists, and geneticists is paramount to addressing the diagnostic and therapeutic challenges posed by this intriguing yet formidable clinical entity. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a major global health concern, with its prevalence increasing steadily. While plasma proteins have been implicated in NAFLD, establishing causal relationships has been challenging due to confounding factors in observational studies. This study aims to explore the causal relationships between plasma proteins and NAFLD using Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data from multiple sources to conduct MR analyses. Plasma protein data were obtained from the deCODE open database, and NAFLD data were sourced from the Finnish genetic sample collection (FinnGen). We performed MR analysis to identify plasma proteins causally related to NAFLD and explored the potential mediation effect of antibody-immune responses. Our MR analysis identified three plasma proteins—KNG1, MICB, and PKD2—with significant causal relationships to NAFLD. Mediation analysis further revealed that KNG1 negatively mediated the risk of NAFLD through Epstein-Barr virus EA-D antibody levels, while MICB and PKD2 positively mediated NAFLD risk through the same antibody levels. This study provides novel genetic evidence of causal relationships between specific plasma proteins and NAFLD risk. Measuring the levels of KNG1, MICB, PKD2, and Epstein-Barr virus EA-D antibody levels in patients may help clinicians assess NAFLD risk more accurately. Further clinical research is warranted to validate these findings and explore their potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Mimicry of host protein structures, or 'molecular mimicry', is a common mechanism employed by viruses to evade the host's immune system. Short linear amino acid (AA) molecular mimics can elicit cross-reactive antibodies and T cells from the host, but the prevalence of such mimics throughout the human virome has not been fully explored. Here we evaluate 134 human-infecting viruses and find significant usage of linear mimicry across the virome, particularly those in the Herpesviridae and Poxviridae families. Furthermore, host proteins related to cellular replication and inflammation, autosomes, the X chromosome, and thymic cells are enriched as viral mimicry targets. Finally, we find that short linear mimicry from Epstein-Barr virus (EBV) is higher in auto-antibodies found in patients with multiple sclerosis than previously appreciated. Our results thus hint that human-infecting viruses leverage mimicry in the course of their infection, and that such mimicry may contribute to autoimmunity, thereby prompting potential targets for therapies. Viruses often evolve molecular mimicry with host proteins for immune evasion. Here the authors assess short linear mimicry of 134 viruses to find abundance of such mimicry in herpes and pox viruses, while overlaps between Epstein-Barr virus antigens and auto-antibodies from patients with multiple sclerosis hints at a crosstalk between viral infection and autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Tuberculous meningitis (TBM) with adults Epstein-Barr (EB) virus encephalitis is a very rare infectious disease, with a high mortality and disability. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) is highly diagnostic. We report on a case of severe meningoencephalitis caused by coinfection with mycobacterium tuberculosis and EB virus. Brain MRI indicated a parenchyma lesion in the brain. mNGS of CSF indicated Mycobacterium tuberculosis and EB virus amplification, positive serum EB virus IgG antibodies, and improved symptoms after anti-tuberculosis and antiviral treatment. A reexamination of the brainMRI revealed that the significantly absorption of the lesions. Case report: A 49-year-old male patient presented with a chief complaint of headache and fever with consciousness disturbance. The brain magnetic resonance imaging showed a lesions in the right parenchymal brain with uneven enhancement, accompanied by significantly increased intracranial pressure, elevated CSF cell count and protein levels, as well as notably decreased glucose and chloride levels. mNGS of CSF showed the coexistence of Mycobacterium tuberculosis and EBV. The patient was diagnosed as TBM with EBV encephalitis. The patient's symptoms gradually improved with the active administration of anti-tuberculosis combined with antiviral agents, the use of hormones to reduce inflammatory reaction, dehydration to lower intracranial pressure, and intrathecal injection. Subsequent follow-up brain magnetic resonance imaging indicated significant absorption of the lesions, along with a marked decrease in CSF count and protein levels, as well as obvious increase in glucose and chloride levels. Conclusion: TBM associated with adult EBV encephalitis is extremely rare. The disease's early stages are severe and have a high fatality rate. A prompt and accurate diagnosis is particularly important. NGS of CSF is of great value for early diagnosis. [ABSTRACT FROM AUTHOR]

Immune deficiency and dysregulation‐associated lymphoproliferative disorders and lymphomas (IDD‐LPDs) encompass a heterogeneous clinical and pathological spectrum of disorders that range from indolent lymphoproliferations to aggressive lymphomas. They arise in a variety of clinical settings and are associated with oncogenic viruses such as the Epstein–Barr virus (EBV) and Kaposi sarcoma‐associated herpesvirus/human herpes virus (KSHV/HHV8) in some, but not all, cases. The recognition of IDD‐LPDs as distinct from LPDs in immune competent patients is essential to tailor clinical management options for affected patients. The 5th edition of the World Health Organisation classification has introduced an integrated classification of IDD‐LPDs with the goal of standardising diagnoses among different settings to enhance clinical decision support. In parallel, new knowledge in the field, particularly surrounding the role of oncogenic viruses and the tumour microenvironment, has led to clearer understanding of the complex pathogenesis of IDD‐LPDs and how these features can be precisely harnessed for therapeutic purposes. In this perspective, we highlight the need for multidisciplinary decision‐making to augment patient care as well as key areas where evolving concepts offer challenges and opportunities for clinical management, research and future iterations of the classification. [ABSTRACT FROM AUTHOR]

Long COVID, or Post-Acute Sequelae of COVID-19 (PASC), was characterized by persistent symptoms such as fatigue, shortness of breath, and cognitive impairments. These symptoms, emerging one to 2months post-infection and persisting for several months, cannot be attributed to other diagnoses. The pathophysiology of long COVID remained elusive; however, emerging studies suggested multiple potential mechanisms, including the reactivation of Epstein-Barr virus, persistent SARS-CoV-2 reservoirs, neuroinflammation, and vascular damage, which may contribute to its development. Long COVID affected multiple organ systems, including respiratory, circulatory, and nervous systems, leading to a range of functional impairments. Additionally, it showed a profound impact on mental health, manifesting as anxiety and depression, which significantly degraded the quality of life. The absence of definitive treatments underscored the importance of prevention. Recent evidence indicated that early antiviral intervention--particularly with small-molecule drugs such as Metformin, Ensitrelvir, Molnupiravir, and Nirmatrelvir--may effectively reduce the incidence of longCOVID. This underscored the promising role of small-molecule compounds in mitigating long-term COVID-19 consequences, offering a novel preventive strategy against long COVID and its extensive impacts on patients. [ABSTRACT FROM AUTHOR]

In Burkitt's lymphoma (BL), Epstein–Barr virus-encoded microRNAs (EBV miRNAs) are emerging as crucial regulatory agents that impact cellular and viral gene regulation. This review investigates the multifaceted functions of EBV miRNAs in the pathogenesis of Burkitt lymphoma. EBV miRNAs regulate several cellular processes that are essential for BL development, such as apoptosis, immune evasion, and cellular proliferation. These small, non-coding RNAs target both viral and host mRNAs, finely adjusting the cellular environment to favor oncogenesis. Prominent miRNAs, such as BART (BamHI-A rightward transcript) and BHRF1 (BamHI fragment H rightward open reading frame 1), are emphasized for their roles in tumor growth and immune regulation. For example, BART miRNAs prevent apoptosis by suppressing pro-apoptotic proteins, whereas BHRF1 miRNAs promote viral latency and immunological evasion. Understanding the intricate connections among EBV miRNAs and their targets illuminates BL pathogenesis and suggests novel treatment approaches. Targeting EBV miRNAs or their specific pathways offers a feasible option for developing innovative therapies that aim to disrupt the carcinogenic processes initiated by these viral components. future studies should focus on precisely mapping miRNA‒target networks and developing miRNA-based diagnostic and therapeutic tools. This comprehensive article highlights the importance of EBV miRNAs in Burkitt lymphoma, indicating their potential as biomarkers and targets for innovative treatment strategies. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE. [Display omitted] • Neoself-antigens are presented on MHC-II at low levels of the invariant chain • Lupus-like disease developed upon deletion of the invariant chain from adult mice • Clonal expansion of neoself-reactive T cells was found in SLE patients • Epstein-Barr virus reactivation is one of the factors for neoself-antigen presentation The discrimination of self- and neoself-antigens by T cells plays a crucial role in the activation of autoreactive T cells, leading to the development of autoimmunity. The reactivation of the Epstein-Barr virus is a possible factor that causes MHC class II molecules to present neoself-antigens by decreasing the expression of the invariant chain. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the epidemiology characteristics of Herpes simplex virus type 2 (HSV-2), Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) infection in children from January 2018 to December 2023, in Nanjing, China. Methods: We conducted a retrospective analysis of 21,210, 49,494 and 32,457 outpatients and inpatients aged 1 day to 17 years who were subjected to the three herpesviruses (HSV-2, EBV, and CMV) nucleic acid testing from January 2018 to December 2023, respectively. Demographic information, laboratory findings, etc. were collected and analyzed. HSV-2, EBV and CMV nucleic acid testing were performed by real-time PCR. Results: The total rate of detection of the three herpesviruses for all specimens was 0.32% (67/21,210), 14.99% (7419/49,494), and 8.88% (2881/32,457), respectively. A declining trend in the incidence of viral infections over the years was observed for the three herpesviruses (all P<0.05). The detection rate for HSV-2, EBV, and CMV was highest among patients aged 1-3 years, 3-7 years, and 28 days to 1 year, respectively (all P<0.05). The presence of HSV-2 and CMV infection did not exhibit a discernible seasonal pattern, whereas EBV typically demonstrated an elevation during the summer and autumn. Conclusion: EBV and CMV were both prevalent among children in China, except for HSV-2. The annual prevalence of the three herpesviruses show decreasing trend from 2018 to 2023, and no difference in gender (except for EBV). EBV infections usually occur in the summer and autumn, whereas HSV-2 and CMV do not exhibit significant seasonality. The positivity rate of HSV-2 is highest in 1-3 years, EBV is highest in 3-7 years, and that of CMV is highest in 28 days to 1 year. Positive detection rates are higher in outpatients than in inpatients. [ABSTRACT FROM AUTHOR]

Simple Summary: Epstein-Barr virus (EBV) latently infects over 90% of adults worldwide and is linked to several cancers such as Burkitt lymphoma. Amongst the few factors expressed by the EBV during latent infection are microRNAs (miRNAs) that can regulate both viral and cellular gene expression. In this study, we examined cellular targets of EBV miRNAs. Through bioinformatics and molecular analysis, we provide evidence of 52 new functional interactions for EBV miRNAs with protein-coding transcripts involved in B cell differentiation, cell cycle, and intracellular trafficking. Collectively, these data provide a resource for EBV miRNA targets and yield important insight into functional roles for these viral factors in B cell cancers. MicroRNAs are key post-transcriptional regulators of gene expression and their dysregulation is often linked to cancer. Epstein-Barr virus encodes 22 BamHI A Rightward Transcript (BART) miRNAs, which are expressed in nearly all EBV-associated cancers and implicated in viral pathogenesis. To investigate biological targets for BART miRNAs in B cell lymphomas, we performed a meta-analysis of publicly available Ago-CLIP datasets from EBV-positive Burkitt lymphomas (BLs), primary effusion lymphomas (PELs), AIDS-associated diffuse large B cell lymphomas (DLBCLs), and lymphoblastoid cell lines (LCLs). Our analysis focused on comparing targets of EBV BART miRNAs across the different types of transformed B cells. Using reporter assays, we then experimentally validated over 50 functional interactions between BART miRNAs and cellular protein-coding transcripts involved in activities such as B cell differentiation (PRDM1, IRF4, and MYC), cell cycle regulation (UHMK1, CDKN1A, MDM2, and NPAT), apoptosis (MCL1), signaling and intracellular trafficking (GAB1, SOS1, MAPK1, RAB11A, CAV1, and RANBP9), and tumor suppression (CCDC6). Moreover, ectopic BART miRNA expression in several EBV-negative BL cells induced transcriptional changes that may influence molecular signatures of EBV-associated BLs. Collectively, our findings reveal novel, functional interactions for BART miRNAs in lymphomas and provide insights into their roles in these B cell cancers. [ABSTRACT FROM AUTHOR]

Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group (p = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 102 to < 1 × 104 copies/mL) was greater in the LTV group than in the control group (23% vs. 10%, p = 0.01). The proportion of patients with CMV reactivation was lower in the LTV group than in the control group (35% vs. 56%, p = 0.002). There was no significant difference between the groups in terms of neutrophil and platelet count recovery, the cumulative incidence of acute/chronic graft-versus-host disease, overall survival, cumulative relapse rate or nonrelapse mortality. Our results show that the increased incidence of EBV reactivation may be associated with LTV prophylaxis for CMV after haploidentical HSCT. [ABSTRACT FROM AUTHOR]

Chronic active Epstein-Barr virus infection (CAEBV) is a progressive and life-threatening disease characterized by persistent or recurrent EBV activation. It has been reported that, γδ T cells, a type of cytotoxic lymphocyte, play a critical role in restricting EBV. However, the functional status of γδ T cells in pediatric CAEBV patients has not yet been described. In this study, flow cytometry analysis was conducted to explore the cytokine production capacity of γδ T cells in CAEBV patients. A diminished frequency of γδ T cells and decreased expression of cytolytic molecule granzyme B were found in CAEBV patients, suggesting a dysfunction in the immune regulatory function of γδ T cells in this disease. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) risk prediction models based on Epstein–Barr virus (EBV)‐antibody testing have shown potential for screening of NPC; however, the long‐term stability is unclear. Here, we investigated the kinetics of two EBV‐antibody NPC risk scores within the Taiwan NPC Multiplex Family Study. Among 545 participants with multiple blood samples, we evaluated the stability of a 2‐marker enzyme‐linked immunosorbent assay score and 13‐marker multiplex serology score using the intra‐class correlation coefficient (ICC) by fitting a linear mixed model that accounted for the clustering effect of multiple measurements per subject and age. We also estimated the clustering of positive tests using Fleiss's kappa statistic. Over an average 20‐year follow‐up, the 2‐marker score showed high stability over time, whereas the 13‐marker score was more variable (p <.05). Case–control status is associated with the kinetics of the antibody response, with higher ICCs among cases. Positive tests were more likely to cluster within the same individual for the 2‐marker score than the 13‐marker score (p <.05). The 2‐marker score had an increase in specificity from ~90% for single measurement to ~96% with repeat testing. The 13‐marker score had a specificity of ~73% for a single measurement that increased to ~92% with repeat testing. Among individuals who developed NPC, none experienced score reversion. Our findings suggest that repeated testing could improve the specificity of NPC screening in high‐risk NPC multiplex families. Further studies are required to determine the impact on sensitivity, establish optimal screening intervals, and generalize these findings to general population settings in high‐risk regions. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectivesMethodsResultsConclusionsMycotoxins, fungal metabolites prevalent in many foods, are recognized for their role in carcinogenesis, especially when interacting with oncogenic viruses.This scoping review synthesizes current evidence on the human cancer risk associated with mycotoxin exposure and oncogenic virus infections.Searches were conducted on PubMed, Embase, and Web of Science. Studies were selected based on the PECOS framework. Data extraction involved narrative and qualitative presentation of findings, with meta-analysis where feasible. Risk of bias and outcome quality were assessed using the OHAT tool and GRADE approach.From 25 included studies, 18 focused on aflatoxins and hepatitis viruses in hepatocellular carcinoma (HCC). Four studies examined aflatoxin B1 (AFB1) and human papilloma virus (HPV) in cervical cancer, while three investigated AFB1 with Epstein-Barr virus (EBV) in lymphomagenesis. The review highlights a significant synergistic effect between AFB1 and hepatitis B and C viruses in HCC development. Significant interactions between AFB1 and HPV, as well as AFB1 and EBV, were observed, but further research is needed.The synergistic impact of mycotoxins and oncogenic viruses is a critical public health concern. Future research, especially prospective cohort studies and investigations into molecular mechanisms, is essential to address this complex issue. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo explore the potential risk factors for the occurrence of human cytomegalovirus (HCMV) retinitis (CMVR) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients.This is a retrospective, nested case-control study conducted in hematological patients with CMVR who underwent allo-HSCT. Patients diagnosed with CMVR after allo-HSCT were included as the case group, and those without CMVR were matched by a ratio of 1:2 and were recruited as controls. We selected 19 pre- and post-transplant indicators for univariate analysis between the cases and controls, and then Logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for exploration of risk factors of the CMVR occurrence.A total of 1308 allo-HSCT patients from January 1, 2020 to July 31, 2023 were analyzed, and 27 patients were diagnosed CMVR with a median onset time of 222 days after transplantation. In univariate analysis, donors of stem cells source, HLA-match types (including matched sibling donor, haploidentical donor, and unrelated donor), post-transplant Epstein-Barr virus (EBV) viremia, platelet implantation time, and serostatus of CMV-IgG were more easily to develop CMVR than controls (p < 0.001, p = 0.003, p < 0.001, p = 0.032, p = 0.038, respectively). Multivariate logistic regression analysis showed that stem cells source (OR 7.823, 95% CI 1.759-34.800), HLA-match types (OR 7.452, 95% CI 1.099-50.542), and post-transplant EBV infection (OR 7.510, 95% CI 1.903-29.640) were positively associated with the onset of CMVR.Stem cells derived from bone marrow and peripheral blood, HLA-match types, and post-transplant EBV viremia are important risk predictors of CMVR in allo-HSCT patients. These results suggest that clinicians should pay more attention to these indicators when formulating preventive measures pre- and post-transplant. [ABSTRACT FROM AUTHOR]

A study published in Acta Neuropathologica explores the use of targeted whole-viral genome sequencing from formalin-fixed paraffin-embedded (FFPE) neuropathology specimens. The researchers conducted a proof-of-concept study using a viral nucleic acid enrichment protocol on 23 FFPE samples with confirmed viral infections. They found that the viral enrichment panel led to a significant enrichment of viral sequences, resulting in a high genome coverage and improved detection of viral integration sites. The study demonstrates that metagenomic sequencing of virus-enriched libraries from FFPE specimens is a valuable method for viral whole-genome sequencing, even in low-quality and low-biomass samples. [Extracted from the article]

Purpose: This study aimed to assess the long-term risks associated with a history of infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV). Specifically analyzing the potential increase in developing nasopharyngeal cancer (NPC) and lymphoma in patients with a history of IM and exploring the prevalence of other EBV-associated conditions. Materials and Methods: The Korean National Health Insurance Service (NHIS) database was utilized for a retrospective analysis, covering data from 2002 to 2021. A total of 25,582 IM patients and controls were included, with 1:1 propensity score matching. The study monitored outcomes, including lymphoma, NPC, gastric cancer, multiple sclerosis, and all-cause mortality. Results: Patients with a history of IM demonstrated a significantly higher incidence of lymphoma (hazard ratio [HR], 5.320; 95% confidence interval [CI], 3.208 to 8.820; p < 0.001) and NPC (HR, 7.116; 95% CI, 1.617 to 31.314; p=0.009) during the follow-up period compared with the control group. Additionally, the IM group showed an increased rate of all-cause mortality (HR, 2.225; 95% CI, 1.858 to 2.663; p < 0.001). Conclusion: This study suggests that individuals with a history of IM have an elevated risk of developing lymphoma and NPC in South Korea, emphasizing the importance of vigilant follow-up and monitoring. The results advocate for heightened awareness and potential national monitoring policies to address the long-term health implications of EBV infection and to implement preventive measures. [ABSTRACT FROM AUTHOR]

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3 months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1 months, and the median overall survival (OS) was 7.1 months. The failure group, which was characterized by Deaville score (DS) 3–4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected) and low-risk groups (DS 1–2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1–2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL. [ABSTRACT FROM AUTHOR]

The Herpesviridae include the Epstein–Barr Virus (EBV) and the Kaposi Sarcoma-associated Herpesvirus (KSHV), both of which are oncogenic gamma-herpesviruses. These viruses manipulate host cellular mechanisms, including through ubiquitin-mediated pathways, to promote viral replication and oncogenesis. Ubiquitin, a regulatory protein which tags substrates for degradation or alters their function, is manipulated by both EBV and KSHV to facilitate viral persistence and cancer development. EBV infects approximately 90% of the global population and is implicated in malignancies including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), post-transplant lymphoproliferative disorder (PTLD), and nasopharyngeal carcinoma. EBV latency proteins, notably LMP1 and EBNA3C, use ubiquitin-mediated mechanisms to inhibit apoptosis, promote cell proliferation, and interfere with DNA repair, contributing to tumorigenesis. EBV's lytic proteins, including BZLF1 and BPLF1, further disrupt cellular processes to favor oncogenesis. Similarly, KSHV, a causative agent of Kaposi's Sarcoma and lymphoproliferative disorders, has a latency-associated nuclear antigen (LANA) and other latency proteins that manipulate ubiquitin pathways to degrade tumor suppressors, stabilize oncogenic proteins, and evade immune responses. KSHV's lytic cycle proteins, such as RTA and Orf64, also use ubiquitin-mediated strategies to impair immune functions and promote oncogenesis. This review explores the ubiquitin-mediated interactions of EBV and KSHV proteins, elucidating their roles in viral oncogenesis. Understanding these mechanisms offers insights into the similarities between the viruses, as well as provoking thought about potential therapeutic targets for herpesvirus-associated cancers. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV) is a double‐stranded DNA herpesvirus and establishes life‐long infection in 95% of the world's populations. Main body: EBV is critically involved in multiple diseases. Aberrant signaling pathways, immune escape, and metabolic reprogramming play essential roles in EBV‐mediated pathogenesis. However, the underlying mechanisms have not yet been fully elucidated. Here we reviewed recent advances on the epigenetic regulation of EBV pathogenesis, which may translate to potential therapeutic strategies in EBV‐associated diseases. Conclusion: Growing evidence has suggested that viral infections reconstruct epigenome to modulate gene expression both in the host and the virus levels. [ABSTRACT FROM AUTHOR]

Background: Thymoma is a tumor that originates in the thymus gland, a part of the human body located behind the breastbone. It is a malignant disease that is rare in children but more common in adults and usually does not spread outside the thymus. The exact cause of thymic disease is not known, but it is thought to be more common in people infected with the EBV virus at an early age. Various surgical methods are used in clinical settings to treat thymoma. Expert opinion is very important in the diagnosis of the disease. Recently, next-generation technologies have become increasingly important in disease detection. Today's early detection systems already use transformer models that are open to technological advances. Methods: What makes this study different is the use of transformer models instead of traditional deep learning models. The data used in this study were obtained from patients undergoing treatment at Fırat University, Department of Thoracic Surgery. The dataset consisted of two types of classes: thymoma disease images and non-thymoma disease images. The proposed approach consists of preprocessing, model training, feature extraction, feature set fusion between models, efficient feature selection, and classification. In the preprocessing step, unnecessary regions of the images were cropped, and the region of interest (ROI) technique was applied. Four types of transformer models (Deit3, Maxvit, Swin, and ViT) were used for model training. As a result of the training of the models, the feature sets obtained from the best three models were merged between the models (Deit3 and Swin, Deit3 and ViT, Deit3 and ViT, Swin and ViT, and Deit3 and Swin and ViT). The combined feature set of the model (Deit3 and ViT) that gave the best performance with fewer features was analyzed using the mRMR feature selection method. The SVM method was used in the classification process. Results: With the mRMR feature selection method, 100% overall accuracy was achieved with feature sets containing fewer features. The cross-validation technique was used to verify the overall accuracy of the proposed approach and 99.22% overall accuracy was achieved in the analysis with this technique. Conclusions: These findings emphasize the added value of the proposed approach in the detection of thymoma. [ABSTRACT FROM AUTHOR]

This study aimed to explore the intricate relationship between mitochondrial dysfunction, infection, and neuroinflammation, focusing specifically on the impact of pathogenic epitopes of the Epstein–Barr Virus (EBV) nuclear antigen 1 (EBNA1) in a mouse model of mitochondrial dysfunctions. The investigation included female middle-aged PARK2−/− and C57BL/6J wild-type mice immunized with EBNA1386–405 or with active experimental autoimmune encephalomyelitis (EAE) induction by the myelin oligodendrocyte glycoprotein (MOG)35–55 peptide. The PARK2−/− mice developed more severe EAE than the wild-type mice. Following immunization with EBNA1386–405, only PARK2−/− exhibited symptoms resembling EAE. During the acute phase, PARK2−/− mice immunized with either MOG35–55 or EBNA1386–405 exhibited a similar infiltration of the T cells and macrophages in the spinal cord and decreased glial fibrillary acidic protein (GFAP) expression in the brain. However, the EBNA1386–405 -immunized PARK2−/− mice showed significantly increased frequencies of CD8a+ T cells and CD11c+ B cells, and distinct cytokine profiles in the periphery compared to the wild-type controls. These findings highlight the role of EBV in exacerbating inflammation, particularly in the context of mitochondrial deficiencies. [ABSTRACT FROM AUTHOR]

Background and objective: The DNA load of EBV may play a part in CLL pathogenesis and prognosis. The objective of this cross-sectional study was to examine the prognostic value of EBV viral load in CLL patients in comparison with other common laboratory prognostic factors. Materials and methods: Whole blood and sera from forty untreated CLL patients were collected. Next, DNA was extracted from total white blood cells (WBC), and TaqMan real-time PCR was performed to determine the EBV-DNA load by amplifying a specific fragment in the BNRF1 gene. In addition, parameters such as complete blood counts (CBC) and lactate dehydrogenase (LDH) were determined using an automated clinical laboratory analyzer. Results: Twenty-one patients (52.5%) were positive for EBV by real-time PCR analysis (ranged 20 to 30000 copies/µL). The difference in LDH mean levels between EBV positive and negative patients was marginally significant (P = 0.05). Furthermore, platelet (PLT) count (P = 0.03) and CD5+/CD19+ count (P = 0.04), between EBV positive and negative subgroups, were substantially different. In addition, individuals with a severe form of illness, as defined by an increase in LDH, a decrease in PLT, and an 11q deletion, had considerably higher EBV-DNA copy numbers (the ranges of viral loads were 9966.66 ± 20033 in the severe form vs. 137.13 ± 245.41 in the mild form). Conclusion: The EBV-DNA load could be used as a prognostic factor in the initial examination of CLL patients to better characterize the disease outcome and prognosis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate a possible link between acute Epstein-Barr virus infection and Lemierre syndrome, a rare yet life-threatening infection. Methods: A systematic review was conducted adhering to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Diagnosis criteria for Lemierre syndrome were established, and data extraction encompassed demographic data, clinical, and laboratory information. Results: Out of 985 initially identified papers, 132 articles were selected for the final analysis. They reported on 151 cases of Lemierre syndrome (76 female and 75 male patients with a median of 18 years) alongside interpretable results for Epstein-Barr virus serology. Among these, 38 cases (25%) tested positive for acute Epstein-Barr virus serology. There were no differences in terms of age, sex, or Fusobacterium presence between the serologically positive and negative groups. Conversely, instances of cervical thrombophlebitis and pulmonary complications were significantly higher (P = 0.0001) among those testing negative. The disease course was lethal in one case for each of the two groups. Conclusions: This analysis provides evidence of an association between acute Epstein-Barr virus infection and Lemierre syndrome. Raising awareness of this link within the medical community is desirable. [ABSTRACT FROM AUTHOR]

Purpose: Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. Methods: Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. Results: The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein–Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68 A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. Conclusions: The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease. [ABSTRACT FROM AUTHOR]

The Epstein–Barr virus (EBV) is responsible for a spectrum of human diseases and demonstrates a considerable prevalence among various populations. Advances in molecular epidemiological research have enhanced our comprehension of EBV‐related pathologies. In this study, our objective was to examine the epidemiological profile and clinical features of EBV infection in Chongqing, China. We enrolled patients suspected of EBV‐related diseases who were admitted to the First Affiliated Hospital of Chongqing Medical University between May 2013 and November 2022. Inclusion criteria were based on those who underwent EBV‐specific immunofluorescence or plasma EBV‐DNA testing. Among 13 584 inpatients, the overall seropositivity rates for EBNA‐1‐IgG, EBV‐VCA‐IgM, EBV‐EA‐IgG, EBV‐EA‐IgA, EBV‐VCA‐IgA, and EBV‐DNA were 91.89%, 7.22%, 18.00%, 16.19%, 30.78%, and 18.00%, respectively. The seropositivity rate for EBNA‐1‐IgG steadily increased with age. The seropositivity rate for VCA‐IgM, an indicator of acute EBV infection, was highest in patients aged 11–20 years at 26.41%, decreasing to 2%–6% in older patients. Additionally, among 205 outpatients, the EBV‐DNA positivity rate was 14.15%. In 3670 individuals from health check‐up centers, the seropositivity rates for EBV‐EA‐IgA and EBV‐VCA‐IgA were 11.96% and 28.09%, respectively, and the EBV‐DNA positivity rate was 11.92%, all of which were lower than those in inpatients. Among the 762 EBV‐DNA positive inpatients, adults aged 31–40 years were the least affected, with a seropositivity rate of 12.00%, which increased with age. The most common diseases associated with primary EBV infection were infectious mononucleosis (IM) (35.49%), followed by EBV infection (14.15%) and pneumonia (7.19%). The most common diseases associated with EBV reactivation were pneumonia (16.80%), nasopharyngeal carcinoma (NPC) (11.02%), and autoimmune diseases (7.04%). Patients with hemophagocytic lymphohistiocytosis (HLH) had the highest viral load, significantly higher than those with NPC, pneumonia, and liver cirrhosis. This large‐scale retrospective study explores the epidemiological characteristics and disease spectrum of EBV infection across all age groups. The findings contribute to the improvement of diagnostic and management strategies for EBV infection. [ABSTRACT FROM AUTHOR]

Epstein‒Barr virus (EBV) regulates the expression of host genes involved in functional pathways for viral infection and pathogenicity. Long noncoding RNAs (lncRNAs) have been found to be important regulators of cellular biology. However, how EBV affects host biological processes via lncRNAs remains elusive. Eukaryotic initiation factor 4A3 (EIF4A3) was recently identified as an essential controller of cell fate with an unknown role in EBV infection. Here, the expression of lncRNA brain cytoplasmic 200 (BC200) was shown to be significantly upregulated in EBV‐infected cell lines. RNA immunoprecipitation and RNA pulldown assays confirmed that BC200 bound to EIF4A3. Moreover, BC200 promoted EIF4A3 expression at the protein level but not at the mRNA level. Mechanistically, BC200 stabilized the EIF4A3 protein by impeding the K48‐linked polyubiquitination of the K195 and K198 residues of EIF4A3. In addition, RNA‐seq analysis of EBV‐positive cells with knockdown of either BC200 or EIF4A3 revealed that a broad range of cellular genes were differentially regulated, particularly those related to virus infection and immune response pathways. This study is the first to reveal the key residues involved in EIF4A3 polyubiquitination and elucidate the novel regulatory role of EBV in host gene expression via the BC200/EIF4A3 axis. These results have implications for the pathogenesis and treatment of EBV‐related diseases. [ABSTRACT FROM AUTHOR]

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R-loops are triple-stranded nucleic acid structures that occur when newly synthesized single-stranded RNA anneals to duplex DNA upon the collision of replication forks with transcription complexes. These RNA–DNA hybrids facilitate several transcriptional processes in the cell and have been described extensively in the literature. Recently, evidence has emerged that R-loops are key regulators of DNA tumor virus transcription and the replication of their lifecycle. Studies have demonstrated that R-loops on the Human Papillomavirus (HPV) genome must be resolved to maintain genome maintenance and avoid viral integration, a hallmark of HPV cancers. For Epstein–Barr virus (EBV), R-loops are formed at the oriLyt to establish lytic replication. Structural maintenance of chromosome proteins 5/6 (SMC5/6) bind to these viral R-loops to repress EBV lytic replication. Most viruses in the herpesvirales order, such as KSHV, contain R-loop-forming sequences. In this perspective, we will describe the current, although limited, literature demonstrating the importance of RNA–DNA hybrids to regulate DNA virus transcription. We will also detail potential new areas of R-loop research and how these viruses can be used as tools to study the growing field of R-loops. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is a rare cause of acute retinal necrosis (ARN) and is known for its poor prognosis and limited response to conventional antiviral treatment. Herein, we report a case of EBV ARN successfully treated with conventional systemic acyclovir and intravitreal ganciclovir injection. An 85-year-old man presented with visual disturbance of the right eye from 10 days prior. His visual acuity was 20/200 in the right eye and slit lamp examination showed keratic precipitates, 4+ anterior chamber cells, and 1+ anterior vitreous cells. Fundus examination revealed multiple retinal hemorrhages and yellow-whitish necrotic lesion. The patient was clinically diagnosed with ARN. A few days later, EBV DNA was identified in the aqueous humor and in the serum PCR assay. The patient received 350 mg of intravenous acyclovir three times a day with oral prednisolone, and an intravitreal ganciclovir injection (2 mg per dose) was given five times. Over the course of seven weeks, systemic acyclovir was switched to 1g of per-oral valaciclovir three times a day, and oral steroids were successfully tapered. His visual acuity improved to 20/100, and the previous necrotic lesion was markedly decreased in size. Intravenous acyclovir combined with intravitreal ganciclovir may yield successful treatment outcomes in acute retinal necrosis caused by EBV. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection has a strong correlation with the development of nasopharyngeal carcinoma (NPC). Aquaporin 3 (AQP3), a member of the aquaporin family, plays an important role in tumor development, especially in epithelial-mesenchymal transition. In this study, the expression of AQP3 in EBV-positive NPC cells was significantly lower than that in EBV-negative NPC cells. Western blot and qRT-PCR analysis showed that LMP1 down-regulated the expression of AQP3 by activating the ERK pathway. Cell biology experiments have confirmed that AQP3 affects the development of tumor by promoting cell migration and proliferation in NPC cells. In addition, AQP3 can promote the lysis of EBV in EBV-positive NPC cells. The inhibition of AQP3 expression by EBV through LMP1 may be one of the mechanisms by which EBV maintains latent infection-induced tumor progression. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is the first human oncogenic virus known to express microRNAs (miRNAs), which are closely associated with the development of various tumors, including nasopharyngeal and gastric cancers. Stearoyl-CoA Desaturase 1 (SCD1) is a key enzyme in fatty acid synthesis, highly expressed in numerous tumors, promoting tumor growth and metastasis, making it a potential therapeutic target. In this study, we found that SCD1 expression in EBV-associated gastric cancer (EBVaGC) was significantly lower than in EBV-negative gastric cancer (EBVnGC) at both cellular and tissue levels. In addition, EBV-miR-BART20-5p targets the 3′-UTR of SCD1, downregulating its expression. Moreover, overexpression of SCD1 in EBVaGC cells promoted cell migration and proliferation while inhibiting autophagy. These results suggest that EBV-encoded miRNA-BART20-5p may contribute to EBVaGC progression by targeting SCD1. [ABSTRACT FROM AUTHOR]

Introduction: Epstein-Barr virus (EBV) is an oncogenic human herpesvirus associated with ~350,000 cases of lymphoid and epithelial malignancies every year, and is etiologically linked to infectious mononucleosis and multiple sclerosis. Despite four decades of research, no EBV vaccine candidate has yet reached licensure. Most previous vaccine attempts focused on a single viral entry glycoprotein, gp350, but recent data from clinical and pre-clinical studies, and the elucidation of viral entry mechanisms, support the inclusion of multiple entry glycoproteins in EBV vaccine design. Methods: Here we generated a modified vaccinia Ankara (MVA)-vectored EBV vaccine, MVA-EBV5-2, that targets five EBV entry glycoproteins, gp350, gB, and the gp42gHgL complex. We characterized the genetic and translational stability of the vaccine, followed by immunogenicity assessment in BALB/c mice and rhesus lymphocryptovirus-negative rhesus macaques as compared to a gp350-based MVA vaccine. Finally, we assessed the efficacy of MVA-EBV5-2-immune rhesus serum at preventing EBV infection in human CD34+ hematopoietic stem cell-reconstituted NSG mice, under two EBV challenge doses. Results: The MVA-EBV5-2 vaccine was genetically and translationally stable over 10 viral passages as shown by genetic and protein expression analysis, and when administered to female and male BALB/c mice, elicited serum EBV-specific IgG of both IgG1 and IgG2a subtypes with neutralizing activity in vitro. In Raji B cells, this neutralizing activity outperformed that of serum from mice immunized with a monovalent MVA-vectored gp350 vaccine. Similarly, MVA-EBV5-2 elicited EBV-specific IgG in rhesus macaques that were detected in both serum and saliva of immunized animals, with serum antibodies demonstrating neutralizing activity in vitro that outperformed serum from MVA-gp350-immunized macaques. Finally, pre-treatment with serum from MVA-EBV5-2-immunized macaques resulted in fewer EBV-infected mice in the two challenge experiments than pretreatment with serum from pre-immune macaques or macaques immunized with the monovalent gp350-based vaccine. Discussion: These results support the inclusion of multiple entry glycoproteins in EBV vaccine design and position our vaccine as a strong candidate for clinical translation. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein‐Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV‐ (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC‐associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene‐edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV‐coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV‐ and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies. [ABSTRACT FROM AUTHOR]

Background: Respiratory illness affects individuals across all age demographics on a global scale, often precipitated by viral infections. The symptomatic manifestations of these diseases bear clinical resemblance, complicating the accurate determination of their etiological origins. Furthermore, the diagnostic panels for respiratory pathogens used within local medical practices, may not encompass the full spectrum of viral agents responsible for such ailments. Consequently, a significant number of clinically important viral pathogens may remain undetected. Methods and findings: In the light of this, we conducted a metagenomic examination of 66 nasopharyngeal swab specimens, obtained from patients presenting with acute respiratory conditions yet tested negative by the standard diagnostic panels available locally. These specimens were obtained from the Public Health Laboratory, Maceio, State of Alagoas. Our findings indicate a predominant diagnostic escape of rhinoviruses and notably enterovirus D68. Moreover, our study identified a substantial quantity of sequence reads attributed to human respirovirus 3 (human parainfluenza 3) along with various herpresviruses including human herpesvirus-1, Epstein-Barr virus (Human herpesvirus-4), Human herpesviruses 6 and 7 and human parvovirus B19 (B19V). Notably, the metagenomic analysis uncovered a widespread presence of the emerging human vientovirus FB in most of sample pools, though its clinical importance remains to be elucidated. Conclusions: The obtained results in this study underscore the invaluable role of viral metagenomics in the identification of underrecognized viruses bearing clinical relevance. Furthermore, it offers insights into the dissemination of these pathogens within the studied area, thereby informing public health strategies aimed at enhancing diagnostic accuracy and improving patient care. Author summary: The emergence of SARS-CoV-2 has reshaped our understanding of respiratory viruses, highlighting the challenges in etiological diagnosis due to symptom similarities. Metagenomics, an innovative approach, has revolutionized respiratory infection diagnosis by unbiasedly sequencing all genetic material in a sample, enabling the identification of previously unknown or unsuspected viruses where traditional methods often fail. In a study conducted in Alagoas, a Northeast Brazilian state with low human development indexes, samples obtained from patients with flu-like symptoms negative for locally applied diagnostic kits revealed diagnostic escape of rhinoviruses and a notably prevalent enterovirus D68. Additionally, substantial reads attributed to human respirovirus 3 (parainfluenza virus 3) and various herpesviruses, including human herpesvirus-1, Epstein-Barr virus, human herpesviruses 6 and 7, and human parvovirus B19, were identified. These findings are pivotal for differentiating viruses not detected by routinely implemented diagnostic procedures. Metagenomics shows great promise in diagnosing and surveilling respiratory viruses, providing insights into their epidemiology, evolution, and public health impact. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein–Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up. [ABSTRACT FROM AUTHOR]