Epstein-Barr Research Articles

Exploring atypical manifestations and multisystem involvement of Epstein-Barr virus infection in hospitalized pediatric patients from Mexico: insights from a tertiary hospital (2012-2022).

Epstein-Barr virus (EBV) infection, with a global prevalence exceeding 95%, typically manifests in children as infectious mononucleosis. However, clinical practice frequently encounters diverse atypical presentations characterized by multisystem involvement, often resulting in an unfavorable clinical course. Our objective is to describe the clinical manifestations and results of EBV infection in a tertiary pediatric hospital in Mexico. An observational, transversal, retrospective, and descriptive study that included a systematic review of medical records (2012-2022) of patients under 18 years of age with detectable EBV particles in peripheral blood. The study included 26 patients with a median age of 5 years and a male predominance of 53.8%. Predominant symptoms were fever (85%) and lymphadenopathy (35%). Sixty-five percent had severe and atypical manifestations, including pneumonia and hepatic, hematologic-oncologic, and autoimmune diseases. Anemia, thrombocytopenia and leukopenia were common, with lymphocytosis in 19% of cases. The median EBV viral load was 2816 copies/mL (range: 555-355,500 copies/mL). Four deaths related to EBV infection were reported. Viral load in these cases also varied widely from 594 to 121,000 copies/mL. Supportive care was administered to 85% of patients, while others received antiviral treatment, steroids, and rituximab. Atypical manifestations were common, especially in children with multisystem involvement. EBV should be considered as a potential contributor to a diverse spectrum of clinical presentations, emphasizing the need for comprehensive evaluation and awareness in clinical diagnosis.

Immune triggers preceding neuralgic amyotrophy.

Infections and vaccinations have been identified as potential immunological triggers of neuralgic amyotrophy (NA), but the exact type and frequency of the preceding agents is unknown. This was a multicentre, prospective, observational, matched case-control study. NA was diagnosed by neuromuscular experts according to validated clinical criteria and electrodiagnostic studies. Clinical data and biological samples of NA patients were collected within 90 days from disease onset between June 2018 and December 2023. All NA patients were asked about prior infection and vaccination in the month before disease onset. Serological tests for hepatitis E virus, human immunodeficiency virus, severe acute respiratory syndrome coronavirus 2, Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella-zoster virus, Borrelia burgdorferi, Mycoplasma pneumoniae and Bartonella henselae were performed in a central laboratory. Each case was matched with a healthy control for age, sex, place of residence and time of blood collection. Fifty-seven patients and corresponding controls were included. The mean age was 45 years for both groups. NA onset was preceded by a symptomatic infectious trigger confirmed by microbiological tests in 15/57 (26.3%) patients. Coronavirus disease 2019 vaccination was considered a potential trigger in 7/57 (12.3%) subjects. An acute viral infection was associated with a bilateral involvement of the brachial plexus (p = 0.003, Cramèr's V = 0.43). Confirmed immune triggers (infection or vaccination) preceded disease onset in 22/57 (38.6%) NA cases. We suggest to test NA patients in the acute phase for intracellular antigens, especially in the case of concomitant bilateral involvement and hepatitis.

Impact of Epstein-Barr Virus Nuclear Antigen 1 on Neuroinflammation in PARK2 Knockout Mice.

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.

Epstein–Barr virus flare: A multiple sclerosis attack

Epstein–Barr virus flare: A multiple sclerosis attack

Epidemiological characteristics of three herpesviruses infections in children in Nanjing, China, from 2018 to 2023.

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. 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. 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. 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.

Course and outcome of pregnancy in a woman with Epstein-Barr virus infection: clinical case

Epstein-Barr virus, due to the variety of clinical forms and transmission routes, is widespread throughout the world. The mechanisms of immunopathogenesis of infection caused by Epstein-Barr virus remain incompletely understood. The management of pregnant women with this infection requires special attention. The clinical case described in the article demonstrates the clear course of Epstein-Barr virus infection and the complications resulting from it.

Exploring genetic and immune cell dynamics in systemic lupus erythematosus patients with Epstein-Barr virus infection via machine learning.

Epstein-Barr Virus (EBV) is a widespread virus implicated in various diseases, including Systemic Lupus Erythematosus (SLE). However, the specific genes and pathways altered in SLE patients with EBV infection remain unclear. We aimed to identify key genes and immune cells in SLE patients with EBV infection. The datasets of SLE (GSE50772 and GSE81622) or EBV infection (GSE85599 and GSE45918) were obtained from the Gene Expression Omnibus (GEO) database. Next, differential gene expression (DEGs) analysis were conducted to identify overlapping DEGs and then enrichment analysis was performed. Machine learning was applied to identify key genes. Validation was conducted using ROC curve analysis and expression level verification in test datasets and single-cell RNA sequencing. Immune cell infiltration patterns were analyzed using CIBERSORTx, and clinical data were reviewed for SLE patients. We identified 58 overlapping DEGs enriched in interferon-related pathways. Five overlapping DEGs (IFI27, TXK, RAPGEF6, PIK3IP1, PSENEN) were selected as key genes by machine learning algorithms, with IFI27 showing the highest diagnostic performance. The expression level of IFI27 was found higher in CD4 CTL, CD8 naïve and various B cell subsets of SLE patients with EBV infection. IFI27 showed significant correlation with B intermediate and CD4 CT. Clinical data showed lower CD4 T cell proportions in SLE patients with EBV infection. This study identifies IFI27 as a key gene for SLE patients with EBV infection, influencing CD4 CTL and B cell subtypes. These findings enhance the understanding of the molecular mechanisms linking SLE and EBV infection, providing potential targets for diagnostic and therapeutic strategies.

Identification of High-Incidence Populations in the United States for anti-Epstein Barr Virus Serologic Screening for Nasopharyngeal Carcinoma.

In the United States (US), Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) disproportionately impacts Asian Americans (AA) and Native Hawaiians and other Pacific Islanders (NHPI) who have no access to screening. EBV-based screening trials in Asia have detected most cases at early stages. We sought to identify a US target population for NPC screening and hypothesized that once-lifetime screening could be cost-effective. We obtained NPC incidence data from the SEER Asian and Pacific Islander datasets. We estimated the number needed to screen, mortality reduction, and resource utilization using a validated model and performance data from trials. Six evaluated strategies incorporated serology, nasopharyngeal swab PCR, and endoscopy or MRI. Intermediate-incidence and high-incidence populations accounted for 10.7% of US person-years yet 42.7% of cases. Anti-BNLF2b screening with selective endoscopy was the preferred strategy. In high-incidence populations, the median NNS to detect one case was 1,992, with a median of 7.12 NPC deaths averted per 100,000 screened. Screening met the willingness-to-pay threshold in all five high-incidence populations (median ICER/GDP 0.82) and among men in intermediate-incidence populations. Nearly half of NPC in the US arises among the 10% with AA or NHPI ethnicity. A suitable target population for US screening trials would be men and women age 35-65 of Chinese, Sāmoan, or Southeast Asian ethnicity, or men age 35-60 of Guamanian/Chamorro, Filipino, or Native Hawaiian ethnicity. Once-lifetime anti-BNLF2b screening could be cost-effective. These data may aid the design of US screening trials. Targeted NPC screening might mitigate health disparities.

B-100 Utilization and Performance of Monospot and Epstein-Barr Virus Antibody Profile Testing for Diagnosis of Infectious Mononucleosis in Adolescents and Adults

Abstract Background Epstein-Barr virus (EBV) antibody profile, which includes IgM and IgG antibodies against EBV viral capsid antigen (VCA), IgG antibodies against early antigen (EA) and nuclear antigen (EBNA), is recommended by the CDC for diagnosing infectious mononucleosis (IM) and differentiating acute versus past infection. Conversely, the monospot test, which detects reactive heterophile antibodies, is not recommended by the CDC due to its low sensitivity in young children and non-specific nature. However, monospot tests remain widely used, especially as point-of-care testing at emergency department visits, likely related to their technical ease, rapid turnaround, and low cost. In this study, we compared the utilization and performance of the monospot test and EBV profile for the diagnosis of primary IM in adolescent and adult patients. Methods A retrospective review was conducted on consecutive monospot tests (Acceava Mono Cassette, Abbott) and EBV profiles (multiplex assay on Bioplex analyzer, Bio-Rad) performed between August 16, 2020, and August 15, 2021 in our hospital system. Cases with concurrent monospot and EBV profile testing were evaluated for qualitative agreement between the two methods. A chart review was conducted for cases with discrepant results between monospot and EBV antibody profile tests to assess the performance of these two methods. The final EBV infection status for each case was determined by clinical manifestation, relevant lab findings, and EBV profile results. Results A total of 1,524 monospot tests were performed, with an overall positive rate of 12.4%. The majority of tests were from the emergency departments (ED, 47.5%) and outpatient settings (48.7%), with inpatient tests comprising 3.8%. Notably, the positive rate was highest among outpatients (13.4%), followed by ED patients (12.3%), and lowest among inpatients (1.5%). In contrast, 3,769 EBV profile tests were performed, yielding an overall VCA IgM positive rate of 11.8% and 2.9% equivocal cases. Outpatient settings accounted for the majority of EBV profile tests (81.5%), followed by inpatients (16.2%) and ED patients (2.3%). Inpatients also exhibited a lower positive rate (7.5%) than ED (13.1%) or outpatients (13.1%). Among 364 cases concurrently tested by both the mono spot and the EBV profile, the negative agreement between the two tests was 97.7%, while the positive agreement was 52.8%. Discrepancies included 8 monospot-positive but VCA IgM-negative cases and 58 VCA IgM-positive but monospot-negative cases. Chart review revealed that monospot and EBV profiles missed 4 and 40 cases of primary IM, respectively. Additionally, 7 cases of past EBV infection exhibited prolonged VCA IgM positivity, and 2 cases of VCA IgM were falsely positive, likely due to cross-reaction with cytomegalovirus or B. burgdorferi IgM. Sensitivity/specificity for EBV profile and monospot were 96.4%/97.4% and 64.0%/100.0%, respectively. Conclusions The EBV profile demonstrates high sensitivity and specificity and is suitable as the primary test for diagnosing IM. While the monospot test exhibits good specificity, its lower sensitivity necessitates further testing with the EBV profile, particularly for patients with a high suspicion of IM, to avoid missed diagnoses.

A-276 Unraveling Pathogen Dynamics In Pediatric Meningitis Complications During The Omicron Variant Outbreak In Taiwan

Abstract Background Taiwan, once celebrated for its remarkable control over COVID-19, faced an unexpected surge in pediatric cases during the first wave of the omicron variant in April 2022. Alarming data revealed acute encephalitis emerging in half of the severe or fatal COVID-19 cases in children within the initial two months of the omicron epidemic. This study delves into the intricate microbiota patterns and viral pathogens contributing to encephalitis complications in affected children. Methods The study enrolled 36 pediatric patients, comprising 11 patients with severe encephalitis, 12 patients with mild encephalitis, and 13 normal controls. Nasal swabs were collected for pathogen detection. For respiratory microbiota analysis, 16S rRNA metagenomic sequencing was employed, while the Illumina Respiratory Pathogen ID/AMR Enrichment Panel was used for respiratory pathogen identification. Results Microbiota analysis of nasal swabs from COVID-19 pediatric patients with meningitis complications revealed prevalent Corynebacterium, Staphylococcus, Dolosigranulum, Acinetobacter, Moraxella, and Streptococcus. Conversely. No predominant bacterial species were detected in the normal control group. Nasal swab respiratory pathogen detection identified coinfections, particularly Herpesviridae viruses such as human herpesvirus 6, Epstein-Barr virus, and Cytomegalovirus in pediatric patients with meningitis complications. Notably, two severe encephalitis cases exhibited coinfections involving rhinovirus, SARS-CoV-2, and Herpesviridae viruses (HHV-6, EBV). In one fatal case, distribution of Streptococcus genes among total geneomes reaches 40.69%, 7 drug resistant genes were detected. Conclusions This study suggests a potential link between latent Herpesviridae virus coinfections (HHV-6, CMV, EBV) and meningitis complications in pediatric patients. Furthermore, the presence of a secondary respiratory virus (rhinovirus) coinfection appears to be associated with severe complications. These findings shed light on the complex pathogen dynamics contributing to the emergence of encephalitis in pediatric COVID-19 cases during the omicron variant outbreak in Taiwan.

Explore genetic susceptibility association between viral infections and Guillain-Barré syndrome risk using two-sample Mendelian randomization

BackgroundNumerous observational studies have indicated that patients with Guillain-Barré syndrome (GBS) frequently had infections with various pathogens before the onset of the disease, particularly several viral infections. Some of these infections are linked to specific clinical and immunological subgroups of GBS, suggesting a potential correlation between viral infections and the development of GBS. However, observational studies have several limitations, including the presence of confounding factors.MethodWe explored the potential correlation between HIV, SARS-CoV-2, varicella-zoster virus, herpes simplex virus, Epstein-Barr virus, hepatitis B virus, and influenza virus with GBS using a two-sample Mendelian randomization approach. The data was derived from published summary statistics from genome-wide association studies (GWAS). After removing linkage disequilibrium, selecting strong instrumental variables and addressing confounding factors, we would conduct a two-sample Mendelian randomization analysis along with sensitivity testing and the MR-Steiger directional test.ResultHIV may have a causal association with GBS (IVW: p = 0.010, OR [95% CI] 1.240 [1.052–1.463]), while no such relationship exists with COVID-19 (IVW: p = 0.275, OR [95% CI] 0.831[0.596–1.159]), varicella (IVW: p = 0.543, OR [95% CI] 0.919 [0.701–1.206]), herpes zoster (IVW: p = 0.563, OR [95% CI] 0.941 [0.766–1.156]), HSV (IVW: p = 0.280, OR [95% CI] 1.244 [0.837–1.851]), EBV (IVW: p = 0.218, OR [95% CI] 0.883 [0.724–1.076]), HBV (IVW: p = 0.179, OR [95% CI] 1.072 [0.969–1.187]), or influenza virus (IVW: p = 0.917, OR [95% CI] 0.971 [0.553–1.703]). We did not find any abnormal SNPs, pleiotropy, or heterogeneity, nor is there any reverse causation.ConclusionOur study results indicate a causal relationship between HIV and GBS, providing new research directions for the etiology of GBS.

A-156 Comparison of blast and variant lymphocyte flagging between the Alinity hq from Abbott and XN-1000 from Sysmex

Abstract Background Blast cells are immature white blood cells (WBC). The presence of blasts in the peripheral blood may be associated with certain diseases such as myelodysplastic syndrome and acute myelogenous leukemia. Variant lymphocytes (i.e., reactive lymphocytes, atypical lymphocytes) are WBCs produced by the immune system in reaction to infections caused by pathogens such as Epstein-Barr virus, cytomegalovirus, etc. It is clinically useful that the automated hematology analyzer is capable of flagging these cells. In this study, the blast (shown as ‘BLAST’ on the Alinity hq and ‘Blast/Abn Lympho?’ or ‘Blast?’ on XN-1000) and variant lymphocyte (shown as ‘VAR LYM’ on the Alinity hq, and ‘Atypical Lympho?’ on XN-1000) flagging was compared between the Alinity hq from Abbott and XN-1000 from Sysmex. Alinity hq has different sensitivity settings available for BLAST and VAR LYM flagging. In this study, the default setting for Alinity hq was used. For XN-1000, the Q-Flag default setting is 100. In this study, the setting was 120 for ‘Blast/Abn Lympho’ and 100 for “Atypical lympho?’. Methods Blood specimens were tested on the Alinity hq and XN-1000 analyzers. Two smears per specimen were made manually or by the Alinity hs slide maker stainer and read by two independent readers. The specimens showing any of the following flagging were included in the analysis: ‘BLAST’ on Alinity hq, ‘VAR LYM’ on Alinity hq, ‘Blast/Abn Lympho?’ or ‘Blast?’ on XN-1000, ‘Atypical lympho?’ on XN-1000. The flagging reports of these samples from both analyzers were compared to the smear review to determine if each analyzer's blast and variant lymphocyte flagging were true positive, false positive, true negative, or false negative. Results A total of 520 specimens were tested, yielding 41 specimens for blast flagging analysis and 80 specimens for variant lymphocyte flagging analysis. Due to the scarce availability of true positive samples from the manual review, true positive and false negative rate were not compared. For blast flagging using smear results of &amp;gt;=1% or &amp;gt;=5% as the positive criterion, Alinity hq yielded a 9.8% (=4/41) false positive rate and 87.8% (=36/41) true negative rate. XN-1000 yielded a 75.6% (=31/41) false positive rate and 22.0% (=9/41) true negative rate. For variant lymphocyte flagging using smear results of &amp;gt;=5% as the positive criterion, Alinity hq yielded a 6.3% (=5/80) false positive rate and 92.5% (=74/80) true negative rate. XN-1000 yielded a 91.3% (=73/80) false positive rate and 7.5% (=6/80) true negative rate. Conclusions This study demonstrated that Alinity hq achieved a much lower false positive rate and much higher true negative rate for both blast and variant lymphocyte flagging when compared to the XN-1000. Manual blast and variant lymphocyte morphology classification is laboratory- and technician-dependent. Both analyzers allow different sensitivity/specificity levels to flag blasts and variant lymphocytes. Each individual laboratory should evaluate and choose the setting that is most suitable for their specific patient populations to obtain the desired flagging rate.

Comparison of long-term quality of life and their predictors in survivors between paediatric and adult nasopharyngeal carcinoma in the intensity-modulated radiotherapy era

BackgroundTo compare the differences in long-term quality of life (QoL) between survivors of paediatric and adult patients with nasopharyngeal carcinoma (NPC) and assess the clinical factors that predict long-term QoL.MethodsWe enrolled 420 long-term NPC survivors who were alive for at least 8 years after treatment, including 195 paediatric and 225 adult patients diagnosed and treated with intensity-modulated radiotherapy (IMRT) at Sun Yat-sen University Cancer Centre (SYSUCC) between 2011 and 2015. Data on clinical factors and EORTC QLQ-C30 were collected from all participants. The QoL of paediatric and adult NPC survivors was compared.ResultsThe paediatric group had significantly better outcomes in global health status (paediatric: 80.2 ± 12.7; adult: 77.2 ± 11.5; P = 0.027), physical function (paediatric: 98.5 ± 4.6; adult: 95.1 ± 7.0; P < 0.001), role function (paediatric: 97.0 ± 9.2; adult: 90.5 ± 15.2; P < 0.001), social function (paediatric: 96.0 ± 8.9; adult: 93.5 ± 11.8; P = 0.038), insomnia (paediatric: 1.9 ± 7.8; adult: 13.1 ± 22.3; P < 0.001), constipation (paediatric: 1.3 ± 7.5; adult: 8.0 ± 17.4; P < 0.001), diarrhea (paediatric: 0.7 ± 4.6; adult: 2.8 ± 9.3; P = 0.010), and financial difficulties (paediatric: 1.9 ± 7.8; adult: 11.0 ± 19.8; P < 0.001), but poorer cognitive function (paediatric: 88.3 ± 9.9; adult: 93.8 ± 12.6; P < 0.001) than the adult group. Pretreatment clinical factors, including T stage, N stage, and pre-treatment EBV (Epstein-Barr Virus) DNA, showed a strong association with QoL. However, the factors that affected the QoL outcomes differed between the two groups. In survivors of paediatric cancer, global health status/QoL was strongly correlated with T stage (P < 0.001) and clinical stage (P = 0.018), whereas it was strongly correlated with pre-treatment EBV DNA (P = 0.008) in adults.ConclusionPaediatric survivors of NPC have a significantly better QoL than adult NPC survivors. Moreover, pre-treatment T stage, N stage, and EBV DNA significantly influenced the overall health status of the survivors. These results highlight the need to tailor care to both age groups to promote better long-term health outcomes.

Regulation of R-Loops in DNA Tumor Viruses.

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.

EIF4A3 is stabilized by the long noncoding RNA BC200 to regulate gene expression during Epstein-Barr virus infection.

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.

EBV infection alters DNA methylation in primary human colon cells: A path to inflammation and carcinogenesis?

Epstein-Barr Virus (EBV) is associated with several types of human cancers, and changes in DNA methylation are reported to contribute to viral-driven carcinogenesis, particularly in cancers of epithelial origin. In a previous study, we demonstrated that EBV infects human primary colonic cells (HCoEpC) and replicates within these cells, leading to pro-inflammatory and pro-tumorigenic effects. Notably, these effects were mostly prevented by inhibiting viral replication with PAA. Interestingly, the EBV-induced effects correlated with the upregulation of DNMT1 and were counteracted by pretreating cells with 5-AZA, suggesting a role for DNA hypermethylation.Building on this background, the current study investigates the methylation changes induced by EBV infection in HCoEpC, both in the presence and absence of PAA, or ERK1/2 and STAT3 inhibitors, pathways known to be activated by EBV and involved in the dysregulation of methylation in tumor cells. The genome-wide methylation analysis conducted in this study allowed us to identify several biological processes and genes affected by these epigenetic changes, providing insights into the possible underlying mechanisms leading to the pathological effects induced by EBV. Specifically, we found that the virus induced significant methylation changes, with hypermethylation being more prevalent than hypomethylation. Several genes involved in embryogenesis, carcinogenesis, and inflammation were affected.

Human papillomavirus (HPV) and Epstein-Barr virus (EBV) in Penile Cancer in Thailand.

Human papillomavirus (HPV) and Epstein-Barr virus (EBV) are important etiological factors for several cancers. This study aimed to determine the prevalence of HPV and EBV infection in penile cancer. Forty-three formalin-fixed paraffin-embedded penile cancer tissue samples were analyzed for the HPV-induced p16INK4A protein by immunohistochemistry and Epstein-Barr encoding region in situ hybridization. Demographic data and overall survival were analyzed. The median age of patients was 59 years, ranging from 23 to 91 years old. Most of the tumors (86%) were located at the tip of the penis. HPV infection was positive in 12/43 (27.9%) patients. EBV infection was observed in 2/43 (4.6%) of cases and there was no co-infection detected in this cohort. Patients who had p16INK4A overexpression had a trend toward longer survival compared to those without; the median survival time of 104.4 vs 89 months, the hazard ratio of 0.48 (95% CI: 0.16-1.42, p = 0.173). One-third of penile cancer patients were positive for HPV-induced p16INK4A expression and there was a trend toward better survival in HPV-positive patients. EBV infection was infrequent in penile cancer in Thailand.

Analysis of the epidemiology and clinical characteristics of Epstein-Barr virus infection.

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.

Structure‐based design of antibodies targeting the EBNA1 DNA‐binding domain to block Epstein–Barr virus latent infection and tumor growth

AbstractThe Epstein–Barr virus (EBV) nuclear antigen 1 (EBNA1) is critically involved in maintaining episomes during latent infection and promoting tumorigenesis. The development of an epitope‐specific monoclonal antibody (mAb) for EBNA1 holds great promise due to its high affinity and specificity, offering a new and innovative approach for the treatment of EBV‐related diseases. In this proof‐of‐concept study, we employed a structure‐based design strategy to create three unique immunogens specifically targeting the DNA binding state of the EBNA1 DBD. By immunizing mice, we successfully generated a mAb, named 5E2‐12, which selectively targets the DNA binding interface of EBNA1. The 5E2‐12 mAb effectively disrupts the interaction between EBNA1 and DNA binding, resulting in reduced proliferation of EBV‐positive cells and inhibition of xenograft tumor growth in both cellular assays and mouse tumor models. These findings open up new avenues for the development of innovative biological macromolecular drugs that specifically target EBNA1 and provide potential for clinical therapy options for early‐stage EBV‐positive tumors. The epitope‐specific mAb approach demonstrates novelty and innovation in tackling EBV‐related diseases and may have broad implications for precision medicine strategies in the field of viral‐associated cancers.

XMEN-associated Systemic EBV-positive T-cell Lymphoma of Childhood: Report of Two Cases and Literature Review.

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) is an extremely rare inborn error of immunity (IEI) caused by X-linked recessive inheritance and loss-of-function mutations in the MAGT1 gene, resulting in magnesium ion channel defects. This article reports 2 cases of systemic EBV-positive T-cell Lymphoma of childhood (SETLC) associated with XMEN, which have not been reported before. Whole exome sequencing (WES) in their family revealed previously unreported MAGT1 gene mutations (c.77T>C, p.I26T; c.956-957del: p.Ser319Tyrfs) inherited from their mothers. These mutations expand the spectrum of gene mutations in XMEN disease. The importance of genetic testing for MAGT1 mutations in the initial diagnosis of SETLC was emphasized. We also review the literature on this uncommon IEI.