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Introduction: Many patients report neuropsychiatric symptoms after SARS‐CoV‐2 infection. Data on prevalence of post‐COVID‐19 condition (PCC) vary due to the lack of specific diagnostic criteria, the report of unspecific symptoms, and reliable biomarkers. Methods: PCC patients seen in a neurological outpatient department were followed for up to 18 months. Neurological examination, SARS‐CoV‐2 antibodies, Epstein–Barr virus antibodies, and cortisol levels as possible biomarkers, questionnaires to evaluate neuropsychiatric symptoms and somatization (Patient Health Questionnaires D [PHQ‐D]), cognition deficits (Montreal Cognitive Assessment [MoCA]), sleep disorders (ISS, Epworth Sleepiness Scale [ESS]), and fatigue (FSS) were included. Results: A total of 175 consecutive patients (78% females, median age 42 years) were seen between May 2021 and February 2023. Fatigue, subjective stress intolerance, and subjective cognitive deficits were the most common symptoms. Specific scores were positive for fatigue, insomnia, and sleepiness and were present in 95%, 62.1%, and 44.0%, respectively. Cognitive deficits were found in 2.3%. Signs of somatization were identified in 61%, who also had an average of two symptoms more than patients without somatization. Overall, 28% had a psychiatric disorder, including depression and anxiety. At the second visit (n = 92), fatigue (67.3%) and insomnia (45.5%) had decreased. At visit three (n = 43), symptom load had decreased in 76.8%; overall, 51.2% of patients were symptom‐free. Biomarker testing did not confirm an anti‐EBV response. SARS‐CoV‐2‐specific immune reactions increased over time, and cortisol levels were within the physiological range. Conclusion: Despite high initial symptom load, 76.8% improved over time. The prevalence of somatization and psychiatric disorders was high. Our data do not confirm the role of previously suggested biomarkers in PCC patients. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are equipped with anti-Epstein-Barr virus (EBV) function, however, whether EBV infection will affect NK cells reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. To identify the characteristics of NK cells, we prospectively enrolled 11 patients who occurred EBV reactivation post allo-HSCT and 11 patients without EBV infection as control. We found that that EBV infection induced the expansion of CD56bright and NKG2A+KIR− NK subsets,and decreased the cytotoxicity function of NK cells. The frequency of NKG2A+KIR- NK cells were higher in patients who progressed into post-transplant lymphoproliferative disorder (PTLD) than EBV viremia patients, which also correlated with decreased proliferation and cytotoxic function. By screening the activation receptors of NK cells, we found the DNAM-1+CD56bright NK cells is significantly increased after EBV stimulation, further we demonstrated that DNAM-1 is essential for EBV induced NK cells activation as the cytokine release against EBV-transformed lymphoblastoid cell lines(EBV-LCLs) of CD56bright NK cells were significantly decreased after DNAM-1 blockade. NK cells infusion suppressed the progression of EBV-related tumor mice model. A prospective cohort indicated that old donor age was an independent risk factor for EBV infection. Rapid CD56bri expansion and high expression of DNAM-1 on CD56bri NK cells in response to EBV reactivation correlated with rapid EBV clearance post allo-HSCT in patients with younger donors. In summary, our data showed that high expression of DNAM-1 receptors on NK cell may participate protective CD56bri NK cells response to EBV infection after allo-HSCT. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Many patients report neuropsychiatric symptoms after SARS‐CoV‐2 infection. Data on prevalence of post‐COVID‐19 condition (PCC) vary due to the lack of specific diagnostic criteria, the report of unspecific symptoms, and reliable biomarkers. Methods PCC patients seen in a neurological outpatient department were followed for up to 18 months. Neurological examination, SARS‐CoV‐2 antibodies, Epstein–Barr virus antibodies, and cortisol levels as possible biomarkers, questionnaires to evaluate neuropsychiatric symptoms and somatization (Patient Health Questionnaires D [PHQ‐D]), cognition deficits (Montreal Cognitive Assessment [MoCA]), sleep disorders (ISS, Epworth Sleepiness Scale [ESS]), and fatigue (FSS) were included. Results A total of 175 consecutive patients (78% females, median age 42 years) were seen between May 2021 and February 2023. Fatigue, subjective stress intolerance, and subjective cognitive deficits were the most common symptoms. Specific scores were positive for fatigue, insomnia, and sleepiness and were present in 95%, 62.1%, and 44.0%, respectively. Cognitive deficits were found in 2.3%. Signs of somatization were identified in 61%, who also had an average of two symptoms more than patients without somatization. Overall, 28% had a psychiatric disorder, including depression and anxiety. At the second visit (n = 92), fatigue (67.3%) and insomnia (45.5%) had decreased. At visit three (n = 43), symptom load had decreased in 76.8%; overall, 51.2% of patients were symptom‐free. Biomarker testing did not confirm an anti‐EBV response. SARS‐CoV‐2‐specific immune reactions increased over time, and cortisol levels were within the physiological range. Conclusion Despite high initial symptom load, 76.8% improved over time. The prevalence of somatization and psychiatric disorders was high. Our data do not confirm the role of previously suggested biomarkers in PCC patients.

Purpose of Review: Epstein-Barr Virus (EBV) is a ubiquitous herpesvirus that affects almost all humans and establishes lifelong infections by infecting B-lymphocytes leading to their immortalization. EBV has a discrete life cycle with latency and lytic reactivation phases. EBV can reactivate and cause lymphoproliferation in both immunocompetent and immunocompromised individuals. There is sparse literature on monitoring protocols for EBV reactivation and no standardized treatment protocols to treat EBV-driven lymphoproliferation. Recent Findings: While there are no FDA-approved therapies to treat EBV, there are several strategies to inhibit EBV replication. These include immunosuppression reduction, nucleoside analogs, HDAC inhibitors, EBV-specific cytotoxic T-lymphocytes (CTLs), and monoclonal antibodies, such as rituximab. There is currently an open clinic trial combining the use of a HDAC inhibitor, nanatinostat, and ganciclovir to treat refractory/relapsed EBV lymphomas. Another novel therapy includes tabelecleucel, which is an allogenic EBV-directed T-cell immunotherapy that was approved by the European Medicines Agency, but is currently only available in the US for limited use in relapsed or refractory EBV-positive PTLD. Summary: Further research is needed to establish EBV monitoring protocols in high-risk populations, such as those with autoimmune disease, cancer, HIV, or receiving immunosuppressive therapy. Additionally, standardized treatments for both the prevention of EBV reactivation in high-risk populations and treatment of EBV reactivation and lymphoproliferation need to be established. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disease (PTLD) is a fatal complication of hematopoietic cell transplantation (HCT) associated with the Epstein–Barr virus (EBV). Multiple factors such as transplant type, graft-versus-host disease (GVHD), human leukocyte antigens (HLA) mismatch, patient age, and T-lymphocyte-depleting treatments increase the risk of PTLD. EBV reactivation in hematopoietic cell transplant recipients is monitored through periodic quantitative polymerase chain reaction (Q-PCR) tests. However, substantial uncertainty persists regarding the clinically significant EBV levels for these patients. Guidelines recommend initiating EBV monitoring no later than four weeks post-HCT and conducting it weekly. Pre-emptive therapies, such as the reduction of immunosuppressive therapy and the administration of rituximab to treat EBV viral loads are also suggested. In this study, we investigated the occurrence of EBV-PTLD in 546 HCT recipients, focusing on the clinical manifestations and risk factors associated with the disease. We managed to identify 67,150 viral genomic copies/mL as the cutoff point for predicting PTLD, with 80% sensitivity and specificity. Among our cohort, only 1% of the patients presented PTLD. Anti-thymocyte globulin (ATG) and GVHD were independently associated with lower survival rates and higher treatment-related mortality. According to our findings, prophylactic measures including regular monitoring, pre-emptive therapy, and supportive treatment against infections can be effective in preventing EBV-related complications. This study also recommends conducting EBV monitoring at regular intervals, initiating pre-emptive therapy when viral load increases, and identifying factors that increase the risk of PTLD. Our study stresses the importance of frequent and careful follow-ups of post-transplant complications and early intervention in order to improve survival rates and reduce mortality. [ABSTRACT FROM AUTHOR]

Although Epstein–Barr virus (EBV) reactivation has long been associated with the pathogenesis of systemic lupus erythematosus (SLE), many aspects of this relationship remain unclear. Our objective was to investigate the association between EBV reactivation and the achievement of SLE remission and lupus low disease activity state (LLDAS) over a six-month period. Clinical, laboratory, and virological tests (anti-EBV antibodies and EBV DNA) were performed among 51 patients with the active form of SLE on two occasions six months apart. SLE remission and LLDAS achievement were assessed at the end of the follow-up period. Active EBV infection was detected in 45% of active SLE patients at baseline, and 77% transitioned to latent EBV infection at six months (p < 0.001). Multivariate regression revealed a higher titer of anti-EA(D) IgM-Abs and the presence of anti-EA(D) IgM-Abs as independent predictors of remission and LLDAS in SLE patients with mucocutaneous manifestations (p = 0.042) and rash only (p = 0.023), respectively. Since a higher C3 level was an independent predictor of transition to latent EBV infection (p = 0.027), the estimated cut-off value that could identify active SLE patients who will transition to latent EBV infection after six months was ≥0.780 g/L with a sensitivity of 70.6% and a specificity of 75.0% (AUC = 0.756, p = 0.003). EBV reactivation is common in patients with active SLE, and most of them transition to latent EBV infection after six months. Achieving remission and LLDAS in SLE patients with mucocutaneous manifestations can be predicted by a higher titer, whereas in SLE patients who have only a rash, the presence of anti-EA (D) IgM-Abs was a predictor of remission and LLDAS. [ABSTRACT FROM AUTHOR]

We probed the lifecycle of Epstein‐Barr virus (EBV) on a cell‐by‐cell basis using single cell RNA sequencing (scRNA‐seq) data from nine publicly available lymphoblastoid cell lines (LCLs). While the majority of LCLs comprised cells containing EBV in the latent phase, two other clusters of cells were clearly evident and were distinguished by distinct expression of host and viral genes. Notably, both were high expressors of EBV LMP1/BNLF2 and BZLF1 compared to another cluster that expressed neither gene. The two novel clusters differed from each other in their expression of EBV lytic genes, including glycoprotein gene GP350. The first cluster, comprising GP350–LMP1hi cells, expressed high levels of HIF1A and was transcriptionally regulated by HIF1‐α. Treatment of LCLs with Pevonedistat, a drug that enhances HIF1‐α signaling, markedly induced this cluster. The second cluster, containing GP350+LMP1hi cells, expressed EBV lytic genes. Host genes that are controlled by super‐enhancers (SEs), such as transcription factors MYC and IRF4, had the lowest expression in this cluster. Functionally, the expression of genes regulated by MYC and IRF4 in GP350+LMP1hi cells were lower compared to other cells. Indeed, induction of EBV lytic reactivation in EBV+ AKATA reduced the expression of these SE‐regulated genes. Furthermore, CRISPR‐mediated perturbation of the MYC or IRF4 SEs in LCLs induced the lytic EBV gene expression, suggesting that host SEs and/or SE target genes are required for maintenance of EBV latency. Collectively, our study revealed EBV‐associated heterogeneity among LCLs that may have functional consequence on host and viral biology. [ABSTRACT FROM AUTHOR]

This study aims to investigate the effect of Epstein-Barr virus (EBV) reactivation or EBV reactivation with dexamethasone (DXM) in patients with adverse drug reactions (ADRs) through evaluating the levels of monocyte, macrophage M2/M1, and cytokines, and investigating whether expression of EBV receptor EphA2 could specifically influence EBV activation in ADRs. We performed a prospective longitudinal study to analyze the monocytes, macrophages, M2/M1 ratio, and cytokines, including interleukin (IL)-4, IL-13, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IFN-β, C-X-C motif chemokine ligand (CXCL)9, and CXCL10, in patients with maculopapular exanthema (MPE) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and control groups after disease onset. Skin biopsy samples from these patients were subjected to hematoxylin and eosin (H&E) staining to examine tissue architecture and inflammatory cell infiltration, as well as Epstein-Barr virus-encoded RNA (EBER) staining to detect the presence of EBV within the skin lesions. Peripheral blood mononuclear cells collected from these patients were co-cultured with EBV or EBV combined with DXM to assess the impact on monocytes, macrophages, the M2/M1 ratio, and the associated cytokine profile. Furthermore, we sought to identify which cytokines might be crucial in mediating the interaction between the M2/M1 ratio and EBV. EPhA2 expression was evaluated to determine its role in the reactivation of EBV and its correlation with increased viral load in MPE and SJS/TEN patients. Selective depletion of macrophages occurred during the acute stage of SJS/TEN, while a shift towards M2 macrophages was observed in MPE. Both IFN-β and CXCL9 levels were elevated in MPE and SJS/TEN. Additionally, our study demonstrated the presence of EBV in the skin lesions of SJS/TEN and MPE patients through H&E and EBER staining, confirming EBV's involvement in these conditions. Activation of EBV and EBV combined with DXM led to a shift from M1 to M2 macrophages, accompanied by increased levels of IL-4, IFN-γ, and CXCL9 in MPE and SJS/TEN, compared to healthy individuals. Specifically, EBV combined with DXM primarily drove IFN-γ and IL-4 expansions in MPE, while CXCL9 was predominantly elevated in SJS/TEN. The increased IL-4 levels were associated with the relative rise in EBV viral loads after EBV combined with DXM stimulation. Furthermore, EphA2 expression in monocytes was significantly higher in SJS/TEN and MPE patients compared to controls, with further increases on EBV stimulation. This elevation in EPhA2 correlated with increased EBV viral load, particularly in MPE and SJS/TEN patients. The gradual shift from M1 to M2 cell development observed during the clinical course of MPE and SJS/TEN is mediated by the predominance of EBV and EBV with DXM at the acute stage, leading to elevated IL-4, IFN-γ, and CXCL9 levels, which may exacerbate allergic reactions. The elevation in EPhA2 correlated with increased EBV viral load, particularly in MPE and SJS/TEN patients, suggesting that adverse drug reactions may induce EPhA2 expression, facilitating EBV replication and activation. EphA2 could thus serve as an indicator of EBV activation and a marker for assessing the risk of EBV in patients with adverse drug reactions., (© 2024 Japanese Dermatological Association.)

Objectives: Epstein-Barr virus (EBV) causes different clinical presentations in immunocompetent and immunocompromised persons, and thus indications for testing vary between these populations. We reviewed our institution's EBV DNA testing across these populations to understand its clinical utility and appropriateness., Methods: We conducted a retrospective chart review of adult patients with positive EBV nucleic acid amplification (NAAT) testing from November 2022 to 2023. We recorded demographics, indications for testing, EBV-related diagnosis, laboratory results, and whether testing influenced patient treatment., Results: Of 3560 EBV NAAT tests, 187 (5.3%) were positive, representing 124 unique adult patients (51 immunocompetent and 73 immunocompromised). Reactivation of EBV was the most common diagnosis in both populations, followed by acute EBV infection in the immunocompetent and non-posttransplant lymphoproliferative disorder malignancies in the immunocompromised. In immunocompromised patients, positive tests led to treatment changes more frequently than in immunocompetent patients (27.4% vs 11.7%, P = .06). Testing affected clinical management in 0% to 2% of cases when sent for sepsis/shock and nonspecific viral syndromes compared to 37% to 49% of cases when sent for posttransplant and malignancy screening/monitoring., Discussion: EBV NAAT testing infrequently influenced clinical management in immunocompetent individuals but had a notable impact in immunocompromised patients, particularly those undergoing posttransplant or malignancy screening. This underscores the need for targeted testing to optimize resource utilization and cost-effectiveness., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background Epstein-Barr virus (EBV) reactivation from latent to lytic infection has been considered as a key step in nasopharyngeal carcinoma oncogenesis. However, epidemiological evidence regarding environmental risk factors for EBV reactivation on a population level remains largely lacking. Methods We enrolled 1916 randomly selected adults from the general population of Guangdong and Guangxi, China, from 2010 to 2014. Information on environmental factors was collected via a structured interview. Serum immunoglobulin A antibodies against EBV viral capsid antigen and nuclear antigen 1 were measured by enzyme-linked immunosorbent assay to evaluate EBV reactivation status. We used logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the associations of EBV reactivation with various environmental factors. Results No associations were observed between EBV reactivation and extensive environmental factors, including alcohol or tea drinking, a history of chronic ear/nose/throat diseases, use of medications or herbs, consumption of salted fish or preserved foods, oral hygiene, sibship structure, and various residential and occupational exposures. Only cigarette smoking was associated with EBV reactivation (current smokers vs never smokers; OR = 1.37; 95% CI = 1.02–1.83), with positive exposure-response trends with increasing intensity, duration, and pack-years of smoking. Conclusions Consistent with previous studies, we found an association between cigarette smoking and EBV reactivation. Other examined exposures were not associated with EBV reactivation. These null results could suggest either more complex interactions between exposures and EBV reactivation or a predominant role of host and/or viral genetic variation. [ABSTRACT FROM AUTHOR]

Background: Systemic reactivation of Epstein–Barr virus (EBV) may occur in novel coronavirus disease 2019 (COVID‐19) caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). However, the clinical consequences of EBV reactivation remain uncertain. Methods: In this retrospective study, we screened 1314 patients with confirmed COVID‐19 who died or were discharged between January 1, 2020 and March 12, 2020, in Wuhan Infectious Disease Hospital, Wuhan, China. Patients who had complete data for EBV serology and cytomegalovirus (CMV) serology were eligible. Serum levels of viral capsid antigen (VCA)‐immunoglobulin G (IgG), Epstein–Barr nuclear antigen‐IgG, VCA‐IgM, early antigen (EA)‐IgG, CMV‐IgG, and CMV‐IgM were compared between survivors and nonsurvivors. Dynamic changes of laboratory tests and outcomes were compared in patients with and without ganciclovir treatment. We used 1:1 matching based on age, gender, and illness severity to balance baseline characteristics. Results: EBV reactivation was present in 55 of 217 patients. EBV reactivation was associated with age (57.91 [13.19] vs. 50.28 [12.66] years, p <.001), female gender (31 [56%] vs. 60 [37%], p =.02). Patients with EBV reactivation have statistically nonsignificant higher mortality rate (12 [22%] vs. 18 [11%], p =.08). EA‐IgG levels were significantly higher in nonsurvivors than in survivors (median difference: −0.00005, 95% confidence interval, CI [−3.10, 0.00], p =.05). As compared to patients with COVID‐19 who did not receive ganciclovir therapy, ganciclovir‐treated patients had improved survival rate (0.98, 95% CI [0.95, 1.00] vs. 0.88, 95% CI [0.81, 0.95], p =.01). Hemoglobin (p <.001) and prealbumin (p =.02) levels were significantly higher in ganciclovir‐treated patients. Conclusion: A high proportion of COVID‐19 patients had EBV reactivation that may be associated with an increased risk of death. Whether treatment with ganciclovir may decrease the mortality of COVID‐19 patients complicated with EBV reactivation warrants to be addressed in a placebo‐controlled randomized trial in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic reactivation of Epstein–Barr virus (EBV) may occur in novel coronavirus disease 2019 (COVID‐19) caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). However, the clinical consequences of EBV reactivation remain uncertain. Methods In this retrospective study, we screened 1314 patients with confirmed COVID‐19 who died or were discharged between January 1, 2020 and March 12, 2020, in Wuhan Infectious Disease Hospital, Wuhan, China. Patients who had complete data for EBV serology and cytomegalovirus (CMV) serology were eligible. Serum levels of viral capsid antigen (VCA)‐immunoglobulin G (IgG), Epstein–Barr nuclear antigen‐IgG, VCA‐IgM, early antigen (EA)‐IgG, CMV‐IgG, and CMV‐IgM were compared between survivors and nonsurvivors. Dynamic changes of laboratory tests and outcomes were compared in patients with and without ganciclovir treatment. We used 1:1 matching based on age, gender, and illness severity to balance baseline characteristics. Results EBV reactivation was present in 55 of 217 patients. EBV reactivation was associated with age (57.91 [13.19] vs. 50.28 [12.66] years, p

SARS-CoV-2 infection causes COVID-19, ranging from mild to critical disease in symptomatic subjects. It is essential to better understand the immunologic responses occurring in patients with the most severe outcomes. In this study, parameters related to the humoral immune response elicited against SARS-CoV-2 were analysed in 61 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centres in Madrid, Spain, during the first pandemic peak between April and June 2020. Subjects were allocated as mild patients without hospitalization, severe patients hospitalized or critical patients requiring ICU assistance. Critical patients showed significantly enhanced levels of B cells with memory and plasmablast phenotypes, as well as higher levels of antibodies against SARS-CoV-2 with neutralization ability, which were particularly increased in male gender. Despite all this, antibody-dependent cell-mediated cytotoxicity was defective in these individuals. Besides, patients with critical COVID-19 also showed increased IgG levels against herpesvirus such as CMV, EBV, HSV-1 and VZV, as well as detectable CMV and EBV viremia in plasma. Altogether, these results suggest an enhanced but ineffectual immune response in patients with critical COVID-19 that allowed latent herpesvirus reactivation. These findings should be considered during the clinical management of these patients due to the potential contribution to the most severe disease during SARS-CoV-2 infection.

SARS-CoV-2 infection causes COVID-19, ranging from mild to critical disease in symptomatic subjects. It is essential to better understand the immunologic responses occurring in patients with the most severe outcomes. In this study, parameters related to the humoral immune response elicited against SARS-CoV-2 were analysed in 61 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centres in Madrid, Spain, during the first pandemic peak between April and June 2020. Subjects were allocated as mild patients without hospitalization, severe patients hospitalized or critical patients requiring ICU assistance. Critical patients showed significantly enhanced levels of B cells with memory and plasmablast phenotypes, as well as higher levels of antibodies against SARS-CoV-2 with neutralization ability, which were particularly increased in male gender. Despite all this, antibody-dependent cell-mediated cytotoxicity was defective in these individuals. Besides, patients with critical COVID-19 also showed increased IgG levels against herpesvirus such as CMV, EBV, HSV-1 and VZV, as well as detectable CMV and EBV viremia in plasma. Altogether, these results suggest an enhanced but ineffectual immune response in patients with critical COVID-19 that allowed latent herpesvirus reactivation. These findings should be considered during the clinical management of these patients due to the potential contribution to the most severe disease during SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Abstract Background The Epstein-Barr virus (EBV) is closely associated with several types of malignancies. EBV is normally present in the latent state in the peripheral blood B cell compartment. The EBV latent-to-lytic switch is required for virus spread and virus-induced carinogenesis. Immunosuppression or DNA damage can induce the reactivation of EBV replication. EBV alone is rarely sufficient to cause cancer. In this study, we investigated the roles of host microRNAs and environmental factors, such as DNA-damage agents, in EBV reactivation and its association with lymphomagenesis. Methods We first analyzed the publicly available microRNA array data containing 45 diffuse large B-cell lymphoma patients and 10 control lymph nodes or B cells with or without EBV infection. In situ hybridization for miR-18a and immunohistochemitry were performed to evaluate the correlation between the expression of miR-18a and nuclear EBV protein EBNA1 in lymphoid neoplasm. The proliferative effects of miR-18a were investigated in EBV-positive or –negative lymphoid neoplasm cell lines. EBV viral load was measured by a quantitative real-time EBV PCR and FISH assay. The genomic instability was evaluated by CGH-array. Results In this study, we analyzed the publicly available microRNA array data and observed that the expression of the miR-17-92 cluster was associated with EBV status. In situ hybridization for miR-18a, which is a member of the miR-17-92 cluster, showed a significant upregulation in lymphoma samples. miR-18a, which shares the homolog sequence with EBV-encoded BART-5, promoted the proliferation of lymphoma cells in an EBV status-dependent manner. The DNA-damaging agent UV or hypoxia stress induced EBV activation, and miR-18a contributed to DNA damaging-induced EBV reactivation. In contrast to the promoting effect of ATM on the lytic EBV reactivation in normoxia, ATM inhibited lytic EBV gene expression and decreased the EBV viral load in the prescence of hypoxia-induced DNA damage. miR-18a reactivated EBV through inhibiting the ATM-mediated DNA damage response (DDR) and caused genomic instability. Conclusions Taken together, these results indicate that DNA-damaging agents and host microRNAs play roles in EBV reactivation. Our study supported the interplay between host cell DDR, environmental genotoxic stress and EBV.

Purpose: Anti-VCA IgM is a marker for establishing primary infection with Epstein-Barr Virus (EBV), it usually appears in combination with anti-VCA IgG. It has been shown that there is a risk of non-specific IgM reactivity due to cross-reactions, interference with rheumatoid factor or autoantibodies. These antibodies may also occur during reactivation. In these cases, Immunoblot based tests may be useful to confirm the ELISA result. We compared the results of anti-VCA IgM in ELISA and Immunoblot IgM in patients with evidence of primary EBV infection (infectious mononucleosis, IM) and/or reactivation/reinfection. Materials/Methods: We examined 32 serum samples with commercial immunoblot (Euroline Anti-EBV Profile 2 (IgM), Euroimmun, Germany). Samples were tested primarily for anti-VCA IgM/IgG in ELISA. Patients with IM were 11, and those with probable reactivation/reinfection - 21. Results: We found positive results at 31.3% (95% CI: 16.1% -50.0 %, n = 10) of all subjects. Patients with IM and isolated anti-VCA IgM in ELISA (81.8%) were negative in Immunoblot IgM. Positive in Immunoblot IgM was 38.1% (n = 8) of the patients with suspected reactivation. We confirmed a primary infection in three of them due to the low avidity of anti-VCA IgG and missing anti-EBNA1 IgG. In five of the patients, the presence of anti-VCA IgM may be interpreted as reactivation/reinfection. Conclusion: Patients with IM and isolated anti-VCA IgM models in ELISA were not confirmed in the Immunoblot test. Approximately 43% of patients of possible reactivation was also negative in the test.

High levels of IL-10 expression in Epstein-Barr virus (EBV) associated tumors have been reported and it is likely to be important for maintaining EBV latency and EBV-associated tumors. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. Here, we found that knockdown of IL-10 induced EBV lytic replication. Subsequently, we demonstrated that IL-10 knockdown activated BZLF1 promoter through PI3K-p38 MAPK-NF-κB signaling pathway. Interestingly, we verified that VEGF-A was required for IL-10 knockdown to activate PI3K signaling and the accompanying EBV lytic induction. Exogenous recombinant human VEGF-A induced PI3K activation and EBV lytic infection, and inhibition of VEGF-A signaling prevented the PI3K/AKT phosphorylation and EBV reactivation responded to IL-10 knockdown. Most importantly, IL-10 knockdown synergized with chemotherapeutic agent Doxorubicin to kill EBV associated tumor cells in vitro and repress EBV-positive tumor growth in vivo. Our results suggest that inhibition of IL-10 has the potential to serve as a new supplemental strategy for the treatment of EBV-associated tumors. [ABSTRACT FROM AUTHOR]

This systematic review was undertaken to identify risk factors associated with post-transplant Epstein–Barr virus (EBV) active infection and post-transplant lymphoproliferative disease (PTLD) in pediatric and adult recipients of hematopoietic stem cell transplants (HSCT). A literature search was conducted in PubMed and EMBASE to identify studies published until 30 June 2020. Descriptive information was extracted for each individual study, and data were compiled for individual risk factors, including, when possible, relative risks with 95% confidence intervals and/or p-values. Meta-analyses were planned when possible. The methodological quality and potential for bias of included studies were also evaluated. Of the 3362 titles retrieved, 77 were included (62 for EBV infection and 22 for PTLD). The overall quality of the studies was strong. Several risk factors were explored in these studies, but few statistically significant associations were identified. The use of anti-thymocyte globulin (ATG) was identified as the most important risk factor positively associated with post-transplant active EBV infection and with PTLD. The pooled relative risks obtained using the random-effect model were 5.26 (95% CI: 2.92–9.45) and 4.17 (95% CI: 2.61–6.68) for the association between ATG and post-transplant EBV infection and PTLD, respectively. Other risk factors for EBV and PTLD were found in the included studies, such as graft-versus-host disease, type of conditioning regimen or type of donor, but results are conflicting. In conclusion, the results of this systematic review indicate that ATG increases the risk of EBV infection and PTLD, but the link with all other factors is either nonexistent or much less convincing.

Primary gastrointestinal plasmablastic lymphoma (GI-PBL) is a rare variant of diffuse B-cell lymphoma with an aggressive clinical course. PBL was initially reported among HIV-positive patients; however, subsequent studies have shown that it also occurs among HIV-negative patients. Its clinical characteristics remain poorly understood. This study aims to retrospectively analyze the clinicopathological findings of primary GI-PBLs in HIV-negative patients. Primary HIV-negative GI-PBL cases from 2008 to 2022 were reviewed. Clinicopathologic features and outcomes were analyzed. The cohort of 13 patients had a male-to-female ratio of 9:1 (3 patients' genders not available), with an average age of 61 (range, 30–92) years. The most involved location was the colon (n = 7 [53.8 %]), followed by the small bowel (n = 3 [23.1 %]), stomach (n = 2 [15.4 %]), rectum (n = 1 [7.7 %]), and anus (n = 1 [7.7 %]). Most patients (n = 10 [77 %]) showed isolated GI tract involvement. Eight patients had chronic inflammatory and/or immunocompromised status, including 4 with inflammatory bowel disease (all of whom underwent treatment), 3 with post–organ transplant status, and 1 with irritable bowel syndrome. All cases exhibited cytokeratin-/CD20-/PAX-5-/CD138+ and/or MUM1+ immunophenotype. Based on available data, 8 of 11 (72.7 %) patients had Epstein-Barr virus reactivation. Among 11 patients with follow-up data, the mean follow-up duration was 13.5 (range, 3–40) months; at the end of follow-up, 45.5 % of patients (5 of 11 patients) showed complete remission after chemotherapy. Primary HIV-negative GI-PBL occurs predominantly in the colon of relatively elderly males with immunosuppression. Its clinical course can be heterogenous, presenting a comorbidity with inflammatory bowel disease or post–organ transplantation status. • HIV(−) GI-PBL often occurs in relatively elderly patients with a male predominance. • HIV(−) GI-PBL mainly involves the colon and can be isolated. • HIV(−) GI-PBL patients are frequently in immunocompromised status. • Inflammatory bowel disease may be an important risk factor for developing GI-PBL in HIV(−) patients. • HIV(−) GI-PBL shows characteristic immunophenotypes: positive for CD138 and MUM1 and negative for CD20 and PAX5 [ABSTRACT FROM AUTHOR]

Background: The Epstein-Barr virus (EBV) is closely associated with several types of malignancies. EBV is normally present in the latent state in the peripheral blood B cell compartment. The EBV latent-to-lytic switch is required for virus spread and virus-induced carinogenesis. Immunosuppression or DNA damage can induce the reactivation of EBV replication. EBV alone is rarely sufficient to cause cancer. In this study, we investigated the roles of host microRNAs and environmental factors, such as DNA-damage agents, in EBV reactivation and its association with lymphomagenesis.Methods: We first analyzed the publicly available microRNA array data containing 45 diffuse large B-cell lymphoma patients and 10 control lymph nodes or B cells with or without EBV infection. In situ hybridization for miR-18a and immunohistochemitry were performed to evaluate the correlation between the expression of miR-18a and nuclear EBV protein EBNA1 in lymphoid neoplasm. The proliferative effects of miR-18a were investigated in EBV-positive or -negative lymphoid neoplasm cell lines. EBV viral load was measured by a quantitative real-time EBV PCR and FISH assay. The genomic instability was evaluated by CGH-array.Results: In this study, we analyzed the publicly available microRNA array data and observed that the expression of the miR-17-92 cluster was associated with EBV status. In situ hybridization for miR-18a, which is a member of the miR-17-92 cluster, showed a significant upregulation in lymphoma samples. miR-18a, which shares the homolog sequence with EBV-encoded BART-5, promoted the proliferation of lymphoma cells in an EBV status-dependent manner. The DNA-damaging agent UV or hypoxia stress induced EBV activation, and miR-18a contributed to DNA damaging-induced EBV reactivation. In contrast to the promoting effect of ATM on the lytic EBV reactivation in normoxia, ATM inhibited lytic EBV gene expression and decreased the EBV viral load in the prescence of hypoxia-induced DNA damage. miR-18a reactivated EBV through inhibiting the ATM-mediated DNA damage response (DDR) and caused genomic instability.Conclusions: Taken together, these results indicate that DNA-damaging agents and host microRNAs play roles in EBV reactivation. Our study supported the interplay between host cell DDR, environmental genotoxic stress and EBV. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is a gamma-herpesvirus persisting mainly in human B lymphocytes. EBV reactivation induces host cells to differentiate into plasma cells and is related to autoimmune diseases. Graves’ disease, an autoimmune hyperthyroidism, is caused by the thyrotropin receptor antibody (TRAb), which overstimulates thyroid stimulating hormone receptor. The disease occurs predominantly in women, which suggests involvement with estrogen. Graves’ disease patients and healthy controls have EBV-infected lymphocytes with TRAb on the surface (TRAb(+)EBV(+) cells) in peripheral blood mononuclear cells (PBMCs). TRAb can be produced by reactivation of EBV in vitro, which is an alternative system of antibody production. In this study, we cultured PBMCs from Graves’ disease patients and healthy controls with 0, 1, and 100 nM estradiol, corresponding to control, midluteal, and pregnancy levels, respectively, and analyzed the levels of TRAb, total-IgG, and total-IgM during EBV reactivation. We found that 1 nM estradiol increased TRAb levels and 100 nM estradiol slightly lowered them in both patients and controls. In patients, IgM production at 100 nM estradiol was significantly lower than that at 0 nM estradiol (p = 0.028). Estradiol increased the ratio of IgG production to immunoglobulin G (IgG) and immunoglobulin M (IgM) production (IgG/IgG + IgM), which suggested an increase in class switch recombination in the process of EBV reactivation-induced Ig production. Moreover, TRAb production was stimulated by a midluteal level of estradiol and was suppressed by a pregnancy level of estradiol in controls and patients. These results were consistent with premenstrual worsening and maternity improving of autoimmune diseases, including Graves’ disease. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV), a human herpesvirus, is linked to both epithelial and lymphoid malignancies. Induction of EBV reactivation is a potential therapeutic strategy for EBV-associated tumors. In this study, we assessed the effects of rapamycin on EBV reactivation in gastric carcinoma cells. We found that rapamycin upregulated expression of EBV lytic proteins and increased the viral proliferation triggered by the EBV lytic inducer sodium butyrate. Reverse transcription-qPCR, luciferase activity assays, chromatin immunoprecipitation and western blotting were employed to explore the mechanism by which rapamycin promotes EBV reactivation. Our results showed that rapamycin treatment resulted in increased mRNA levels of EBV immediate-early genes. Rapamycin also enhanced the transcriptional activities of the EBV immediate-early lytic promoters Zp and Rp by strengthening Sp1 binding. Repression of the cellular ataxia telangiectasia-mutated/p53 pathway by siRNA-mediated knockdown of the ataxia telangiectasia-mutated gene significantly abrogated virus reactivation by rapamycin/sodium butyrate treatment, indicating that the ataxia telangiectasia-mutated/p53 pathway is involved in rapamycin-promoted EBV reactivation. Taken together, these findings demonstrate that rapamycin might have the potential to enhance the effectiveness of oncolytic viral therapies developed for EBV-associated malignancies. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is a highly prevalent human herpesvirus that persists for life in more than 95% of the adult population. EBV usually establishes an asymptomatic life-long infection, but it is also associated with malignancies affecting B lymphocytes and epithelial cells mainly. The virus alternates between a latent phase and a lytic phase, both of which contribute to the initiation of the tumor process. So far, there is only a limited number of antiviral molecules against the lytic phase, most of them targeting viral replication. Recent studies provided evidence that EBV uses components of the NLRP3 inflammasome to enter the productive phase of its cycle following activation in response to various stimuli. In the present work, we demonstrate that shikonin, a natural molecule with low toxicity which is known to inhibit inflammasome, can efficiently repress EBV reactivation. Similar results were obtained with apigenin and OLT 1177, two other NLRP3 inflammasome inhibitors. It is shown herein that shikonin repressed the transcription of reactivation-induced NLRP3 thereby inhibiting inflammasome activation and EBV lytic phase induction. • Shikonin suppresses the reactivation of the Epstein-Barr virus (EBV). • Shikonin inhibits immediate early and early proteins expression. • Shikonin inhibits NLRP3 expression. • Shikonin could be evaluated in diseases in which EBV reactivation is involved. [ABSTRACT FROM AUTHOR]

• Hypertension was associated with an increased risk of Epstein-Barr virus (EBV) reactivation in high-incidence areas of nasopharyngeal carcinoma (NPC). • The administration of β-adrenergic receptor-blocking agents (β-blockers) and angiotensin converting enzyme inhibitors (ACEIs) were associated with reduced risks of EBV reactivation. • The present study might provide a potential for NPC prevention and other EBV reactivation-related disease in endemic areas. Hypertension may increase the infection risk of multiple viruses. The evidence for the association between hypertension and Epstein-Barr virus (EBV) reactivation is still largely lacking. The study was based on the baseline information of a population-based prospective cohort from high-risk areas of nasopharyngeal carcinoma (NPC). Using two EBV reactivation classification criteria, we explored the relationship between hypertension and EBV reactivation through logistic regression models. We included a total of 12,159 subjects. Among them, 3,945 (32.45%) were EBV arbitrary seropositive, and 1,547 (12.72%) were EBV comprehensive seropositive. Hypertension was associated with an increased risk of EBV reactivation, with odds ratios (ORs) of 1.17 (95% CI = 1.08–1.27) for EBV arbitrary seropositive subjects and 1.16 (95% CI = 1.03–1.30) for EBV comprehensive seropositive subjects. Two types of antihypertensive drugs were associated with decreased risk of EBV reactivation: β-adrenergic receptor-blocking agents (β-blockers) (OR = 0.51, 95% CI = 0.42–0.61 for EBV arbitrary seropositive subjects; OR = 0.62, 95% CI = 0.47–0.81 for EBV comprehensive seropositive subjects) and angiotensin converting enzyme inhibitors (ACEIs) (OR = 0.61, 95% CI = 0.41–0.88 for EBV arbitrary seropositive subjects; OR = 0.58, 95% CI = 0.32–0.98 for EBV comprehensive seropositive subjects). Hypertension was associated with an increased risk of EBV reactivation in high-incidence areas of NPC. β-blockers and ACEIs reduce this risk, and thus might be used for NPC prevention in endemic areas. [ABSTRACT FROM AUTHOR]

Steroid-refractory graft-versus-host disease (SR-GVHD) is a challenging complication of allogeneic hematopoietic stem cell transplantation, and leads to high morbidity and mortality rates. The orally administered, selective Janus-associated kinase 1/2 inhibitor ruxolitinib gives overall response rates (ORR) of more than 70 % in acute and chronic SR-GVHD. However, several studies have highlighted an elevated risk of cytomegalovirus (CMV) reactivation in patients with ruxolitinib-treated SR-GVHD. We therefore analyzed risk of CMV and Epstein-Barr virus (EBV) primary infection or reactivation in 57 patients with ruxolitinib-treated GVHD, while taking account of the competing risk (CR) of death prior to the first reactivation. Initiation of ruxolitinib treatment was a significant adverse prognostic factor for the CR of first CMV reactivation (hazard ratio (HR)= 1.747, 95 % confidence interval (CI): 1.33–2.92, p < 0.0001) and first EBV reactivation (HR=2.657, 95 % CI: 1.82–3.87, p < 0.0001) during GVHD. In our cohort of ruxolitinib-treated patients, the ORR (48 % and 58 % for acute and chronic GVHD, respectively) and the toxicity profile (haematological adverse events in 29.8 % of the patients) were similar to the literature values. Given ruxolitinib's efficacy in SR-GVHD, use of this drug should not be limited by the fear of viral reactivation; however, our present results emphasize the importance of monitoring the viral load. • Elevated risk of CMV reactivation in ruxolitinib-treated patients with SR-GVHD. • All CMV reactivations occurred in the first 2 months after ruxolitinib initiation. • EBV was usually reactivated in the first 5 months. • Ruxolitinib initiation was an adverse prognostic factor for first CMV reactivation. • Ruxolitinib initiation was an adverse prognostic factor for the first EBV reactivation. [ABSTRACT FROM AUTHOR]

Immune reconstitution was studied prospectively in 86 children who underwent allogeneic haematopoietic stem cell transplantation (HSCT). We analysed the risk of cytomegalovirus (CMV) and Epstein- Barr virus (EBV) reactivation in correlation with the kinetics of immune recovery and in relation to other potential risk factors that may influence the reactivation of these viruses including: diagnosis, type of HSCT, source of stem cells, type of conditioning, or the occurrence of graft-versus-host disease (GvHD). The absolute number of lymphocyte subpopulations in peripheral blood was evaluated in seven timepoints following HSCT. Significantly lower values of both CD3+ and CD3+CD8+ lymphocytes on day +14 and significantly higher values of both these subsets on day +168 post-transplant in patients with CMV reactivation were observed. Significantly lower values of CD3+CD4+ subpopulation were noted in patients with CMV reactivation on day +28 post allo-HSCT. Significantly lower lymphocyte values in the group with EBV reactivation comparing with the group without EBV reactivation were confirmed only in the case of pan-B lymphocytes (CD19+) subpopulation on day +21, +28, and +84 post allo-HSCT. We identified the impact of CMV reactivation on occurrence of the intestinal acute GvHD, which occurred more frequently in the group with CMV reactivation compared with patients without reactivation. Higher incidence of chronic GvHD was also observed in patients with CMV reactivation compared to the group without reactivation. EBV reactivation occurred more frequently in patients receiving transplants from matched unrelated donors, in particular after peripheral blood stem cell transplantation and while implementing antithymocyte globulin as GvHD prophylaxis [ABSTRACT FROM AUTHOR]

Background: Romidepsin, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of relapsed and refractory peripheral T-cell lymphoma. However, the efficacy and safety of romidepsin has never been studied in patients with relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma (ENKTL). Patients and methods: We conducted an open-label, prospective pilot study to evaluate the efficacy and feasibility of romidepsin in the treatment of patients with ENKTL. The treatment was intravenous infusion of romidepsin (14 mg/m2) for 4 h on days 1, 8, and 15 of a 28-day cycle, and was repeated until disease progression or the occurrence of unacceptable toxicity. Results: A total of five patients enrolled on to this pilot study. However, three patients developed fever and elevated liver enzyme and bilirubin levels immediately after their first administration of romidepsin. We suspected that these events were associated with Epstein-Barr virus (EBV) reactivation because of the rapidly elevated EBV DNA titers in blood from these patients. An in vitro study with the ENKTL cell line SNK-6 cells also showed that HDAC inhibitors including romidepsin increased the copy number of EBV DNA in a dose-dependent manner. These findings suggested that romidepsin-induced histone acetylation reversed the repressed state of the genes required for EBV reactivation and that romidepsin treatment may have caused EBV reactivation in EBV-infected tumor cells in ENKTL patients. Therefore, we discontinued the enrollment of patients into this pilot study. Conclusions: Our study suggests that the use of romidepsin may cause severe EBV reactivation in patients with ENKTL. [ABSTRACT FROM AUTHOR]

Twenty-four whole blood and serum samples were drawn from an eight year-old heart transplant child during a 36 months follow-up. EBV serology was positive for VCA-IgM and IgG, and negative for EBNA-IgG at the age of five years old when the child presented with signs and symptoms suggestive of acute infectious mononucleosis. After 14 months, serological parameters were: positive VCA-IgG, EBNA-IgG and negative VCA-IgM. This serological pattern has been maintained since then even during episodes suggestive of EBV reactivation. PCR amplified a specific DNA fragment from the EBV gp220 (detection limit of 100 viral copies). All twenty-four whole blood samples yielded positive results by PCR, while 12 out of 24 serum samples were positive. We aimed at analyzing whether detection of EBV-DNA in serum samples by PCR was associated with overt disease as stated by the need of antiviral treatment and hospitalization. Statistical analysis showed agreement between the two parameters evidenced by the Kappa test (value 0.750; p < 0.001). We concluded that detection of EBV-DNA in serum samples of immunosuppressed patients might be used as a laboratory marker of active EBV disease when a Real-Time PCR or another quantitative method is not available.Vinte e quatro amostras de sangue total e de soro foram colhidas durante seguimento por 36 meses de criança de oito anos de idade, imunodeprimida devido a transplante cardíaco. O paciente apresentou VCA-IgG e IgM positivos e EBNA-IgG negativo aos cinco anos de idade quando foi diagnosticada mononucleose infecciosa. Quatorze meses depois o VCA-IgG e o EBNA-IgG eram positivos e o VCA-IgM negativo. Este padrão sorológico persiste desde aquela época mesmo durante episódios sugestivos de reativação. As amostras de sangue total e de soro foram analisadas pela Reação em Cadeia da Polimerase (PCR) que amplificou fragmento oriundo da gp220 do EBV (detecção de 100 cópias virais). Todas as 24 amostras de sangue total e 12 amostras de soro foram positivas por PCR. Com o objetivo de verificar se a detecção de DNA do EBV em soro estaria associada à reativação da doença, os resultados de PCR foram analisados em relação à necessidade de hospitalização e uso de anti-viral. O teste de Kappa mostrou que existe concordância entre a presença de DNA do EBV em soro e a necessidade de hospitalização e tratamento com anti-virais (valor de 0,750; p < 0,001). Concluímos que a detecção de DNA do EBV em amostras de soro de pacientes imunosuprimidos poderia ser usada como marcador laboratorial de atividade da infecção quando técnicas quantitativas de amplificação não estiverem disponíveis.

Purpose: Rabbit antithymocyte globulin (ATG) is commonly used before allogeneic hematopoietic stem cell transplantation (allo-HSCT) to prevent graft-versus-host disease. Studies comparing the effect of different ATG preparations and dosages on immune reconstitution and risk for Epstein-Barr virus (EBV)-mediated post-transplant lymphoproliferative disorder (PTLD) are rare. Methods: In this retrospective study, we determined T and B cell subsets by flow cytometry after allo-HSCT in children, who received ATG-Genzyme (ATG-G, n = 15), ATG-Fresenius (ATG-F, n = 25) or no-ATG treatment ( n = 19). Additionally, PCR-quantified EBV-genome copy counts were correlated with incidence of PTLD. Results: We could confirm a dose-dependent impairment of CD8 and CD4 T cell regeneration by ATG-G, including naïve and memory CD4 T cells. No differences were seen between the currently applied dosages of 5-10 mg/kg ATG-G and 20-60 mg/kg ATG-F. Significantly delayed T cell subset reconstitution was determined only at high dosages of 20-60 mg/kg ATG-G compared to ATG-F. B cell reconstitution was comparably impaired in ATG-G- and ATG-F-treated patients. Although the incidence of EBV reactivation was similar in both ATG groups, EBV copy counts of >10 copies/10 peripheral blood mononuclear cells and the occurrence of PTLD were only found in ATG-G-treated patients. Conclusions: We conclude that high, but importantly not currently applied low dosages of ATG-G, impair thymic T cell regeneration and memory T cell immunity to a greater extent than ATG-F in pediatric patients. In addition, our results suggest an increased risk for EBV-PTLD when treated with ATG-G. Prospective studies are warranted to compare different ATG preparations with regard to the immune reconstitution and EBV-PTLD. [ABSTRACT FROM AUTHOR]

Background: Despite the use of combined antiretroviral therapy, HIV-infected individuals have a higher risk of developing B-cell lymphoma compared to the general population. We aim to explore whether lymphocyte activation, increase in Th1 response as well as markers of EBV reactivation, may precede lymphoma diagnosis. Methods: Thirteen cases and 26 controls matched on CD4 T-cell count and HIV plasma viral load were identified. Samples were collected 0 to 5 years prior to B-cell lymphoma diagnosis. Seven out of 13 (54 %) and 16/26 (61.5 %) of cases and controls were receiving antiretroviral therapy at the time of sampling, respectively. CD8 T-cell activation and Th1 cytokine concentrations were measured before lymphoma onset, together with IgG antibodies directed against viral capsid antigen (VCA) and serum levels of EBV DNA. Results: A higher level of CD8 T-cell activation was observed in patients developing lymphoma. Four out of seven Th1 cytokine serum concentrations were significantly higher in patients with lymphoma than in the control group: IL-2R, IL-12p40/70, IFN-γ-inducible protein 10 (IP-10) and monokine induced by IFN-γ (MIG). Anti-VCA IgG level were significantly higher in cases than in controls. Four cases (30 %) but no controls had detectable EBV DNA in serum. Conclusion: A higher level of T-cell activation, Th1 cytokine serum concentration and markers of EBV replication, preceded B-cell lymphoma diagnosis. This may suggest that viral antigen stimulation is associated with the genesis of lymphoma in HIV-infected patients. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV)-associated postallogeneic stem cell transplantation (SCT) lymphoproliferative disorder (PTLD) is often life threatening. The risk of EBV reactivation is highest in older patients, T cell-depleted SCT (in vivo or vitro), and in unrelated or mismatched SCT. Cumulative numbers of patients with EBV reactivation and PTLD are rising as more patients at high risk for EBV reactivation and PTLD are receiving allo-SCT. Novel but easily applicable strategies are needed to prevent EBV reactivation and PTLD to serve the needs of the increasingly enlarging population of high-risk SCT recipients across the globe. [Copyright &y& Elsevier]

Abstract: The critical step in the Epstein–Barr virus (EBV) transition from latency to lytic replication is activation of the viral immediate early (IE) genes, BZLF1 and BRLF1. Their induction in Burkitt''s lymphoma Akata cells is directly targeted by B cell receptor (BCR) signaling. On the other hand, BCR stimulation causes an outwardly directed superoxide (O2 •−) burst leading to massive generation of reactive oxygen species in the cell environment. Our goal was to investigate the role of BCR-related redox changes in the IE reactivation of EBV. Production of O2 •− by stimulated Akata cells was characterized using chemiluminescent dyes, lucigenin, MCLA, and coelenterazine. Expression of the EBV IE genes was analyzed by real-time PCR and Western blot assays. Catalase activity and H2O2 concentration were evaluated using Amplex Red assays and by measuring light absorption at 240 nm. We show here that elevation of H2O2 concentration in Akata cell suspensions inhibits the induction of the virus IE mRNA and BZLF1 protein. It was further found that Akata cells exhibit catalase-like activity that is stimulated by BCR cross-linking. The results reveal that H2O2 is instrumental in the maintenance of EBV latency. Altogether they provide new evidence demonstrating the essential role of H2O2 in BCR signaling. [Copyright &y& Elsevier]

EBV reactivation is a serious complication affecting the recipients of allogeneic haematopoietic stem cell transplants (allogeneic HSCT). Recent reports have suggested that EBV reactivation induces increased expression of C-C chemokine receptor-5 (CCR5) or its ligands. Therefore, the 32-nucleotide deletion within the CCR5-encoding gene (CCR5Δ32 polymorphism) was analysed in 92 recipients of allogeneic HSCT and their donors and related with EBV load. In addition in 30 patients, at the same time points employing a real-time PCR technique, the number of viral copies and CCR5 transcripts were assessed. The incidence of EBV reactivation 2–3 months after transplantation was significantly lower in patients carrying the CCR5Δ32 allele (P=0.008). The association was confirmed in multivariate analysis, in which recipient CCR5Δ32 (OR=0.166, P=0.026) in addition to recipient age (OR=1.536, P=0.034) were identified as independent risk factors for EBV reactivation. Moreover, EBV reactivation was more frequently seen when patients and their donors were lacking the CCR5 deletion mutation as compared to other donor–recipient pairs (P=0.022). The CCR5 expression was significantly higher in the group of patients having EBV reactivation than in those lacking it (R=25.354, P=0.024). These results suggest that the expression of functional CCR5 plays a role in initiation/perpetuation of EBV reactivation.Bone Marrow Transplantation (2007) 40, 145–150; doi:10.1038/sj.bmt.1705703; published online 28 May 2007 [ABSTRACT FROM AUTHOR]