Persistent Epstein-Barr Virus Research Articles

The nucleic acid binding protein SFPQ represses EBV lytic reactivation by promoting histone H1 expression.

Epstein-Barr virus (EBV) uses a biphasic lifecycle of latency and lytic reactivation to infect >95% of adults worldwide. Despite its central role in EBV persistence and oncogenesis, much remains unknown about how EBV latency is maintained. We used a human genome-wide CRISPR/Cas9 screen to identify that the nuclear protein SFPQ was critical for latency. SFPQ supported expression of linker histone H1, which stabilizes nucleosomes and regulates nuclear architecture, but has not been previously implicated in EBV gene regulation. H1 occupied latent EBV genomes, including the immediate early gene BZLF1 promoter. Upon reactivation, SFPQ was sequestered into sub-nuclear puncta, and EBV genomic H1 occupancy diminished. Enforced H1 expression blocked EBV reactivation upon SFPQ knockout, confirming it as necessary downstream of SFPQ. SFPQ knockout triggered reactivation of EBV in B and epithelial cells, as well as of Kaposi's sarcoma-associated herpesvirusin B cells, suggesting a conserved gamma-herpesvirus role. These findings highlight SFPQ as a major regulator of H1 expression and EBV latency.

Evaluation of the Epstein–Barr virus occurrence at the present stage (literature review)

The purpose of this article is to review and analyze the foreign and domestic scientific papers to assess the Epstein-Barr virus (EBV) occurrence in the human population. 
 A search of Russian and foreign publications in the PubMed and E-library databases was conducted. The high ecological and medical significance 
 of EBV-infection is due to its global spread in the human population, lifelong persistence of EBV in the human body. Evidence has been collected EBV to be involved in the development of various somatic pathologies, such as rheumatic diseases and vasculitis, chronic kidney disease, cardiovascular pathologies, pathologies of the gastrointestinal tract, T- and B-cell lymphomas in children and adults, nasopharyngeal carcinoma. These diseases are the main causes of population disability and premature death not only in Russia, but also in the World. The deterioration of the ecological and epidemic situation for 
 EBV-infection is associated with the other infectants spread that change the population immunological status. These include the human immunodeficiency virus, hepatitis B and C viruses, SARS-CoV-2, Mycobacterium tuberculosis. With the simultaneous persistence of these infectants, their synergistic or antagonistic effect on the human body occurs. In the modern World, the COVID-19 and the EBV-infection are simultaneously developing. It is difficult to say which infection is more significant in terms of medical, social. and economic losses of the human population. The EBV has been undeservedly given little attention. 
 It is necessary to optimize preventive measures and epidemic surveillance for EBV-infection.

X-Linked Lymphoproliferative Syndrome: A Spectrum of Clinical and Immunological Profile and Novel Pathogenic Variants from Chandigarh, India

Introduction: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2. Methods: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021. Results: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia. Discussion/Conclusions: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

Mechanisms of T cell evasion by Epstein-Barr virus and implications for tumor survival.

Epstein-Barr virus (EBV) is a prevalent oncogenic virus estimated to infect greater than 90% of the world's population. Following initial infection, it establishes latency in host B cells. EBV has developed a multitude of techniques to avoid detection by the host immune system and establish lifelong infection. T cells, as important contributors to cell-mediated immunity, make an attractive target for these immunoevasive strategies. Indeed, EBV has evolved numerous mechanisms to modulate T cell responses. For example, it can augment expression of programmed cell death ligand-1 (PD-L1), which inhibits T cell function, and downregulates the interferon response, which has a strong impact on T cell regulation. It also modulates interleukin secretion and can influence major histocompatibility complex (MHC) expression and presentation. In addition to facilitating persistent EBV infection, these immunoregulatory mechanisms have significant implications for evasion of the immune response by tumor cells. This review dissects the mechanisms through which EBV avoids detection by host T cells and discusses how these mechanisms play into tumor survival. It concludes with an overview of cancer treatments targeting T cells in the setting of EBV-associated malignancy.

Caebv Disease Originates from Infected Hematopoietic Stem Cells

Background Chronic active Epstein-Barr Virus (EBV) disease (CAEBV) is lethal syndrome due to persistent EBV infection. When diagnosed as CAEBV, EBV infection was observed in multiple hematopoietic lineages, but the etiology of CAEBV is still elusive. Methods Bone marrow and peripheral cells derived from five CAEBV patients, one EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patient, and two healthy controls were analyzed. Multiple assays were applied to identify and characterize EBV-infected cells, including quantitative PCR (qPCR), PrimeFlow and single-cell RNA-sequencing (scRNA-seq). Based on scRNA-seq data, alterations in gene expression of particular cell types were analyzed between CAEBV patients and controls, and between infected and uninfected cells. One CAEBV patient was treated with allogeneic hematopoietic stem cell transplantation (HSCT), and the samples derived from this patient were analyzed again six month after HSCT. Results EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, so as hematopoietic stem cells (HSCs) in the CAEBV patients. EBV-infected HSCs exhibited a higher differentiation rate towards downstream lineages, and the EBV infection had an impact on both the innate and adaptive immunity, resulting in inflammatory symptoms. EBV infected cells were thoroughly removed from the hematopoietic system after HSCT. Conclusions Token together,multiple lines of evidence presented in this study suggest that CAEBV disease originates from the infected hematopoietic stem cells. Figure 1. EBV-infected HSCs were detected in CAEBV patients with multiple assays.

Chronic active Epstein-Barr virus disease originates from infected hematopoietic stem cells

AbstractChronic active Epstein-Barr virus (EBV) disease (CAEBV) is a lethal syndrome because of persistent EBV infection. When diagnosed as CAEBV, EBV infection was observed in multiple hematopoietic lineages, but the etiology of CAEBV is still elusive. Bone marrow and peripheral cells derived from 5 patients with CAEBV, 1 patient with EBV-associated hemophagocytic lymphohistiocytosis, and 2 healthy controls were analyzed. Multiple assays were applied to identify and characterize EBV-infected cells, including quantitative polymerase chain reaction, PrimeFlow, and single-cell RNA-sequencing (scRNA-seq). Based on scRNA-seq data, alterations in gene expression of particular cell types were analyzed between patients with CAEBV and controls, and between infected and uninfected cells. One patient with CAEBV was treated with allogeneic hematopoietic stem cell transplantation (HSCT), and the samples derived from this patient were analyzed again 6 months after HSCT. EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, as well as the hematopoietic stem cells (HSCs) of the patients with CAEBV. EBV-infected HSCs exhibited a higher differentiation rate toward downstream lineages, and the EBV infection had an impact on both the innate and adaptive immunity, resulting in inflammatory symptoms. EBV-infected cells were thoroughly removed from the hematopoietic system after HSCT. Taken together, multiple lines of evidence presented in this study suggest that CAEBV disease originates from the infected HSCs, which might potentially lead to innovative therapy strategies for CAEBV.

EBV-induced T-cell responses in EBV-specific and nonspecific cancers.

Epstein-Barr virus (EBV) is a ubiquitous human tumor virus associated with various malignancies, including B-lymphoma, NK and T-lymphoma, and epithelial carcinoma. It infects B lymphocytes and epithelial cells within the oropharynx and establishes persistent infection in memory B cells. With a balanced virus-host interaction, most individuals carry EBV asymptomatically because of the lifelong surveillance by T cell immunity against EBV. A stable anti-EBV T cell repertoire is maintained in memory at high frequency in the blood throughout persistent EBV infection. Patients with impaired T cell immunity are more likely to develop life-threatening lymphoproliferative disorders, highlighting the critical role of T cells in achieving the EBV-host balance. Recent studies reveal that the EBV protein, LMP1, triggers robust T-cell responses against multiple tumor-associated antigens (TAAs) in B cells. Additionally, EBV-specific T cells have been identified in EBV-unrelated cancers, raising questions about their role in antitumor immunity. Herein, we summarize T-cell responses in EBV-related cancers, considering latency patterns, host immune status, and factors like human leukocyte antigen (HLA) susceptibility, which may affect immune outcomes. We discuss EBV-induced TAA-specific T cell responses and explore the potential roles of EBV-specific T cell subsets in tumor microenvironments. We also describe T-cell immunotherapy strategies that harness EBV antigens, ranging from EBV-specific T cells to T cell receptor-engineered T cells. Lastly, we discuss the involvement of γδ T-cells in EBV infection and associated diseases, aiming to elucidate the comprehensive interplay between EBV and T-cell immunity.

No Additional Risk of Ampicillin Rash Among Pediatric Liver Transplant Recipients With Concurrent Epstein-Barr Virus Infection.

Epstein-Barr virus (EBV) infection frequently develops in children undergoing liver transplantation (LT) because of mandated immunosuppressive therapy. There is a risk of ampicillin rash when penicillin derivatives are used in patients with EBV-associated infectious mononucleosis. Hence, the administration of penicillin derivatives may raise concerns about ampicillin rash in patients with high EBV loads. However, no studies confirmed the risk of administering penicillin derivatives to EBV-infected children after LT. This retrospective study was conducted at the largest pediatric transplantation center in Japan. We investigated all pediatric liver transplant recipients who received penicillin derivatives within 2 years of LT between 2014 and 2020. We separated the cohort into EBV-positive and EBV-negative groups to assess the frequency of ampicillin and antibiotic-associated rash. Two hundred eighty-six liver transplant recipients were enrolled. There were 111 recipients in the EBV-positive group and 175 recipients in the EBV-negative group. In the EBV-positive group, 49 patients had high EBV DNA loads (≥1000 copies/µg DNA). None of the patients in either group developed ampicillin rash, and the frequency of antibiotic-associated rash did not differ [8/111 (7.2%) vs. 10/175 (5.7%), P = 0.797]. Additional subgroup analysis revealed no difference in the frequency of antibiotic-associated rashes regardless of the presence or absence of high EBV loads. In this study, ampicillin rash was not observed, and antibiotic-associated rash was not associated with concurrent EBV infection. Penicillin derivatives can be used safely, even in liver transplant recipients with persistent asymptomatic EBV infection.

Effect of Malaria Infection on Epstein-Barr Virus Persistence in Kenyan Children.

The 2 cofactors in the etiology of Burkitt lymphoma (BL) are Epstein-Barr virus (EBV) and repeated Plasmodium falciparum malaria infections. This study evaluated EBV loads in mucosal and systemic compartments of children with malaria and controls. Age was analyzed as a covariate because immunity to malaria in endemic regions is age dependent. Children (2-10 years) with clinical malaria from Western Kenya and community controls without malaria were enrolled. Saliva and blood samples were collected, EBV viral load was assessed by quantitative polymerase chain reaction, and EpiTYPER MassARRAY was used to assess methylation of 3 different EBV genes. Regardless of the compartment, we detected EBV more frequently in malaria cases compared to controls, although the difference was not significant. When EBV was detected, there were no differences in viral load between cases and controls. However, EBV methylation was significantly lower in the malaria group compared to controls in both plasma and saliva (P < .05), indicating increased EBV lytic replication. In younger children before development of immunity to malaria, there was a significant effect of malaria on EBV load in peripheral blood mononuclear cells (P = .04). These data suggest that malaria can directly modulate EBV persistence in children, increasing their risk for BL.

Pathogenesis, treatment and prevention of diseases caused by Epstein–Barr virus

Studying diseases associated with viruses belonging to the family of Herpesviridae is an important challenge for medical researchers and clinicians because of the specific tropism of herpesviruses for immune cells, life-long persistence in human target cells, the ability to reactivate and the potential to cause a wide variety of clinical manifestations. Unlike other members of Herpesviridae, Epstein–Barr virus (EBV), also known as human herpes 4, displays tropism for B cells and mucosal epithelial cells, has the capacity to cause not only productive infection (infectious mononucleosis), but also establish various types of latency in cells, causes benign and malignant transformation of immune system cells (hemoblastoses) and mucosal epithelial cells (oral cavity cancer and gastric cancer). EBV causes 200 000 deaths worldwide every year, the majority of which are attributable to cancers associated with EBV persistence. Moreover, EBV is associated with a group of autoimmune disorders, such as multiple sclerosis, and secondary immunodeficiencies occurring in patients with infection of immune system cells. Mechanisms of the interaction between EBV and human cells implicated in cancer induction should be a focus of further research in fundamental virology, oncology and medicine as a whole. The interactions between EBV and target cells in mother-fetus-child system appear to be the most complicated. The inevitability of facing the virus and associated long-term consequences is determined by the time and mode of mother-to-child transmission of EBV, the presence of innate immune defense factors, genetics and molecular mechanisms of EBV latency. Recent scientific insights allow us to establish control over the evolution of EBV interactions with its host and to identify promising approaches to the prevention and treatment of previously incurable diseases associated with EBV.

Modification of the course of post-COVID syndrome associated with reactivation of chronic persistent Epstein−Barr virus infection and chronic nasopharyngotonsillitis of mixed etiology

A wide range of symptoms that occur in patients with post-COVID syndrome can include both manifestations of the clinical consequences of COVID-19 and symptoms of an exacerbation of a chronic pathology that they had before the development of coronavirus infection. Correct assessment of clinical data can help determine the origin of the existing manifestations of the disease and build a plan for adequate diagnostic and therapeutic measures.&#x0D; In the article, on the example of a clinical case, a variant of the modified (exacerbation of chronic pathology) course of the post-COVID syndrome was analyzed. An example of modern laboratory diagnostics of reactivation of chronic persistent EpsteinBarr virus infection and exacerbation of chronic nasopharyngotonsillitis of mixed viral-bacterial-mycotic etiology, developed against the background of post-COVID syndrome, is given. The principles of therapy for this comorbid condition are presented and explained.

Epstein-Barr Virus Envelope Glycoprotein gp110 Inhibits IKKi-Mediated Activation of NF-κB and Promotes the Degradation of β-Catenin.

Epstein-Barr virus (EBV) infects host cells and establishes a latent infection that requires evasion of host innate immunity. A variety of EBV-encoded proteins that manipulate the innate immune system have been reported, but whether other EBV proteins participate in this process is unclear. EBV-encoded envelope glycoprotein gp110 is a late protein involved in virus entry into target cells and enhancement of infectivity. Here, we reported that gp110 inhibits RIG-I-like receptor pathway-mediated promoter activity of interferon-β (IFN-β) as well as the transcription of downstream antiviral genes to promote viral proliferation. Mechanistically, gp110 interacts with the inhibitor of NF-κB kinase (IKKi) and restrains its K63-linked polyubiquitination, leading to attenuation of IKKi-mediated activation of NF-κB and repression of the phosphorylation and nuclear translocation of p65. Additionally, gp110 interacts with an important regulator of the Wnt signaling pathway, β-catenin, and induces its K48-linked polyubiquitination degradation via the proteasome system, resulting in the suppression of β-catenin-mediated IFN-β production. Taken together, these results suggest that gp110 is a negative regulator of antiviral immunity, revealing a novel mechanism of EBV immune evasion during lytic infection. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects almost all human beings, and the persistence of EBV in the host is largely due to immune escape mediated by its encoded products. Thus, elucidation of EBV's immune escape mechanisms will provide a new direction for the design of novel antiviral strategies and vaccine development. Here, we report that EBV-encoded gp110 serves as a novel viral immune evasion factor, which inhibits RIG-I-like receptor pathway-mediated interferon-β (IFN-β) production. Furthermore, we found that gp110 targeted two key proteins, inhibitor of NF-κB kinase (IKKi) and β-catenin, which mediate antiviral activity and the production of IFN-β. gp110 inhibited K63-linked polyubiquitination of IKKi and induced β-catenin degradation via the proteasome, resulting in decreased IFN-β production. In summary, our data provide new insights into the EBV-mediated immune evasion surveillance strategy.

Challenges to allogeneic hematopoietic stem cell transplantation in a patient with GATA2 deficiency and persistent Epstein-Barr virus infection

The germline Guanine-adenine-thymine-adenine 2 (GATA2) heterozygous mutations (GATA2 deficiency) are identified as a complex immunodeficiency, which entails susceptibility to non-tuberculous mycobacterium (NTM), fungus, or Epstein-Barr virus (EBV) infection, and hematological disorders including myelodysplastic syndrome (MDS)/acute myelogenous leukemia, accompanied by characteristic sighs such as lymphedema or deafness. A 21-year-old woman with persistent EBV infection was diagnosed with GATA2 deficiency based on the onset of MDS and her family history. The patient underwent bone marrow transplantation from an unrelated donor. She developed steroid-resistant graft-versus-host disease (GVHD), leading to an NTM infection, the deterioration of lymphedema, and life-threatening gut bleeding caused by not only GVHD but also thrombotic microangiopathy. Although allogeneic hematopoietic stem cell transplantation is a potential therapeutic option in patients with GATA2 deficiency, GATA2 haploinsufficiency in non-hematopoietic cells may affect the post-transplant complications. Therefore, the establishment of treatment guidelines on donor and graft selection, the intensity of conditioning regimens, GVHD prophylaxis, and prevention of post-transplantation infections based on the history of infection and degree of organ damage is necessary for patients with GATA2 deficiency.

An impact of activated Epstein–Barr Virus and HHV-6 on the course and control of bronchial asthma in children of the Amur Region

The role of viral infection in bronchial asthma (BA) is well-known being reflected particularly in GINA. An effect of pneumotropic intracellular persistent herpesviruses on the course of BA is of particular interest. The most common viruses of this group are cytomegalovirus (CMV), EpsteinBarr virus (EBV), and human herpesvirus 6 (HHV-6). The CMV role has been discussed in our previous publications allowing us to focus here on EBV and HHV-6. We examined 167 children with BA that was diagnosed and clinically assessed in accordance with the current national clinical guidelines. Patients with controlled asthma (70 patients), partially controlled and uncontrolled asthma (97 patients) were stratified into several groups. The detection of EBV and HHV-6 DNA was carried out in throat swabs by PCR; the level of total and virus-specific IgA, IgM, IgG, IgE as well as serum level of IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-8 and TNF was assessed by enzyme linked immunosorbent assay; lymphocyte subpopulations were analyzed by flow cytometry. The dose of topic GCS was taken into account with reference to the fluticosone equivalent; the function of external respiration was studied by spirometry. It was revealed that EBV DNA was found in 14.2% of cases, whereas HHV-6 in 19.0% of cases, but 14.4% and 52.4% of patients, respectively, shed no pathogen-linked DNA. At the same time, patients with uncontrolled BA are significantly more likely to shed the pathogen DNA, so that EBV is released in 17.1% vs 4.5% of patients with controlled BA, HHV-6 in 19.5% vs 13.6%. On the contrary, children with controlled BA were significantly more often (63.6% vs 51.2%) negative for viral DNA shedding. Moreover, virus shedding was paralleled with higher levels of IL-5: it was as high as 0.91 pg/ml and 0.29 pg/ml for EBV and HHV-6, respectively; those shedding DNA of both pathogens vs no shedding had IL-5 at level of 0.25 pg/ml vs 0.11 pg/ml. Similar pattern was observed for higher total IgE: 184.5 IU for EBV, 113.1 IU for HHV-6, and 371.7 IU shedding both viruses vs 95.2 IU in without DNA pathogen shedding; lower level of FEV1: EBV 96.6%, HHV-6 98.8%, and 106.2% in patients shedding both viruses vs 109.8% in patients not shedding the pathogen DNA. Patients shedding EBV DNA require higher doses of topic GCS to achieve disease control: EBV 325.0 mg, HHV-6 186.4 mg; shedding both viruses 328.1 mg of topic GCS vs 198.6 mg in patients without pathogen DNA shedding. Thus, activation of both EBV and HHV-6 worsens BA control and aggravates its course, but EBV persistence has a more pronounced effect on the course and control of the disease.

EBV infection mediated BDNF expression is associated with bladder inflammation in interstitial cystitis/bladder pain syndrome with Hunner's lesion.

Interstitial cystitis/bladder pain syndrome with Hunner's lesion (HIC) is characterized by chronic inflammation and nerve hyperplasia; however, the pathogenesis of HIC remains a mystery. In this study, we detected both Epstein-Barr virus (EBV) latency infection genes EBNA-1 and LMP-1 and EBV lytic infection BZLF-1 and BRLF-1 expression in the HIC bladders, indicating the coexistence of EBV persistence and reactivation in the B cells in HIC bladders. Upregulation of EBV-associated inflammatory genes in HIC bladders, such as TNF-α and IL-6, suggests EBV infection is implicated in the pathogenesis of bladder inflammation. Nerve hyperplasia and upregulation of brain-derived neurotrophic factor (BDNF) were noted in the HIC bladders. Double immunochemical staining and flow cytometry revealed the origin of BDNF to be EBV-infected B cells. Inducible BDNF expression was noted in B cells upon EBV infection, but not in the T cells. A chromatin immunoprecipitation study revealed BDNF transcription could be promoted by cooperation between EBV nuclear antigens, chromatin modifiers, and B-cell-specific transcription. Knockdown of BDNF in EBV-infected B cells resulted in the inhibition of cell proliferation and viability. Downregulation of phosphorylated SMAD2 and STAT3 after BDNF knockdown may play a role in the mechanism. Implantation of latent EBV-infected B cells into rat bladder walls resulted in a higher expression level of CD45 and PGP9.5, suggesting tissue inflammation and nerve hyperplasia. In contrast, implantation of BDNF depleted EBV-infected B cells abrogated these effects. This is the first study to provide insights into the mechanisms underlying the involvement of EBV-infected B cells in HIC pathogenesis. © 2022 The Pathological Society of Great Britain and Ireland.

Plasma EBV-DNA and peripheral blood mononuclear cell EBV-DNA have disparate clinical relevance in patients with extranodal NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related hematological malignancy. The presence of EBV-DNA in peripheral blood is a widely used ENKTCL tumor marker. However, there is no consensus on the preferred blood specimen type for EBV testing. Furthermore, discordance between EBV-based and imaging-based disease assessments is common, and how to interpret this discordance is important. We retrospectively analyzed the data of ENKTCL patients in the Affiliated Cancer Hospital of Zhengzhou university and Sun Yat-sen University Cancer Center. All EBV-DNA and imaging-based disease assessment data were collected at diagnosis, during treatment, at the end of treatment, and during follow-up. We compared matched plasma EBV-DNA and peripheral blood mononuclear cell (PBMC) EBV-DNA and matched EBV-based and imaging-based assessments to uncover their clinical relevance. A total of 450 patients with adequate data were included, of whom 278 had plasma EBV-DNA data, 250 had PBMC EBV-DNA data, and 78 had matched plasma and PBMC EBV-DNA data. No significant correlations were found between PBMC and plasma EBV-DNA and between PBMC EBV-DNA and imaging-based assessment, but patients with positive PBMC EBV-DNA at diagnosis or intermittently/persistently positive PBMC EBV-DNA during follow-up had poorer survival. In contrast, plasma EBV-DNA strongly correlated with lymphoma status. Detectable pre- and post-treatment plasma EBV-DNA was associated with significantly worse survival. Patients with early-stage disease who had detectable plasma EBV-DNA at the end of treatment shared similar survival to those with advanced-stage disease, even if their imaging-based assessments were negative. For disease relapse monitoring, 78 (55.7%) episodes of relapse were detected by both imaging and plasma EBV-DNA; 58 (41.4%) detected by plasma EBV-DNA earlier than imaging, with a median time of 9.3 (0.3 - 37.8) months; and only 4 (2.9%) detected by plasma EBV-DNA later than imaging. The sensitivities of plasma EBV-DNA, PET/CT, and CT/MRI were 97.1%, 76.8%, and 45.1%, respectively, and their specificities were 91.7%, 84.2%, and 96.7%, respectively. Analysis of EBV kinetic patterns in EBV+/imaging- episodes revealed that relapse occurred only in patients with intermittently/persistently positive plasma EBV-DNA. Persistent plasma EBV+ was also seen in patients after autologous hematopoietic stem cell transplantation. Occasional EBV+ was not associated with relapse. Plasma and PBMC EBV-DNA have different clinical relevance in ENKTCL patients. PBMC EBV-DNA does not correlate with imaging-based disease assessment. PBMC or even whole blood should not be used for response evaluation and relapse monitoring. However, PBMC EBV-DNA still has prognostic value. Plasma EBV-DNA is strongly related to tumor status and is not only a prognosticator at diagnosis and end of treatment, but also a sensitive marker in relapse monitoring compared to PET/CT and CT/MRI. The specificity of plasma EBV-DNA is relatively low, but when EBV-DNA kinetic patterns are considered, it can identify at-risk patients.

EBV persistence in gastric cancer cases conventionally classified as EBER-ISH negative

BackgroundThe Epstein-Barr virus (EBV) causes various B-cell lymphomas and epithelial malignancies, including gastric cancer (GC) at frequencies ranging from 5 to 10% in adenocarcinomas (ADK) to 80% in GC with lymphoid stroma (GCLS). Using high-sensitivity methods, we recently detected EBV traces in a large cohort of EBV-negative B-cell lymphomas, suggesting a hit-and-run mechanism.MethodsHere, we used routine and higher-sensitivity methods [droplet digital PCR (ddPCR) for EBV segments on microdissected tumour cells and RNAscope for EBNA1 mRNA] to assess EBV infection in a cohort of 40 GCs (28 ADK and 12 GCLS).ResultsddPCR documented the presence of EBV nucleic acids in rare tumour cells of several cases conventionally classified as EBV-negative (ADK, 8/26; GCLS, 6/7). Similarly, RNAscope confirmed EBNA1 expression in rare tumour cells (ADK, 4/26; GCLS, 3/7). Finally, since EBV induces epigenetic changes that are heritable and retained after complete loss of the virus from the host cell, we studied the methylation pattern of EBV-specifically methylated genes (Timp2, Eya1) as a mark of previous EBV infection. Cases with EBV traces showed a considerable level of methylation in Timp2 and Eya1 genes that was similar to that observed in EBER-ISH positive cases and greater than cases not featuring any EBV traces.ConclusionsThese findings suggest that: (a) EBV may contribute to gastric pathogenesis more widely than currently acknowledged and (b) indicate the methylation changes as a mechanistic framework for how EBV can act in a hit-and-run manner. Finally, we found that the viral state was of prognostic significance in univariate and multivariate analyses.

An in-silico insight into the predictive interaction of Apolipoprotein-E with Epstein-Barr virus proteins and their probable role in mediating Alzheimer’s disease

Recent reports suggest that persistent Epstein-Barr virus (EBV) infection and its recurrent reactivation could instigate the formation of proteinaceous plaques in the brain: a hallmark of Alzheimer’s disease (AD). Interestingly, a major genetic risk factor of AD, the apolipoprotein E (ApoE), could also influence the outcome of EBV infection in an individual. The ApoE is believed to influence the proteinaceous plaque clearance from the brain, and its defective functioning could result in the aggregate deposition. The persistent presence of EBV infection in a genetically predisposed individual could create a perfect recipe for severe neurodegenerative consequences. Therefore, in the present study, we investigated the possible interactions between ApoE and various EBV proteins using computational tools. Our results showed possibly stable de-novo interactions between the C-terminal domain of ApoE3 and EBV proteins: EBV nuclear antigen-1 (EBNA1) and BamHI Z fragment leftward open reading frame-1 (BZLF1). The EBNA1 protein of EBV plays a crucial role in establishing latency and replication of the virus. Whereas BZLF1 is involved in the lytic replication cycle. The proposed interaction of EBV proteins at the ligand-binding site of ApoE3 on CTD could interfere with- its capability to sequester amyloid fragments and, hence their clearance from the brain giving rise to AD pathology. This study provides a new outlook on EBV’s underexplored role in AD development and paves the way for novel avenues of investigation which could further our understanding of AD pathogenesis. Communicated by Ramaswamy H. Sarma

Nasopharyngeal Carcinoma Progression: Accumulating Genomic Instability and Persistent Epstein-Barr Virus Infection.

Genomic instability facilitates the evolution of cells, tissues, organs, and species. The progression of human malignancies can be regarded as the accumulation of genomic instability, which confers a high evolutionary potential for tumor cells to adapt to continuous changes in the tumor microenvironment. Nasopharyngeal carcinoma (NPC) is a head-and-neck squamous-cell carcinoma closely associated with Epstein–Barr virus (EBV) infection. NPC progression is driven by a combination of accumulated genomic instability and persistent EBV infection. Here, we present a review of the key characteristics of genomic instability in NPC and the profound implications of EBV infection. We further discuss the significance of profiling genomic instability for the assessment of disease progression and treatment efficacy, as well as the opportunities and challenges of targeted therapies for NPC based on its unique genomic instability.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.