Science.gov

Sample records for a2-restricted epstein-barr virus

  1. Epstein-Barr virus test

    MedlinePlus

    ... 481. Johannsen EC, Kaye KM. Epstein-Barr virus (infectious mononucleosis, Epstein-Barr virus-associated malignant diseases, and other ... and the A.D.A.M. Editorial team. Infectious Mononucleosis Read more NIH MedlinePlus Magazine Read more Health ...

  2. About Epstein-Barr Virus (EBV)

    MedlinePlus

    ... Submit Search The CDC Epstein-Barr Virus and Infectious Mononucleosis Note: Javascript is disabled or is not supported ... and Mono Home About Epstein-Barr Virus About Infectious Mononucleosis For Healthcare Providers Laboratory Testing References & Resources About ...

  3. Early Detection of Epstein-Barr Virus Related Disease.

    ClinicalTrials.gov

    2018-05-22

    Post-transplant Lymphoproliferative Disorder; Mononucleosis; Epstein-Barr Virus Infections; Epstein-Barr Virus Related Malignancy; Epstein-Barr Viraemia; Epstein-Barr Virus-Related Hodgkin Lymphoma; Epstein-Barr Virus-Related Non-Hodgkin Lymphoma; Hemophagocytic Lymphohistiocytoses; Hemophagocytosis

  4. Epstein Barr Virus and Blood Brain Barrier in Multiple Sclerosis

    DTIC Science & Technology

    2014-01-01

    ABSTRACT Multiple sclerosis (MS) is a chronic, autoimmune neurodegenerative disease . Epstein - Barr virus (EBV) infection is associated with MS...factors such as Epstein - Barr virus (EBV) infections. EBV is a herpesvirus that infects many cell types and associated with other autoimmune diseases . The...AD_________________ Award Number: W81XWH-12-1-0225 TITLE: Epstein Barr virus and

  5. Epstein Barr Virus and Blood Brain Barrier in Multiple Sclerosis

    DTIC Science & Technology

    2013-07-01

    Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple sclerosis (MS) is a chronic, autoimmune neurodegenerative disease . Epstein - Barr ...of EBV in MS disease . 15. SUBJECT TERMS Blood-brain-barrier, Epstein - Barr virus ; EBV; BBB; MS, Multiple sclerosis 16. SECURITY CLASSIFICATION OF...AD_________________ Award Number: W81XWH-12-1-0225 TITLE: Epstein Barr virus and blood brain

  6. Epstein-Barr Virus and Hemophagocytic Lymphohistiocytosis.

    PubMed

    Marsh, Rebecca A

    2017-01-01

    Epstein-Barr virus (EBV) is a ubiquitous virus that infects nearly all people worldwide without serious sequela. However, for patients who have genetic diseases which predispose them to the development of hemophagocytic lymphohistiocytosis (HLH), EBV infection is a life-threatening problem. As a part of a themed collection of articles on EBV infection and human primary immune deficiencies, we will review key concepts related to the understanding and treatment of HLH.

  7. Epstein-Barr virus-associated lymphomas.

    PubMed

    Shannon-Lowe, Claire; Rickinson, Alan B; Bell, Andrew I

    2017-10-19

    Epstein-Barr virus (EBV), originally discovered through its association with Burkitt lymphoma, is now aetiologically linked to a remarkably wide range of lymphoproliferative lesions and malignant lymphomas of B-, T- and NK-cell origin. Some occur as rare accidents of virus persistence in the B lymphoid system, while others arise as a result of viral entry into unnatural target cells. The early finding that EBV is a potent B-cell growth transforming agent hinted at a simple oncogenic mechanism by which this virus could promote lymphomagenesis. In reality, the pathogenesis of EBV-associated lymphomas involves a complex interplay between different patterns of viral gene expression and cellular genetic changes. Here we review recent developments in our understanding of EBV-associated lymphomagenesis in both the immunocompetent and immunocompromised host.This article is part of the themed issue 'Human oncogenic viruses'. © 2017 The Authors.

  8. Chronic Active Epstein-Barr Virus Disease.

    PubMed

    Kimura, Hiroshi; Cohen, Jeffrey I

    2017-01-01

    Chronic active Epstein-Barr virus (CAEBV) disease is a rare disorder in which persons are unable to control infection with the virus. The disease is progressive with markedly elevated levels of EBV DNA in the blood and infiltration of organs by EBV-positive lymphocytes. Patients often present with fever, lymphadenopathy, splenomegaly, EBV hepatitis, or pancytopenia. Over time, these patients develop progressive immunodeficiency and if not treated, succumb to opportunistic infections, hemophagocytosis, multiorgan failure, or EBV-positive lymphomas. Patients with CAEBV in the United States most often present with disease involving B or T cells, while in Asia, the disease usually involves T or NK cells. The only proven effective treatment for the disease is hematopoietic stem cell transplantation. Current studies to find a cause of this disease focus on immune defects and genetic abnormalities associated with the disease.

  9. Epstein-Barr virus and renal transplantation.

    PubMed

    Le, Jade; Durand, Christine M; Agha, Irfan; Brennan, Daniel C

    2017-01-01

    Epstein-Barr virus (EBV) is a gamma herpesvirus associated with diseases ranging from asymptomatic viremia to post-transplant malignancies in kidney transplant recipients. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The diagnosis of PTLD relies on clinical suspicion plus tissue biopsy with polymerase chain reaction (PCR) testing of blood currently used for risk determination in high-risk recipients. Therapeutic strategies for PTLD include reduction of immunosuppression, chemotherapy and rituximab, and consideration of sirolimus-based immunosuppression. Antivirals such as ganciclovir are used to prevent reactivation of cytomegalovirus and other herpes viruses but are not onco-therapeutic. Radiation therapy or surgery is indicated for bulky, disseminated or recalcitrant disease. Prognosis varies depending on the type of malignancy identified and stage of disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. [Chronic active Epstein-Barr virus infection].

    PubMed

    Kimura, Hiroshi

    2011-12-01

    The ubiquitous Epstein-Barr virus (EBV), which establishes latency after primary infection, does not cause any symptomatic diseases as long as cellular immunity is intact. In apparently immunocompetent individuals, a chronic infection can develop, and this has been called as chronic active EBV infection (CAEBV). CAEBV is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and, hepatosplenomegaly. This disease is rare but severe with high morbidity and mortality. Recently, its pathophysiology is not an infection but a clonal expansion of EBV-infected T or natural killer NK cells. In this review, I discuss our current understanding of the pathogenesis of CAEBV and summarize its clinical features, therapies, and prognosis.

  11. Epstein-Barr virus in multiple sclerosis.

    PubMed

    Abdelrahman, Hisham S; Selim, Heba S; Hashish, Mona H; Sultan, Lobna I

    2014-08-01

    Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system. Many diseases are associated with Epstein-Barr virus (EBV) infection, such as infectious mononucleosis and many types of malignancies, and it is thought to be related to some diseases of autoimmune origin, such as rheumatoid arthritis, systemic lupus erythematosis, and others. The present study aimed to assess EBV in patients with MS. This case-control study was conducted from October 2012 to September 2013 on 75 MS patients and non-MS controls. Both were tested quantitatively for immunoglobulin G (IgG) antibodies against Epstein-Barr nuclear antigen-1 (EBNA1) and viral capsid antigen (VCA) using the enzyme linked immunosorbent assay technique. Seventy MS patients (93.3%) were positive for EBNA1 IgG compared with 68 controls (90.7%). In MS patients, the mean EBNA1 IgG serum level was 310.91 (±131.05) U/ml; meanwhile, among controls the mean serum EBNA IgG level was 177.81 (±104.98) U/ml.All patients with MS were positive for VCA IgG, whereas only 60 (80.0%) controls were positive. In the MS group, the VCA IgG mean level was 302.19 (±152.11) U/ml compared with 167.94 (±111.79) U/ml in controls. The differences in the serum levels of both markers between the two groups were statistically significant (P<0.001). EBV proved to have a unique immunological pattern in MS patients when compared with non-MS controls. Further studies for more confirmation of the relation between EBV and MS on a large scale are recommended.

  12. Epstein-Barr virus and nasopharyngeal carcinoma

    PubMed Central

    Young, Lawrence S.; Dawson, Christopher W.

    2014-01-01

    Since its discovery 50 years ago, Epstein-Barr virus (EBV) has been linked to the development of cancers originating from both lymphoid and epithelial cells. Approximately 95% of the world's population sustains an asymptomatic, life-long infection with EBV. The virus persists in the memory B-cell pool of normal healthy individuals, and any disruption of this interaction results in virus-associated B-cell tumors. The association of EBV with epithelial cell tumors, specifically nasopharyngeal carcinoma (NPC) and EBV-positive gastric carcinoma (EBV-GC), is less clear and is currently thought to be caused by the aberrant establishment of virus latency in epithelial cells that display premalignant genetic changes. Although the precise role of EBV in the carcinogenic process is currently poorly understood, the presence of the virus in all tumor cells provides opportunities for developing novel therapeutic and diagnostic approaches. The study of EBV and its role in carcinomas continues to provide insight into the carcinogenic process that is relevant to a broader understanding of tumor pathogenesis and to the development of targeted cancer therapies. PMID:25418193

  13. Epstein-Barr virus and multiple sclerosis.

    PubMed

    Lucas, R M; Hughes, A M; Lay, M-L J; Ponsonby, A-L; Dwyer, D E; Taylor, B V; Pender, M P

    2011-10-01

    This review of the considerable evidence linking Epstein-Barr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a dose-response relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified.

  14. Epstein-Barr virus in autoimmune diseases.

    PubMed

    Toussirot, Eric; Roudier, Jean

    2008-10-01

    Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS) are complex disorders with a genetic background and the involvement of environmental factors, including viruses. The Epstein-Barr virus (EBV) is a plausible candidate for playing a role in the pathophysiology of these diseases. Both SLE and RA are characterized by high titers of anti-EBV antibodies and impaired T-cell responses to EBV antigens. Compared with normal subjects, elevated EBV load in peripheral blood has been observed in SLE and RA. EBV DNA or RNA has been evidenced in target organs of RA (synovium) or pSS (salivary glands). Finally, molecular mimicry has been demonstrated between EBV proteins and self antigens in these three conditions. In addition, SLE, RA, and pSS are associated with an increased risk of lymphoma with a potential role for EBV. The influence of new and emergent treatments of these autoimmune diseases (biological therapies) on EBV load and the course of latent EBV infection requires further studies.

  15. Epstein-Barr virus and rheumatoid arthritis.

    PubMed

    Balandraud, Nathalie; Roudier, Jean

    2018-03-01

    Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, with a 0.5% worldwide prevalence. The cause of RA remains unknown, however both genetic and environmental factors may contribute to its development. Among these is the Epstein-Barr virus (EBV). Here, we discuss several aspects of the close relationship between EBV and RA. Patients with RA have impaired control of EBV infection. Indeed, they have high titres of antibodies against EBV antigens. Their peripheral blood T lymphocytes are less efficient at controlling the outgrowth of EBV-infected B cells. RA patients have more EBV-infected B cells than normal controls, leading to a 10-fold systemic EBV overload. Post-transplant lymphoproliferative disorder (PTLPD) is a polyclonal EBV-positive B lymphocyte proliferation, which can evolve into an EBV-positive B cell lymphoma. RA patients also have an increased risk of developing EBV-associated lymphoproliferative disorder (LPD). Hence the need to monitor EBV load when treating RA patients with immunosuppressors. EBV, a widespread virus, highly recognized by antibodies but never eliminated, is an ideal candidate to trigger chronic immune complex disease. Anti-EBV antibody responses should be considered as one of the chronic autoantibody responses linked to the development of RA, in the same way as anti-citrullinated protein antibodies. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  16. Epstein-Barr virus infection induces lupus autoimmunity.

    PubMed

    Harley, John B; James, Judith A

    2006-01-01

    Systemic lupus erythematosus (SLE or lupus) is a systemic autoimmune disease characterized by a constellation of varied clinical presentations, although the nearly universal presence of autoantibodies is a salient unifying feature. Ongoing research efforts focus on understanding the complex combination of genetic and environmental factors that lead to SLE in select individuals. Our previous work has demonstrated that years before diagnosis abnormal autoantibody responses are present in the sera of patients who will subsequently develop lupus and, further, that the initial targets of two of these key responses (anti-Sm B' and anti-60 kD Ro alone) have been identified for some patients. Indeed, our results suggest that the first lupus-specific autoantibodies arise from particular antibodies directed against Epstein-Barr virus Nuclear Antigen-1 (EBNA-1) and that infection with Epstein-Barr virus (EBV) is an environmental risk factor for lupus. The predicted sequence of events is normal immunity, followed by Epstein- Barr virus infection, the generation of anti-EBNA-1 antibodies, then followed by those particular anti-EBNA-1 antibodies that also bind lupus-specific autoantigens (Sm or Ro), followed by the development of more complex autoimmune responses, and, finally, culminating in clinical disease. Studies from others and those underway suggest that lupus patients have unusual immune responses to Epstein-Barr virus. In aggregate, these results are consistent with an immune response against Epstein-Barr virus being important in at least some patients for the initiation of lupus autoimmunity.

  17. Epstein-Barr Virus in Gastric Carcinoma

    PubMed Central

    Nishikawa, Jun; Yoshiyama, Hironori; Iizasa, Hisashi; Kanehiro, Yuichi; Nakamura, Munetaka; Nishimura, Junichi; Saito, Mari; Okamoto, Takeshi; Sakai, Kouhei; Suehiro, Yutaka; Yamasaki, Takahiro; Oga, Atsunori; Yanai, Hideo; Sakaida, Isao

    2014-01-01

    The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma, all tumor cells harbor the clonal EBV genome. Gastric carcinoma associated with EBV has distinct clinicopathological features, occurs predominately in men and in younger-aged individuals, and presents a generally diffuse histological type. Most cases of EBV-associated gastric carcinoma exhibit a histology rich in lymphocyte infiltration. The immunological reactiveness in the host may represent a relatively preferable prognosis in EBV-positive cases. This fact highlights the important role of EBV in the development of EBV-associated gastric carcinoma. We have clearly proved direct infection of human gastric epithelialcells by EBV. The infection was achieved by using a recombinant EBV. Promotion of growth by EBV infection was observed in the cells. Considerable data suggest that EBV may directly contribute to the development of EBV-associated GC. This tumor-promoting effect seems to involve multiple mechanisms, because EBV affects several host proteins and pathways that normally promote apoptosis and regulate cell proliferation. PMID:25386788

  18. Epstein-Barr virus and multiple sclerosis.

    PubMed

    Pohl, Daniela

    2009-11-15

    Epstein-Barr virus (EBV) is a human DNA herpesvirus infecting more than 90% of the world's population. EBV is the etiological agent of infectious mononucleosis (Pfeiffer's disease). Furthermore, diverse malignancies such as Burkitt and Hodgkin lymphoma have been associated with EBV. More recently, a possible role for EBV has been suggested in chronic inflammatory/autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus as well as in multiple sclerosis (MS). MS is currently regarded as a disease with multifactorial etiology, EBV being one possible factor in MS manifestation: Infectious mononucleosis has been shown to increase the risk of developing MS later in life. EBV seroprevalence rates are higher in MS as compared to controls, in adult as well as in pediatric MS patients. Moreover, EBV antibody titres and EBV specific T-cells are increased in MS patients as compared to healthy individuals. Recently, CNS B-cells of MS patients have been reported to harbour EBV. However, there is still controversy whether EBV could be a causative agent as opposed to an innocent bystander in the pathogenesis of MS. This review summarizes current knowledge on the association of EBV and MS including a critical discussion of equivocal findings.

  19. Lytic Replication of Epstein-Barr Virus During Space Flight

    NASA Technical Reports Server (NTRS)

    Stowe, R. P.; Pierson, D. L.; Barrett, A. D. T.

    1999-01-01

    Reactivation of latent Epstein-Barr virus (EBV) may be an important threat to crew health during extended space missions. Cellular immunity, which is decreased during and after space flight, is responsible for controlling EBV replication in vivo. In this study, we investigated the effects of short-term space flight on latent EBV reactivation.

  20. Epstein-Barr Virus Neuroretinitis in a Lung Transplant Patient.

    PubMed

    Hsia, Yen C; Chin-Hong, Peter V; Levin, Marc H

    2017-03-01

    Epstein-Barr virus (EBV)-associated optic neuropathy is rare with few reported cases, mostly involving immunocompetent patients who developed optic nerve involvement after infectious mononucleosis. We describe a unique case of a patient who developed severe bilateral EBV neuroretinitis after solid organ transplant.

  1. Multiple Epstein-Barr virus infections in healthy individuals

    NASA Technical Reports Server (NTRS)

    Walling, Dennis M.; Brown, Abigail L.; Etienne, Wiguins; Keitel, Wendy A.; Ling, Paul D.; Butel, J. S. (Principal Investigator)

    2003-01-01

    We employed a newly developed genotyping technique with direct representational detection of LMP-1 gene sequences to study the molecular epidemiology of Epstein-Barr virus (EBV) infection in healthy individuals. Infections with up to five different EBV genotypes were found in two of nine individuals studied. These results support the hypothesis that multiple EBV infections of healthy individuals are common. The implications for the development of an EBV vaccine are discussed.

  2. Genetics Home Reference: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia

    MedlinePlus

    ... Share: Email Facebook Twitter Home Health Conditions XMEN X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ... Javascript to view the expand/collapse boxes. Description X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ...

  3. Genome-wide analysis of Epstein-Barr virus identifies variants and genes associated with gastric carcinoma and population structure.

    PubMed

    Yao, Youyuan; Xu, Miao; Liang, Liming; Zhang, Haojiong; Xu, Ruihua; Feng, Qisheng; Feng, Lin; Luo, Bing; Zeng, Yi-Xin

    2017-10-01

    Epstein-Barr virus is a ubiquitous virus and is associated with several human malignances, including the significant subset of gastric carcinoma, Epstein-Barr virus-associated gastric carcinoma. Some Epstein-Barr virus-associated diseases are uniquely prevalent in populations with different geographic origins. However, the features of the disease and geographically associated Epstein-Barr virus genetic variation as well as the roles that the variation plays in carcinogenesis and evolution remain unclear. Therefore, in this study, we sequenced 95 geographically distinct Epstein-Barr virus isolates from Epstein-Barr virus-associated gastric carcinoma biopsies and saliva of healthy donors to detect variants and genes associated with gastric carcinoma and population structure from a genome-wide spectrum. We demonstrated that Epstein-Barr virus revealed the population structure between North China and South China. In addition, we observed population stratification between Epstein-Barr virus strains from gastric carcinoma and healthy controls, indicating that certain Epstein-Barr virus subtypes are associated with different gastric carcinoma risks. We identified that the BRLF1, BBRF3, and BBLF2/BBLF3 genes had significant associations with gastric carcinoma. LMP1 and BNLF2a genes were strongly geographically associated genes in Epstein-Barr virus. Our study provides insights into the genetic basis of oncogenic Epstein-Barr virus for gastric carcinoma, and the genetic variants associated with gastric carcinoma can serve as biomarkers for oncogenic Epstein-Barr virus.

  4. The conundrum of the Epstein-Barr virus-associated gastric carcinoma in the Americas

    PubMed Central

    Carrasco-Avino, Gonzalo; Riquelme, Ismael; Padilla, Oslando; Villaseca, Miguel; Aguayo, Francisco R.; Corvalan, Alejandro H.

    2017-01-01

    Epstein-Barr virus-associated gastric carcinoma shows a higher prevalence in the Americas than Asia. We summarize all studies of Epstein Barr virus-associated gastric carcinoma in the Americas, focusing on host characteristics, environmental associations and phylogeographic diversity of Epstein-Barr virus strains. In the Americas, the prevalence of Epstein Barr virus-associated gastric carcinoma is 11.4%, more frequent in males and portray predominantly diffuse-type histology. EBERs, EBNAs, BARTs and LMP are the highest expressed genes; their variations in healthy individuals may explain the phylogeographic diversity of Epstein-Barr virus across the region. Gastric cancer cases harbor exclusively the western genotype (subtype D and kept Xho I site), suggesting a disrupted co-evolution between the pathogen and its host. Epstein-Barr virus-associated gastric carcinoma molecular subtype cases from The Cancer Genome Atlas display PIK3CA gene mutations, amplification of JAK2, PD-L1 and PD-L2 and CpG island methylator phenotype, leading to more extensive methylation of host and viral genomes than any other subtypes from the study. Environmental conditions include negative- and positive- associations with being firstborn child and smoking, respectively. A marginal association with H. pylori has also been reported. Lymphoepithelioma-like carcinoma is associated with Epstein Barr virus in 80%–86% of cases, most of which have been included as part of Epstein Barr virus-associated gastric carcinoma series (prevalence 1.1%–7.6%). Whether these cases represent a variant of Epstein-Barr virus-associated gastric carcinoma is discussed. We propose novel research strategies to solve the conundrum of the high prevalence of Epstein-Barr virus-associated gastric carcinoma in the Americas. PMID:29088902

  5. 21 CFR 866.3235 - Epstein-Barr virus serological reagents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Epstein-Barr virus serological reagents. 866.3235 Section 866.3235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3235 Epstein-Barr...

  6. 21 CFR 866.3235 - Epstein-Barr virus serological reagents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Epstein-Barr virus serological reagents. 866.3235 Section 866.3235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3235 Epstein-Barr...

  7. 21 CFR 866.3235 - Epstein-Barr virus serological reagents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Epstein-Barr virus serological reagents. 866.3235 Section 866.3235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3235 Epstein-Barr...

  8. 21 CFR 866.3235 - Epstein-Barr virus serological reagents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Epstein-Barr virus serological reagents. 866.3235 Section 866.3235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3235 Epstein-Barr...

  9. 21 CFR 866.3235 - Epstein-Barr virus serological reagents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Epstein-Barr virus serological reagents. 866.3235 Section 866.3235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3235 Epstein-Barr...

  10. Radiation-induced Epstein-Barr virus reactivation in gastric cancer cells with latent EBV infection.

    PubMed

    Nandakumar, Athira; Uwatoko, Futoshi; Yamamoto, Megumi; Tomita, Kazuo; Majima, Hideyuki J; Akiba, Suminori; Koriyama, Chihaya

    2017-07-01

    Epstein-Barr virus, a ubiquitous human herpes virus with oncogenic activity, can be found in 6%-16% of gastric carcinomas worldwide. In Epstein-Barr virus-associated gastric carcinoma, only a few latent genes of the virus are expressed. Ionizing irradiation was shown to induce lytic Epstein-Barr virus infection in lymphoblastoid cell lines with latent Epstein-Barr virus infection. In this study, we examined the effect of ionizing radiation on the Epstein-Barr virus reactivation in a gastric epithelial cancer cell line (SNU-719, an Epstein-Barr virus-associated gastric carcinoma cell line). Irradiation with X-ray (dose = 5 and 10 Gy; dose rate = 0.5398 Gy/min) killed approximately 25% and 50% of cultured SNU-719 cells, respectively, in 48 h. Ionizing radiation increased the messenger RNA expression of immediate early Epstein-Barr virus lytic genes (BZLF1 and BRLF1), determined by real-time reverse transcription polymerase chain reaction, in a dose-dependent manner at 48 h and, to a slightly lesser extent, at 72 h after irradiation. Similar findings were observed for other Epstein-Barr virus lytic genes (BMRF1, BLLF1, and BcLF1). After radiation, the expression of transforming growth factor beta 1 messenger RNA increased and reached a peak in 12-24 h, and the high-level expression of the Epstein-Barr virus immediate early genes can convert latent Epstein-Barr virus infection into the lytic form and result in the release of infectious Epstein-Barr virus. To conclude, Ionizing radiation activates lytic Epstein-Barr virus gene expression in the SNU-719 cell line mainly through nuclear factor kappaB activation. We made a brief review of literature to explore underlying mechanism involved in transforming growth factor beta-induced Epstein-Barr virus reactivation. A possible involvement of nuclear factor kappaB was hypothesized.

  11. Acute dacryocystitis associated with epstein-barr virus infection.

    PubMed

    Ghauri, Abdul-Jabbar; Keane, Pearse A; Scotcher, Stephen M; Clarke, Jayne L; Madge, Simon N

    2011-10-01

    Acute dacryocystitis is a rare complication of infectious mononucleosis with only three previous reports in the English literature. We present two further children with acute dacryocystitis and clinical and laboratory features of Epstein-Barr Virus related infectious mononucleosis. Both were treated with systemic antibiotics and one child additionally required surgical drainage of a lacrimal sac abscess. Both children made a complete recovery without any lacrimal symptoms. Acute dacryocystitis is uncommon in children without a history of congenital nasolacrimal duct obstruction, and an underlying systemic condition such as infectious mononucleosis should be suspected. In such patients, dacryocystitis can be expected to resolve without symptoms of nasolacrimal duct obstruction and dacryocystorhinostomy is seldom required.

  12. A prospective study of primary Epstein-Barr virus infections among university students in Hong Kong.

    PubMed

    Dan, R; Chang, R S

    1990-04-01

    In 1988 at the Chinese University of Hong Kong 1,039 entering freshmen were screened for antibody against the Epstein-Barr virus and 71 (6.8%) were negative. One year later, 16 (25.8%) of 62 negatives converted to positive with asymptomatic infections. There was seroconversion in 14 subjects who did not give histories of deep kissing. There was an association between antibody status of Epstein-Barr and cytomegaloviruses, but not between Epstein-Barr virus and human herpes virus type 6.

  13. Recent advances in understanding Epstein-Barr virus

    PubMed Central

    Stanfield, Brent A.; Luftig, Micah A.

    2017-01-01

    Epstein-Barr virus (EBV) is a common human herpes virus known to infect the majority of the world population. Infection with EBV is often asymptomatic but can manifest in a range of pathologies from infectious mononucleosis to severe cancers of epithelial and lymphocytic origin. Indeed, in the past decade, EBV has been linked to nearly 10% of all gastric cancers. Furthermore, recent advances in high-throughput next-generation sequencing and the development of humanized mice, which effectively model EBV pathogenesis, have led to a wealth of knowledge pertaining to strain variation and host-pathogen interaction. This review highlights some recent advances in our understanding of EBV biology, focusing on new findings on the early events of infection, the role EBV plays in gastric cancer, new strain variation, and humanized mouse models of EBV infection. PMID:28408983

  14. Immune Evasion by Epstein-Barr Virus.

    PubMed

    Ressing, Maaike E; van Gent, Michiel; Gram, Anna M; Hooykaas, Marjolein J G; Piersma, Sytse J; Wiertz, Emmanuel J H J

    2015-01-01

    Epstein-Bar virus (EBV) is widespread within the human population with over 90% of adults being infected. In response to primary EBV infection, the host mounts an antiviral immune response comprising both innate and adaptive effector functions. Although the immune system can control EBV infection to a large extent, the virus is not cleared. Instead, EBV establishes a latent infection in B lymphocytes characterized by limited viral gene expression. For the production of new viral progeny, EBV reactivates from these latently infected cells. During the productive phase of infection, a repertoire of over 80 EBV gene products is expressed, presenting a vast number of viral antigens to the primed immune system. In particular the EBV-specific CD4+ and CD8+ memory T lymphocytes can respond within hours, potentially destroying the virus-producing cells before viral replication is completed and viral particles have been released. Preceding the adaptive immune response, potent innate immune mechanisms provide a first line of defense during primary and recurrent infections. In spite of this broad range of antiviral immune effector mechanisms, EBV persists for life and continues to replicate. Studies performed over the past decades have revealed a wide array of viral gene products interfering with both innate and adaptive immunity. These include EBV-encoded proteins as well as small noncoding RNAs with immune-evasive properties. The current review presents an overview of the evasion strategies that are employed by EBV to facilitate immune escape during latency and productive infection. These evasion mechanisms may also compromise the elimination of EBV-transformed cells, and thus contribute to malignancies associated with EBV infection.

  15. Fulminant infectious mononucleosis and recurrent Epstein-Barr virus reactivation in an adolescent.

    PubMed

    Nourse, Jamie P; Jones, Kimberley; Dua, Ujjwal; Runnegar, Naomi; Looke, David; Schmidt, Chris; Tey, Siok-Keen; Kennedy, Glen; Gandhi, Maher K

    2010-03-15

    We describe a unique case of fulminant infectious mononucleosis and recurrent Epstein-Barr virus reactivation presenting in an adolescent. Detailed assays of Epstein-Barr virus-specific T cell immunity revealed defects in the patient's T cell receptor signalling pathway characterized by a lack of interleukin-2 and CD25 expression, which may have contributed to her clinical course. Allogeneic stem cell transplantation reversed the clinical and laboratory phenotype.

  16. Epstein-Barr virus infection and related hematological diseases.

    PubMed

    Sawada, Akihisa

    2016-01-01

    Once the Epstein-Barr virus (EBV) has infected a person, it then latently infects B cells. This latent infection lasts a lifetime. However, EBV can infect T or NK cells (T/NK cells) in rare cases. Therefore, EBV causes various hematological diseases. Among these diseases, CAEBV is regarded as the most problematic because, although it is not particularly uncommon, the diagnostic tests for this disease are not covered by health insurance, a serious illness in the "non-active" periods is lacking, and the appropriate motivation for early initiation of treatment can easily be lost. However, the symptoms may suddenly change; and if the manifestations are resistant when such exacerbation occurs, CAEBC is potentially lethal. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure. Once the diagnosis has been made, earlier treatment initiation, safer bridging to allogeneic HSCT with multi-drug chemotherapy, and then, planned HSCT can be completed more safely and thereby achieve a better outcome.

  17. Epstein-Barr virus, cytomegalovirus, and infectious mononucleosis.

    PubMed

    Bravender, Terrill

    2010-08-01

    Infectious mononucleosis (IM) is a clinical syndrome that is common in adolescents and young adults and is characterized by fever, lymphadenopathy, pharyngitis, and fatigue. IM is most commonly associated with Epstein-Barr virus (EBV) infection in which case laboratory findings include a lymphocytosis with an elevated number of atypical lymphocytes seen on peripheral smear and a heterophile or EBV-specific antibody response. Approximately 10% of those with IM will not be acutely infected with EBV. Many of these individuals will have their symptoms attributed to cytomegalovirus (CMV) infection. This chapter reviews the history, diagnosis, clinical management, and potential complications of both EBV- and CMV-associated IM in adolescents and young adults.

  18. Biology of Epstein-Barr virus during infectious mononucleosis.

    PubMed

    Sitki-Green, Diane L; Edwards, Rachel Hood; Covington, Mary M; Raab-Traub, Nancy

    2004-02-01

    Infectious mononucleosis is the clinical manifestation of primary infection with Epstein-Barr virus (EBV). We monitored primary infection during convalescence and during the establishment of persistent infection. The profiles of EBV strains in the oral cavity and in peripheral blood were determined by use of a heteroduplex tracking assay specific for the EBV gene encoding latent membrane protein 1. Multiple EBV strains were detected in most patients and persisted in and were possibly transmitted among 3 distinct compartments of infection, including the oral cavity, peripheral blood lymphocytes, and the cell-free fraction of the blood plasma. We also tracked transmission of multiple strains from an asymptomatic carrier to a patient diagnosed with primary EBV infection. These data reveal that primary EBV infection is complex, with transmission of multiple strains and clear differences in relative abundance of strains in distinct compartments.

  19. Quantification of Epstein-Barr virus DNA is helpful for evaluation of chronic active Epstein-Barr virus infection.

    PubMed

    Sakamoto, Yuichi; Mariya, Yasushi; Kubo, Kohmei

    2012-08-01

    Chronic active Epstein-Barr virus infection (CAEBV) presents with chronic or recurrent infectious mononucleosis-like symptoms, such as low-grade fever, liver dysfunction, lymphadenopathy, and hepatosplenomegaly. Immunological methods are useful for the diagnosis of viral infections. However, CAEBV patients do not necessarily have high titers of Epstein-Barr virus (EBV)-specific antibodies. Hosts that are immunocompromised after hematopoietic stem cell transplantations sometimes suffer from systemic EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and EBV-positive lymphoma. Patients with EBV-associated diseases are often diagnosed by analyses of bone marrow. Cytomegalovirus (CMV) can cause serious pneumonia or retinitis in immunocompromised hosts. In order to noninvasively understand the clinical status of patients with EBV-associated diseases, we conducted real-time polymerase chain reaction (PCR) methods in their peripheral blood in order to quantify EBV and CMV DNA levels, which reflect viral activity. Here, we describe a 30-year-old Japanese female patient with CAEBV. The patient had repeated fever, fatigue, and liver dysfunction. The histopathological results of liver biopsies were positive for EBV-encoded RNA-1. Acute hepatitis was associated with the EBV infection. The whole-blood EBV DNA levels were high and above 1.0 × 10⁷ copies/mL. After immunosuppressive and antiviral therapies, EBV DNA levels lowered. However, she had to receive bone marrow transplantation because of her EBV-HLH. As the number of lymphocytes increased in the post-transplantation period, EBV DNA levels gradually increased again. The simultaneous detection of CMV DNA was more sensitive than the CMV antigenemia test that is often used to diagnose CMV infections. Unfortunately, the patient died due to a fungal infection. Observing EBV DNA levels closely with real-time quantitative PCR methods is helpful for evaluating the changes in the clinical course.

  20. Epstein-Barr Virus Sequence Variation—Biology and Disease

    PubMed Central

    Tzellos, Stelios; Farrell, Paul J.

    2012-01-01

    Some key questions in Epstein-Barr virus (EBV) biology center on whether naturally occurring sequence differences in the virus affect infection or EBV associated diseases. Understanding the pattern of EBV sequence variation is also important for possible development of EBV vaccines. At present EBV isolates worldwide can be grouped into Type 1 and Type 2, a classification based on the EBNA2 gene sequence. Type 1 EBV is the most prevalent worldwide but Type 2 is common in parts of Africa. Type 1 transforms human B cells into lymphoblastoid cell lines much more efficiently than Type 2 EBV. Molecular mechanisms that may account for this difference in cell transformation are now becoming clearer. Advances in sequencing technology will greatly increase the amount of whole EBV genome data for EBV isolated from different parts of the world. Study of regional variation of EBV strains independent of the Type 1/Type 2 classification and systematic investigation of the relationship between viral strains, infection and disease will become possible. The recent discovery that specific mutation of the EBV EBNA3B gene may be linked to development of diffuse large B cell lymphoma illustrates the importance that mutations in the virus genome may have in infection and human disease. PMID:25436768

  1. The presence of Epstein-Barr virus (EBV) in diffuse large B-cell lymphomas (DLBCLs) in Turkey: special emphasis on 'EBV-positive DLBCL of the elderly'.

    PubMed

    Uner, Aysegul; Akyurek, Nalan; Saglam, Arzu; Abdullazade, Samir; Uzum, Nuket; Onder, Sevgen; Barista, Ibrahim; Benekli, Mustafa

    2011-04-01

    Accumulated evidence has shown the importance of Epstein-Barr virus in the pathogenesis of various lymphomas. This study aimed to determine the prevalence of Epstein-Barr virus expression and its effect on survival amongst diffuse large B-cell lymphoma (DLBCL) cases from two large tertiary care centres in Turkey with a particular interest in identifying cases of 'Epstein-Barr virus-positive DLBCL of the elderly'. Diffuse large B-cell lymphoma cases diagnosed between 1999 and 2009 were retrieved and 340 cases were used to construct tissue microarrays. The presence of Epstein-Barr virus small ribonucleic acids was examined by in situ hybridization using Epstein-Barr virus (EBV)-encoded small RNA (EBER) oligonucleotides. A total of 18 cases (5.3%) showed Epstein-Barr virus expression. Twelve cases were classified as Epstein-Barr virus-positive DLBCL of the elderly. Epstein-Barr virus-positive DLBCL cases showed a significantly inferior overall survival as compared with Epstein-Barr virus-negative cases (p < 0.001). In our study group Epstein-Barr virus expression is not prevalent in DLBCLs. Epstein-Barr virus-positive DLBCL of the elderly is also rare in the Turkish population. The presence of Epstein-Barr virus, however, is associated with poor prognosis. © 2011 The Authors. APMIS © 2011 APMIS.

  2. GATA2 Deficiency and Epstein-Barr Virus Disease.

    PubMed

    Cohen, Jeffrey I

    2017-01-01

    GATA2 is a transcription factor that binds to the promoter of hematopoietic genes. Mutations in one copy of the gene are associated with haploinsufficiency and reduced levels of protein. This results in reduced numbers of several cell types important for immune surveillance including dendritic cells, monocytes, CD4, and NK cells, as well as impaired NK cell function. Recently, GATA2 has been associated with several different presentations of severe Epstein-Barr virus (EBV) disease including primary infection requiring repeated hospitalizations, chronic active EBV disease, EBV-associated hydroa vacciniforme with hemophagocytosis, and EBV-positive smooth muscle tumors. EBV was found predominantly in B cells in each of the cases in which it was studied, unlike most cases of chronic active EBV disease in which the virus is usually present in T or NK cells. The variety of EBV-associated diseases seen in patients with GATA2 deficiency suggest that additional forms of severe EBV disease may be found in patients with GATA2 deficiency in the future.

  3. Laboratory Assays for Epstein-Barr Virus-Related Disease

    PubMed Central

    Gulley, Margaret L.; Tang, Weihua

    2008-01-01

    Epstein-Barr virus (EBV) infects various cell types in a wide spectrum of benign and malignant diseases. Laboratory tests for EBV have improved and are increasingly used in diagnosis, prognosis, prediction, and prevention of diseases ranging from infectious mononucleosis to selected subtypes of lymphoma, sarcoma, and carcinoma. Indeed, the presence of EBV is among the most effective tumor markers supporting clinical management of cancer patients. In biopsies, localization of EBER transcripts by in situ hybridization remains the gold standard for identifying latent infection. Other RNA- and protein-based assays detect lytic viral replication and can distinguish carcinoma-derived from lymphocyte-derived EBV in saliva or nasopharyngeal brushings. Analysis of blood using EBV viral load and serology reflects disease status and risk of progression. This review summarizes prior research in the context of basic virologic principles to provide a rational strategy for applying and interpreting EBV tests in various clinical settings. Such assays have been incorporated into standard clinical practice in selected settings such as diagnosis of primary infection and management of patients with immune dysfunction or nasopharyngeal carcinoma. As novel therapies are developed that target virus-infected cells or overcome the adverse effects of infection, laboratory testing becomes even more critical for determining when intervention is appropriate and the extent to which it has succeeded. PMID:18556771

  4. Epstein-Barr virus infection and nasopharyngeal carcinoma.

    PubMed

    Tsao, Sai Wah; Tsang, Chi Man; Lo, Kwok Wai

    2017-10-19

    Epstein-Barr virus (EBV) is associated with multiple types of human cancer, including lymphoid and epithelial cancers. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), which is endemic in the southern Chinese population. A strong association between NPC risk and the HLA locus at chromosome 6p has been identified, indicating a link between the presentation of EBV antigens to host immune cells and NPC risk. EBV infection in NPC is clonal in origin, strongly suggesting that NPC develops from the clonal expansion of a single EBV-infected cell. In epithelial cells, the default program of EBV infection is lytic replication. However, latent infection is the predominant mode of EBV infection in NPC. The establishment of latent EBV infection in pre-invasive nasopharyngeal epithelium is believed to be an early stage of NPC pathogenesis. Recent genomic study of NPC has identified multiple somatic mutations in the upstream negative regulators of NF-κB signalling. Dysregulated NF-κB signalling may contribute to the establishment of latent EBV infection in NPC. Stable EBV infection and the expression of latent EBV genes are postulated to drive the transformation of pre-invasive nasopharyngeal epithelial cells to cancer cells through multiple pathways.This article is part of the themed issue 'Human oncogenic viruses'. © 2017 The Author(s).

  5. How we treat chronic active Epstein-Barr virus infection.

    PubMed

    Sawada, Akihisa; Inoue, Masami; Kawa, Keisei

    2017-04-01

    Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of the EBV-associated T- or NK-cell lymphoproliferative diseases, which also include hypersensitivity to mosquito bites and severe-type hydroavacciniforme. The manifestations of CAEBV are often self-limiting with minimum supportive care or only prednisolone and cyclosporine A with or without etoposide. However, allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure, without which patients with CAEBV die within several years. A severe hypercytokinemia and hemophagocytic syndrome, which may occur suddenly, often results in a fatal clinical course. At out institute, we have established a 3-step strategy, including allogeneic HSCT, for the treatment of CAEBV. Seventy-nine patients with CAEBV and related diseases have been treated to date. The 3-year overall survival rate (3y-OS) is currently 87.3 ± 4.2% after planned allogeneic HSCT. However, 3y-OS in patients with uncontrolled active disease is only 16.7 ± 10.8%. To maximize survival rates with minimized late sequelae, we recommend earlier initiation and completion of the 3-step treatment without watchful waiting. We present six illustrative and difficult cases (including severe hypercytokinemia or emergent HSCT) and discuss them together with 73 residual cases.

  6. Epstein-Barr virus lymphoproliferative disease after solid organ transplantation.

    PubMed

    Prockop, Susan E; Vatsayan, Anant

    2017-11-01

    Epstein-Barr virus (EBV) was the first identified human oncovirus and is also one of the most ubiquitous viral infections known with established infections in more than 90% of individuals by early adulthood. EBV establishes latency by controlling expression of the viral genome making it silent to immune surveillance. In immunocompetent individuals, up to 1% of circulating T cells are directed at maintaining control over EBV replication. In addition to being involved in oncogenesis of lymphoid and epithelial tumors in immune-competent individuals, loss of immune surveillance over EBV predisposes individuals to EBV malignancies. Lymphoid proliferations from EBV-infected B cells arise in up to 20% of recipients of solid organ transplants (SOTs). One question not answered is why, when EBV requires such active immune surveillance, EBV malignancies are not even more prevalent in severely immune-compromised individuals. A better understanding of who develops complications related to EBV and what the immunologic risks are will ultimately make it feasible to perform prophylactic trials in those at highest risk. This review summarizes our current understanding of factors in SOT recipients that predispose them to the development of an EBV malignancy and that predict response to initial therapy. We then review the current landscape of those therapies, focusing on the goal of restoring long-term EBV-directed immunity to patients at risk. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  7. Prognostic factors for chronic active Epstein-Barr virus infection.

    PubMed

    Kimura, Hiroshi; Morishima, Tsuneo; Kanegane, Hirokazu; Ohga, Shouichi; Hoshino, Yo; Maeda, Akihiko; Imai, Shosuke; Okano, Motohiko; Morio, Tomohiro; Yokota, Shumpei; Tsuchiya, Shigeru; Yachie, Akihiro; Imashuku, Shinsaku; Kawa, Keisei; Wakiguchi, Hiroshi

    2003-02-15

    Chronic active Epstein-Barr virus infection (CAEBV) is a high-mortality and high-morbidity disease. To clarify the prognostic factors, a national survey was performed in Japan, and data for 82 patients who met the criteria for CAEBV were analyzed. Of these 82 patients, 47 were alive and 35 had already died. Multivariate analysis revealed that thromobocytopenia and age at disease onset were correlated with mortality. The probability of 5-year survival was 0.45 for older patients (onset age, > or = 8 years), 0.94 for younger patients (P<.001), 0.38 for patients with thrombocytopenia (platelet count < 12 x 10(4) platelets/microL at diagnosis), and 0.76 for patients without thrombocytopenia (P=.01). Furthermore, patients with T cell infection by EBV had shorter survival times than patients with natural killer cell infection (probability of 5-year survival, 0.59 vs. 0.87; P<.009). Patients with CAEBV with late onset of disease, thrombocytopenia, and T cell infection had significantly poorer outcomes.

  8. [Chronic active Epstein-Barr virus infection in an adult].

    PubMed

    Kościelak, Jerzy

    2009-01-01

    A chronic active Epstein-Barr virus infection (CAEBV) following infectious mononucleosis in a 58 years old woman is reported. The disease lasted for one year, and in spite of an intensive search for its cause, was diagnosed only at the 8th months since its onset. A low frequency of CAEBV in caucasians and patient's age were likely responsible for the belated diagnosis. The disease presented with a high, intermittent fever, general lymphoadenopathy, splenomegalia, hypoalbuminemia, polyclonal gamma globulinemia and malaise. Starting from the 6th month, i.e. before the diagnosis was established, a high dose oral therapy with methylprednisolone was introduced. The improvement was significant but the disease recurred after drug withdrawal. Nevertheless its course was milder. At the 8th month since the disease onset elevated antibody to viral capsid antigen (VCA) together with antibody to early antigen (EA) and nuclear antigen (EBNA) were still found in patient's blood. DNA of EBV was detected by PCR in patient's blood and saliva. The patient recovered completely after one year, and as of today i.e. June 2009, is feeling well. A likely cause of the successful steroid therapy is discussed. A review part of the article describes etiopathogenesis, complications, occurrence and treatment of CAEBV, as well as its relation to various lymphoproliferation disorders.

  9. An Epstein-Barr virus-associated superantigen

    PubMed Central

    1996-01-01

    More than 90% of adults are latently infected with Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, a self-limiting lymphoproliferative disease characterized by extensive T cell activation. Reactivation of this herpesvirus during immunosuppression is often associated with oncogenesis. These considerations led us to analyze the early events that occur after exposure of the immune system to EBV. Strong major histocompatibility complex (MHC) class II- dependent but not MHC-restricted, T cell proliferation was observed in vitro in response to autologous, lytically infected EBV-transformed B cells. By measuring the appearance of the early activation marker CD69 on individual T cell V beta subsets, we could demonstrate selective activation of human V beta 13- T cells. This was confirmed with murine T cell hybridomas expressing various human BV genes. While EBV- Burkitt's lymphoma cells were nonstimulatory, they induced V beta- restricted T cell activation after EBV infection. EBV specific activation was also demonstrated in cord blood cells, excluding a recall-antigen response. Thus, all of the characteristics of a superantigen-stimulated response are seen, indicating that induction of the EBV lytic cycle is associated with the expression of a superantigen in B cells. A model is presented proposing a role for the superantigen in infection, latency, and oncogenesis. PMID:9064357

  10. The Epstein-Barr Virus Regulome in Lymphoblastoid Cells.

    PubMed

    Jiang, Sizun; Zhou, Hufeng; Liang, Jun; Gerdt, Catherine; Wang, Chong; Ke, Liangru; Schmidt, Stefanie C S; Narita, Yohei; Ma, Yijie; Wang, Shuangqi; Colson, Tyler; Gewurz, Benjamin; Li, Guoliang; Kieff, Elliott; Zhao, Bo

    2017-10-11

    Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers. Deleting EBNA2 sites significantly reduced their target gene expression. Additional EBV super-enhancer (ESE) targets included MCL1, IRF4, and EBF. MYC ESE looping to the transcriptional stat site of MYC was dependent on EBNAs. Deleting MYC ESEs greatly reduced MYC expression and LCL growth. EBNA3A/3C altered CDKN2A/B spatial organization to suppress senescence. EZH2 inhibition decreased the looping at the CDKN2A/B loci and reduced LCL growth. This study provides a comprehensive view of the spatial organization of chromatin during EBV-driven cellular transformation. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Epstein-Barr Virus in Systemic Autoimmune Diseases

    PubMed Central

    Duus, Karen; Houen, Gunnar

    2013-01-01

    Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation. PMID:24062777

  12. Epstein-Barr virus in systemic autoimmune diseases.

    PubMed

    Draborg, Anette Holck; Duus, Karen; Houen, Gunnar

    2013-01-01

    Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation.

  13. Epstein-Barr Virus (EBV)-associated Gastric Carcinoma

    PubMed Central

    Iizasa, Hisashi; Nanbo, Asuka; Nishikawa, Jun; Jinushi, Masahisa; Yoshiyama, Hironori

    2012-01-01

    The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed. PMID:23342366

  14. Sexual history and Epstein-Barr virus infection.

    PubMed

    Crawford, Dorothy H; Swerdlow, Anthony J; Higgins, Craig; McAulay, Karen; Harrison, Nadine; Williams, Hilary; Britton, Kathryn; Macsween, Karen F

    2002-09-15

    To determine the role of sexual contact in transmission of Epstein-Barr virus (EBV) and occurrence of infectious mononucleosis (IM), a cross-sectional study was undertaken of EBV serologic testing and histories of IM and sexual behavior among 1006 new students at Edinburgh University. Prevalence of EBV seropositivity was significantly greater among women (79.2%) than among men (67.4%; P<.001) and among those who had ever been sexually active (82.7%) than among those who had not (63.7%; P<.001). Having a greater number of sex partners was a highly significant risk factor for EBV seropositivity. Two thirds of IM cases, but only a tenth of asymptomatic primary EBV infections, were statistically attributable to sexual intercourse. The findings suggest that EBV transmission occurs during sexual intercourse or closely associated behaviors. Transmission in this way appears to account for most cases of IM but for only a minority of cases of asymptomatic EBV infection, which mainly occur at younger ages.

  15. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient.

    PubMed

    Ates, İhsan; Kaplan, Mustafa; Yilmaz, Nisbet; Çiftçi, Filiz

    2015-01-01

    Acute hepatitis is a disorder that goes with liver cell necrosis and liver inflammation. Among the causes of acute hepatitis, the most common reasons are viral hepatitis. About 95% of the acute hepatitis generate because of hepatotropic viruses. Epstein-barr virus (EBV) and cytomegalovirus (CMV) are from the family of herpes viruses and rare causes of acute hepatitis. In this case report, acute hepatitis due to EBV and CMV coinfection will be described. Ates İ, Kaplan M, Yilmaz N, Çiftçi F. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient. Euroasian J Hepato-Gastroenterol 2015;5(1):60-61.

  16. Epstein-Barr virus and rheumatoid arthritis: is there a link?

    PubMed

    Costenbader, Karen H; Karlson, Elizabeth W

    2006-01-01

    Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic, destructive, debilitating arthritis. Its etiology is unknown; it is presumed that environmental factors trigger development in the genetically predisposed. Epstein-Barr virus, a nearly ubiquitous virus in the human population, has generated great interest as a potential trigger. This virus stimulates polyclonal lymphocyte expansion and persists within B lymphocytes for the host's life, inhibited from reactivating by the immune response. In latent and replicating forms, it has immunomodulating actions that could play a role in the development of this autoimmune disease. The evidence linking Epstein-Barr virus and rheumatoid arthritis is reviewed.

  17. Prevalence of herpes simplex, Epstein Barr and human papilloma viruses in oral lichen planus.

    PubMed

    Yildirim, Benay; Sengüven, Burcu; Demir, Cem

    2011-03-01

    The aim of the present study was to assess the prevalence of Herpes Simplex virus, Epstein Barr virus and Human Papilloma virus -16 in oral lichen planus cases and to evaluate whether any clinical variant, histopathological or demographic feature correlates with these viruses. The study was conducted on 65 cases. Viruses were detected immunohistochemically. We evaluated the histopathological and demographic features and statistically analysed correlation of these features with Herpes Simplex virus, Epstein Barr virus and Human Papilloma virus-16 positivity. Herpes Simplex virus was positive in six (9%) cases and this was not statistically significant. The number of Epstein Barr virus positive cases was 23 (35%) and it was statistically significant. Human Papilloma virus positivity in 14 cases (21%) was statistically significant. Except basal cell degeneration in Herpes Simplex virus positive cases, we did not observe any significant correlation between virus positivity and demographic or histopathological features. However an increased risk of Epstein Barr virus and Human Papilloma virus infection was noted in oral lichen planus cases. Taking into account the oncogenic potential of both viruses, oral lichen planus cases should be detected for the presence of these viruses.

  18. Pediatric Miller Fisher Syndrome Complicating an Epstein-Barr Virus Infection.

    PubMed

    Communal, Céline; Filleron, Anne; Baron-Joly, Sandrine; Salet, Randa; Tran, Tu-Anh

    2016-10-01

    Miller Fisher syndrome, a variant of Guillain-Barré syndrome, is an acute inflammatory demyelinating polyradiculoneuropathy that may occur weeks after a bacterial or viral infection. Campylobacter jejuni and Haemophilus influenzae are frequently reported etiological agents. We describe a boy with Miller Fisher syndrome following Epstein-002DBarr virus primary infectious mononucleosis. He presented with bilateral dysfunction of several cranial nerves and hyporeflexia of the limbs but without ataxia. Miller Fisher syndrome was confirmed by the presence of anti-GQ1b antibodies in a blood sample. Epstein-Barr virus was identified by polymerase chain reaction and serology. Epstein-Barr virus should be considered as a Miller Fisher syndrome's causative agent. The physiopathology of this condition may involve cross-reactive T-cells against Epstein-Barr virus antigens and gangliosides. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Cordycepin enhances Epstein-Barr virus lytic infection and Epstein-Barr virus-positive tumor treatment efficacy by doxorubicin.

    PubMed

    Du, Yinping; Yu, Jieshi; Du, Li; Tang, Jun; Feng, Wen-Hai

    2016-07-01

    The consistent latent presence of Epstein-Barr virus (EBV) in tumor cells offers potential for virus-targeted therapies. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. In this study, we report that a natural small molecule compound, cordycepin, can induce lytic EBV infection in tumor cells. Subsequently, we demonstrate that cordycepin can enhance EBV reactivating capacity and EBV-positive tumor cell killing ability of low dose doxorubicin. The combination of cordycepin and doxorubicin phosphorylates CCAAT/enhancer binding protein β (C/EBPβ) through protein kinase C (PKC)-p38 mitogen activated protein kinases (p38 MAPK) signaling pathway, and C/EBPβ is required for the activation of lytic EBV infection. Most importantly, an in vivo experiment demonstrates that the combination of cordycepin and doxorubicin is more effective in inhibiting tumor growth in SCID mice than is doxorubicin alone. Our findings establish that cordycepin can enhance the efficacy of conventional chemotherapy for treatment of EBV-positive tumors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. [Description of a peculiar form of Hodgkin's disease associated with Epstein-Barr virus infection].

    PubMed

    Elira Dokekias, A; Koko, I; Atipo Galiba, F O; Martin, A

    2007-10-01

    The authors report a peculiar form of Hodgkin's disease that is associated with Epstein-Barr virus infection. A 16-year-old patient was admitted for an autoimmune haemolytic anaemia associated with IgG auto-immune antibodies, linked to general clinical complications, cervical adenopathies and splenomegalia. The patient underwent hemicavectomy that was not histologically investigated. The ganglionar exeresis helped to establish the histological diagnosis of Hodgkin's disease, classic form with nodular sclerosis. Tumour cells were CD30 CD15 positive and neighbouring lymphoid cells were CD3 and CD20 positive. In situ hybridation allowed the detection of Epstein-Barr virus in tumour cells. Under ABVD chemotherapy supplemented with acyclovir and initial corticotherapy, mid-treatment evolution appears to be favourable. This observation is consistent with the hypothesis that tumour cells are of B cell origin during Hodgkin's disease, together with the involvement of Epstein-Barr virus in lymphomagenesis.

  1. Acute acalculous cholecystitis with pericholecystitis in a patient with Epstein-Barr Virus infectious mononucleosis.

    PubMed

    Chalupa, Pavel; Kaspar, Miroslav; Holub, Michal

    2009-02-01

    Acute acalculous cholecystitis is a rare complication of Epstein-Barr virus mononucleosis and involves thickening of the gallbladder wall. We describe the case of a 22-year-old woman with acute acalculous cholecystitis and pericholecystitis associated with Epstein-Barr virus primary infection. Surgical intervention was not performed, even though gallbladder perforation was suspected. The patient was treated conservatively with careful monitoring, including repeated ultrasonographic examinations. Epstein-Barr virus infections are usually self-limited, and surgical treatment of acute acalculous cholecystitis should only be considered when the ultrasonographic criteria persist on follow-up examinations or when they deteriorate. This is the first report of a severe course of acute acalculous cholecystitis with suspected gallbladder perforation associated with infectious mononucleosis.

  2. Epstein-Barr Virus Infection in Chronically Inflamed Periapical Granulomas

    PubMed Central

    Makino, Kosuke; Takeichi, Osamu; Hatori, Keisuke; Imai, Kenichi; Ochiai, Kuniyasu; Ogiso, Bunnai

    2015-01-01

    Periapical granulomas are lesions around the apex of a tooth caused by a polymicrobial infection. Treatment with antibacterial agents is normally performed to eliminate bacteria from root canals; however, loss of the supporting alveolar bone is typically observed, and tooth extraction is often selected if root canal treatment does not work well. Therefore, bacteria and other microorganisms could be involved in this disease. To understand the pathogenesis of periapical granulomas more precisely, we focused on the association with Epstein-Barr virus (EBV) using surgically removed periapical granulomas (n = 32). EBV DNA was detected in 25 of 32 periapical granulomas (78.1%) by real-time PCR, and the median number of EBV DNA copies was approximately 8,688.01/μg total DNA. In contrast, EBV DNA was not detected in healthy gingival tissues (n = 10); the difference was statistically significant according to the Mann-Whitney U test (p = 0.0001). Paraffin sections were also analyzed by in situ hybridization to detect EBV-encoded small RNA (EBER)-expressing cells. EBER was detected in the cytoplasm and nuclei of B cells and plasma cells in six of nine periapical granulomas, but not in healthy gingival tissues. In addition, immunohistochemical analysis for latent membrane protein 1 (LMP-1) of EBV using serial tissue sections showed that LMP-1-expressing cells were localized to the same areas as EBER-expressing cells. These data suggest that B cells and plasma cells in inflamed granulomas are a major source of EBV infection, and that EBV could play a pivotal role in controlling immune cell responses in periapical granulomas. PMID:25884725

  3. Epstein-Barr Virus Shedding by Astronauts During Space Flight

    NASA Technical Reports Server (NTRS)

    Pierson, D. L.

    2004-01-01

    Patterns of Epstein-Barr virus (EBV) reactivation in 32 astronauts and 18 healthy age-matched control subjects were characterized by quantifying EBV shedding. Saliva samples were collected from astronauts before, during, and after 10 space shuttle missions of 5 to 14 d duration. Samples were collected on a similar schedule from control subjects. At one time point or another, EBV was detected in saliva from each of the astronauts. Of 1398 saliva specimens from 32 astronauts, polymerase chain reaction analysis showed that 314 (23%) were positive for EBV DNA. Examination by flight phase showed that 29% of the saliva specimens collected before flight were positive for EBV DNA, as were 16% of those collected during flight and 16% of those collected after flight. The mean number of copies of EBV DNA from samples taken during the flights was 417 plus or minus 31, significantly greater (p less than 0.05) than the number of copies from the preflight (40 plus or minus 2) and postflight (44 plus or minus 5) phases. In contrast, the control subjects shed EBV DNA with a frequency of 3.7% and a mean number of EBV DNA copies of 40 plus or minus 2 per mL of saliva. Ten days before flight and on landing day, titers of antibody to EBV viral capsid antigen were significantly (p less than 0.05) greater than baseline levels. On landing day, urinary levels of cortisol and catecholamines, and plasma levels of substance P and other neuropeptides, were increased over their preflight values. Increases in the number of viral copies and in the amount of EBV-specific antibody were consistent with the occurrence of EBV reactivation before, during, and after space flight.

  4. Porphyromonas endodontalis reactivates latent Epstein-Barr virus.

    PubMed

    Makino, K; Takeichi, O; Imai, K; Inoue, H; Hatori, K; Himi, K; Saito, I; Ochiai, K; Ogiso, B

    2018-06-01

    To determine whether Porphyromonas endodontalis can reactivate latent Epstein-Barr virus (EBV). The concentrations of short-chain fatty acids (SCFAs) in P. endodontalis culture supernatants were determined using high-performance liquid chromatography. A promoter region of BamHI fragment Z leftward open reading frame 1 (BZLF-1), which is a transcription factor that controls the EBV lytic cycle, was cloned into luciferase expression vectors. Then, the luciferase assay was performed using P. endodontalis culture supernatants. Histone acetylation using Daudi cells treated with P. endodontalis culture supernatants was examined using Western blotting. BZLF-1 mRNA and BamHI fragment Z EB replication activator (ZEBRA) protein were also detected quantitatively using real-time polymerase chain reaction (PCR) and Western blotting. Surgically removed periapical granulomas were examined to detect P. endodontalis, EBV DNA, and BZLF-1 mRNA expression using quantitative real-time PCR. Statistical analysis using Steel tests was performed. The concentrations of n-butyric acid in P. endodontalis culture supernatants were significantly higher than those of other SCFAs (P=0.0173). Using B-95-8-221 Luc cells treated with P. endodontalis culture supernatants, the luciferase assay demonstrated that P. endodontalis induced BZLF-1 expression. Hyperacetylation of histones was also observed with the culture supernatants. BZLF-1 mRNA and ZEBRA protein were expressed by Daudi cells in a dose-dependent manner after the treatment with P. endodontalis culture supernatants. P. endodontalis and BZLF-1 in periapical granulomas were also detected. The expression levels of BZLF-1 mRNA were similar to the numbers of P. endodontalis cells in each specimen. n-butyric acid produced by P. endodontalis reactivated latent EBV. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  5. Epstein-Barr virus shedding by astronauts during space flight

    NASA Technical Reports Server (NTRS)

    Pierson, D. L.; Stowe, R. P.; Phillips, T. M.; Lugg, D. J.; Mehta, S. K.

    2005-01-01

    Patterns of Epstein-Barr virus (EBV) reactivation in 32 astronauts and 18 healthy age-matched control subjects were characterized by quantifying EBV shedding. Saliva samples were collected from astronauts before, during, and after 10 space shuttle missions of 5-14 days duration. At one time point or another, EBV was detected in saliva from each of the astronauts. Of 1398 saliva specimens from 32 astronauts, polymerase chain reaction analysis showed that 314 (23%) were positive for EBV DNA. Examination by flight phase showed that 29% of the saliva specimens collected from 28 astronauts before flight were positive for EBV DNA, as were 16% of those collected from 25 astronauts during flight and 16% of those collected after flight from 23 astronauts. The mean number of EBV copies from samples taken during the flights was 417 per mL, significantly greater (p<.05) than the number of viral copies from the preflight (40) and postflight (44) phases. In contrast, the control subjects shed EBV DNA with a frequency of 3.7% and mean number of EBV copies of 40 per mL of saliva. Ten days before flight and on landing day, titers of antibody to EBV viral capsid antigen were significantly (p<.05) greater than baseline levels. On landing day, urinary levels of cortisol and catecholamines were greater than their preflight values. In a limited study (n=5), plasma levels of substance P and other neuropeptides were also greater on landing day. Increases in the number of viral copies and in the amount of EBV-specific antibody were consistent with EBV reactivation before, during, and after space flight.

  6. Mouse model for acute Epstein-Barr virus infection.

    PubMed

    Wirtz, Tristan; Weber, Timm; Kracker, Sven; Sommermann, Thomas; Rajewsky, Klaus; Yasuda, Tomoharu

    2016-11-29

    Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMP-expressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.

  7. Atypical manifestations of Epstein-Barr virus in children: a diagnostic challenge.

    PubMed

    Bolis, Vasileios; Karadedos, Christos; Chiotis, Ioannis; Chaliasos, Nikolaos; Tsabouri, Sophia

    2016-01-01

    Clarify the frequency and the pathophysiological mechanisms of the rare manifestations of Epstein-Barr virus infection. Original research studies published in English between 1985 and 2015 were selected through a computer-assisted literature search (PubMed and Scopus). Computer searches used combinations of key words relating to "EBV infections" and "atypical manifestation." Epstein-Barr virus is a herpes virus responsible for a lifelong latent infection in almost every adult. The primary infection concerns mostly children and presents with the clinical syndrome of infectious mononucleosis. However, Epstein-Barr virus infection may exhibit numerous rare, atypical and threatening manifestations. It may cause secondary infections and various complications of the respiratory, cardiovascular, genitourinary, gastrointestinal, and nervous systems. Epstein-Barr virus also plays a significant role in pathogenesis of autoimmune diseases, allergies, and neoplasms, with Burkitt lymphoma as the main representative of the latter. The mechanisms of these manifestations are still unresolved. Therefore, the main suggestions are direct viral invasion and chronic immune response due to the reactivation of the latent state of the virus, or even various DNA mutations. Physicians should be cautious about uncommon presentations of the viral infection and consider EBV as a causative agent when they encounter similar clinical pictures. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  8. Epstein-Barr virus recombinants from overlapping cosmid fragments.

    PubMed

    Tomkinson, B; Robertson, E; Yalamanchili, R; Longnecker, R; Kieff, E

    1993-12-01

    Five overlapping type 1 Epstein-Barr virus (EBV) DNA fragments constituting a complete replication- and transformation-competent genome were cloned into cosmids and transfected together into P3HR-1 cells, along with a plasmid encoding the Z immediate-early activator of EBV replication. P3HR-1 cells harbor a type 2 EBV which is unable to transform primary B lymphocytes because of a deletion of DNA encoding EBNA LP and EBNA 2, but the P3HR-1 EBV can provide replication functions in trans and can recombine with the transfected cosmids. EBV recombinants which have the type 1 EBNA LP and 2 genes from the transfected EcoRI-A cosmid DNA were selectively and clonally recovered by exploiting the unique ability of the recombinants to transform primary B lymphocytes into lymphoblastoid cell lines. PCR and immunoblot analyses for seven distinguishing markers of the type 1 transfected DNAs identified cell lines infected with EBV recombinants which had incorporated EBV DNA fragments beyond the transformation marker-rescuing EcoRI-A fragment. Approximately 10% of the transforming virus recombinants had markers mapping at 7, 46 to 52, 93 to 100, 108 to 110, 122, and 152 kbp from the 172-kbp transfected genome. These recombinants probably result from recombination among the transfected cosmid-cloned EBV DNA fragments. The one recombinant virus examined in detail by Southern blot analysis has all the polymorphisms characteristic of the transfected type 1 cosmid DNA and none characteristic of the type 2 P3HR-1 EBV DNA. This recombinant was wild type in primary B-lymphocyte infection, growth transformation, and lytic replication. Overall, the type 1 EBNA 3A gene was incorporated into 26% of the transformation marker-rescued recombinants, a frequency which was considerably higher than that observed in previous experiments with two-cosmid EBV DNA cotransfections into P3HR-1 cells (B. Tomkinson and E. Kieff, J. Virol. 66:780-789, 1992). Of the recombinants which had incorporated the

  9. Inflammatory bowel disease exacerbation associated with Epstein-Barr virus infection.

    PubMed

    Dimitroulia, Evangelia; Pitiriga, Vassiliki C; Piperaki, Evangelia-Theophano; Spanakis, Nicholas E; Tsakris, Athanassios

    2013-03-01

    Epstein-Barr virus infection is associated with inflammatory bowel disease, but its role as a pathogenetic or exacerbating factor remains unclear. The aim of this study was to evaluate the association between Epstein-Barr virus infection and inflammatory bowel disease, particularly in regard to exacerbation of disease activity. This was a nonrandomized crosssectional study in subgroups of patients with inflammatory bowel disease compared with a control group with noninflammatory disease. Participants were patients treated for ulcerative colitis or Crohn's disease and individuals undergoing evaluation for noninflammatory disease recruited from 2 urban adult gastrointestinal referral centers in Greece. Diagnosis of inflammatory bowel disease was based on standard clinical and endoscopic criteria. Demographic and clinical characteristics of all participants were recorded. Whole blood samples and fresh tissue samples from biopsy of intestinal sites were obtained from each participant. The presence of Epstein-Barr virus was determined by amplifying the LMP1 gene of the virus in blood and intestinal tissue samples. The study comprised 94 patients with inflammatory bowel disease (63 with ulcerative colitis and 31 with Crohn's disease) and 45 controls with noninflammatory disease. Of the 94 patients, 67 (71.3%) had disease exacerbation and 27 (28.7%) were in remission. The prevalence of Epstein-Barr virus genome was significantly higher in patients than in controls for intestinal tissue (44 patients, 46.8% vs 6 controls, 13.3%; p = 0.001), but not for whole blood (24 patients, 25.5% vs 9 controls, 20%; p = 0.3). The viral genome was found significantly more frequently in intestinal samples from patients with disease exacerbation compared with patients in remission (38 patients with exacerbation, 56.7% vs 6 patients in remission, 22.2%; p = 0.001), but no significant difference was found for whole blood (18 patients with exacerbation, 26.8% vs 6 patients in remission, 22

  10. Emotional Disclosure through Writing or Speaking Modulates Latent Epstein-Barr Virus Antibody Titers.

    ERIC Educational Resources Information Center

    Esterling, Brian A.; And Others

    1994-01-01

    Healthy Epstein-Barr virus (EBV) seropositive undergraduates (n=57) completed personality inventory, provided blood samples, and were randomly assigned to write/talk about stressful events, or to write about trivial events. Those assigned to verbal/stressful condition had significantly lower EBV antibody titers (suggesting better cellular immune…

  11. Epstein-Barr virus myocarditis as the first symptom of infectious mononucleosis.

    PubMed

    Zabala López, Sergio; Vicario, Juana M; Lerín, Francisco J; Fernández, Amalia; Pérez, Gloria; Fonseca, Cherpentier

    2010-01-01

    This case report describes a 20-year-old immunocompetent man with an episode of chest pain radiating into both arms, an increase in the level of myocardial enzymes, electrocardiogram abnormalities (widespread ST-segment elevation and q waves in leads V(4)-V(6)) and serological evidence for acute Epstein-Barr Virus infection preceding typical signs and symptoms of infectious mononucleosis.

  12. [Adoptive transfer of Epstein-Barr virus-specific T-lymphocytes in chronic active Epstein-Barr infection].

    PubMed

    Babel, N; Hammer, M H; Reinke, P

    2003-03-14

    A 27-year-old man was admitted because of intermittent fever, fatigue, lymphadenopathy and splenomegaly for 20 years. Chronic administration of 6 - 8 g aspirin per day (self-prescribed) resulted in limited control of symptoms and in the development of analgesic nephropathy. The patient had prominent splenomegaly and lymphadenopathy without histological signs of malignancy. Monocytosis and T-lymphopenia were also present. Infectious disease testing revealed IgG+/IgM- EBV serology and EA-EBV-mRNA nested PCR clearly demonstrated the presence of lytic EBV-proteins in PBMCs. As chronic active Epstein-Barr virus infection (CAEBV) was highly probable, treatment with aciclovir, gancilovir and steroids was started. Because treatment failed adoptive T-cell transfer with autologous EBV-specific T-cells was performed. After three consecutive infusions the patient responded with a complete remission of fever, fatigue, lymphadenopathy and splenomegaly without adverse effects. Retrospective real-time PCR analysis showed a decrease in viral load from 62847 copies/ microg DNA to 45 - 250 copies after treatment. The patient remains in stable remission without signs of CAEBV (> 4 years). Adoptive transfer of autologous, EBV-specific T-lymphocytes is a promising treatment in CAEBV.

  13. Immune responses to epstein-barr virus in atomic bomb survivors: Study of precursor frequency of cytotoxic lymphocytes and titer levels of anti-Epstein-Barr virus-related antibodies

    SciTech Connect

    Kusunoki, Yoichiro; Kyoizumi, Seishi; Saito, Mayumi

    Precursor frequencies of cytotoxic lymphocytes to autologous Epstein-Barr virus-transformed B cells and serum titers of anti-Epstein-Barr virus-related antibodies were measured in 68 atomic bomb survivors to clarify the immune mechanism controlling Epstein-Barr virus infection. The precursor frequency was negatively correlated with the titer of anti-early antigen lgG, which is probably produced at the stage of viral reactivation. A positive correlation between the precursor frequency and titer of anti-Epstein-Barr virus-associated nuclear antigen antibody was also observed, indicating that the precursor frequency reflects the degree of in vivo destruction by T cells of the virus-infected cells. These results suggest that T-cell memorymore » specific to Epstein-Barr virus keeps the virus under control and that the precursor frequency assay is useful for the evaluation of immune responses to Epstein-Barr virus. However, no significant effect of atomic bomb radiation on the precursor frequency was observed in the present study, probably due to the limited number of participants. 24 refs., 4 figs., 2 tabs.« less

  14. Evaluation of a new reagent for anti-cytomegalovirus and anti-Epstein-Barr virus immunoglobulin G.

    PubMed Central

    Gutierrez, J; Maroto, M D; Piédrola, G

    1994-01-01

    The Enzygnost alpha method was tested against the complement fixation test and anti-VCA immunofluorescence to determine the respective titers of anti-cytomegalovirus and anti-Epstein-Barr virus immunoglobulin G antibodies. For cytomegalovirus, the Enzygnost results showed 97.99% agreement with the readings obtained by the alternative method, with 100% sensitivity and 93.7% specificity. For Epstein-Barr virus, Enzygnost showed 97.71% agreement, 100% sensitivity, and 91.11% specificity. PMID:7814510

  15. Maribavir Inhibits Epstein-Barr Virus Transcription through the EBV Protein Kinase

    PubMed Central

    Whitehurst, Christopher B.; Sanders, Marcia K.; Law, Mankit; Wang, Fu-Zhang; Xiong, Jie; Dittmer, Dirk P.

    2013-01-01

    Maribavir (MBV) inhibits Epstein-Barr virus (EBV) replication and the enzymatic activity of the viral protein kinase BGLF4. MBV also inhibits expression of multiple EBV transcripts during EBV lytic infection. Here we demonstrate, with the use of a BGLF4 knockout virus, that effects of MBV on transcription take place primarily through inhibition of BGLF4. MBV inhibits viral genome copy numbers and infectivity to levels similar to and exceeding levels produced by BGLF4 knockout virus. PMID:23449792

  16. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient

    PubMed Central

    Kaplan, Mustafa; Yilmaz, Nisbet; Çiftçi, Filiz

    2015-01-01

    Acute hepatitis is a disorder that goes with liver cell necrosis and liver inflammation. Among the causes of acute hepatitis, the most common reasons are viral hepatitis. About 95% of the acute hepatitis generate because of hepatotropic viruses. Epstein-barr virus (EBV) and cytomegalovirus (CMV) are from the family of herpes viruses and rare causes of acute hepatitis. In this case report, acute hepatitis due to EBV and CMV coinfection will be described. How to cite this article Ates İ, Kaplan M, Yilmaz N, Çiftçi F. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient. Euroasian J Hepato-Gastroenterol 2015;5(1):60-61. PMID:29201691

  17. Epstein-Barr Virus: The Path from Latent to Productive Infection.

    PubMed

    Chiu, Ya-Fang; Sugden, Bill

    2016-09-29

    The intrinsic properties of different viruses have driven their study. For example, the capacity for efficient productive infection of cultured cells by herpes simplex virus 1 has made it a paradigm for this mode of infection for herpesviruses in general. Epstein-Barr virus, another herpesvirus, has two properties that have driven its study: It causes human cancers, and it exhibits a tractable transition from its latent to its productive cycle in cell culture. Here, we review our understanding of the path Epstein-Barr virus follows to move from a latent infection to and through its productive cycle. We use information from human infections to provide a framework for describing studies in cell culture and, where possible, the molecular resolutions from these studies. We also pose questions whose answers we think are pivotal to understanding this path, and we provide answers where we can.

  18. The Long and Complicated Relationship between Epstein-Barr Virus and Epithelial Cells.

    PubMed

    Hutt-Fletcher, Lindsey M

    2017-01-01

    The roles of epithelial cells in infection and persistence of the Epstein-Barr virus (EBV) have long been difficult to resolve. However, recent developments have reinforced the conclusion that these cells are a major site of virus replication and raised the possibility that, like papillomaviruses, EBV has evolved to take advantage of epithelial differentiation to ensure survival, persistence, and spread. Copyright © 2016 American Society for Microbiology.

  19. Clinical significance of spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia in Epstein-Barr virus-associated and Epstein-Barr virus-negative gastric cancer.

    PubMed

    Zhang, Yu; Chen, Jian-Ning; Dong, Min; Zhang, Zhi-Gang; Zhang, Yi-Wang; Wu, Jun-Yan; Du, Hong; Li, Hai-Gang; Huang, Yan; Shao, Chun-Kui

    2017-05-01

    Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) have been recognized as neoplastic precursors in gastric carcinogenesis. We explored the relationship between SPEM and IM in Epstein-Barr virus-associated (EBVaGC) and Epstein-Barr virus-negative (EBVnGC) gastric cancer. Sixty-four EBVaGC and one hundred and fifty-four EBVnGC patients were included. EBV positivity was identified using Epstein-Barr virus-encoded RNA-1 in situ hybridization. SPEM was subclassified into absent, early, and advanced SPEM. Acute and chronic inflammation was graded as absent, mild, moderate, and marked. Univariate and multivariate logistic regression analyses were conducted to analyze the correlation between SPEM, IM, and inflammation. Our study revealed that SPEM was detected in 87.5% EBVaGC and 85.1% EBVnGC patients. Distribution of patients according to the SPEM classification was significantly different between EBVaGC and EBVnGC groups (P=.038). IM was observed less frequently in EBVaGC when compared with EBVnGC patients (P<.001). No difference was observed between EBVaGC and EBVnGC in the levels of acute and chronic inflammation. A positive correlation between IM and SPEM status was observed in both EBVaGC and EBVnGC patients. Furthermore, advanced SPEM was an independent influential factor to IM in EBVnGC (P=.013). In conclusion, SPEM was associated with both EBVaGC and EBVnGC more frequently than IM. Moreover, advanced SPEM had a stronger association with IM than early SPEM in EBVnGC. These results suggest that identification of SPEM should be used as a high-risk indicator for detecting early gastric carcinoma, and should be brought to the attention of pathologists and clinicians. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Systemic lupus erythematosus due to Epstein-Barr virus or Epstein-Barr virus infection provocating acute exacerbation of systemic lupus erythematosus?

    PubMed

    Kasapcopur, Ozgur; Ergul, Yakup; Kutlug, Seyhan; Candan, Cengiz; Camcioglu, Yildiz; Arisoy, Nil

    2006-06-01

    Systemic lupus erythematosus (SLE) is a rheumatologic disease characterized by an inflammatory destruction of the target organ systems of the body in an unknown way by autoantibodies formed against self-antigens. Infectious agents like Epstein-Barr virus (EBV), cytomegalovirus and parvovirus B19 may have a role in the occurrence or the exacerbation of the SLE. In this report, the clinical follow-up of a 14-year-old girl diagnosed with SLE following an EBV infection with bicytopenia, lymphadenomegaly and hepatomegaly is discussed. This case could support the role of viral infections in the etiology of SLE.

  1. An Adult Case of Chronic Active Epstein-Barr Virus Infection with Interstitial Pneumonitis

    PubMed Central

    Joo, Eun-Jeong; Ha, Young Eun; Jung, Dong Sik; Cheong, Hae Suk; Wi, Yu Mi; Song, Jae-Hoon

    2011-01-01

    Chronic active Epstein-Barr virus (CAEBV) infection is characterized by persistent infectious mononucleosis-like symptoms, an unusual pattern of Epstein-Barr virus (EBV) antibodies, detection of the EBV genome in affected tissues or peripheral blood, and chronic illness that cannot be attributed to any other known disease. This is the first reported Korean case of an immunocompetent adult with CAEBV-associated interstitial pneumonitis. A 28-year-old female was admitted with a fever that persisted for 3 weeks. She had multiple lymphadenopathy, hepatosplenomegaly, pancytopenia, and elevated serum aminotransferase levels. Serology for antibodies was positive and chest computed tomography showed diffuse ground glass opacities in both lungs. Histopathology of the lung tissue showed lymphocyte infiltration, and EBV DNA was detected in those lymphocytes using in situ hybridization with an EBV-encoded RNA probe. After 1 month of hospitalization, she improved without specific treatment. PMID:22205850

  2. An adult case of chronic active Epstein-Barr virus infection with interstitial pneumonitis.

    PubMed

    Joo, Eun-Jeong; Ha, Young Eun; Jung, Dong Sik; Cheong, Hae Suk; Wi, Yu Mi; Song, Jae-Hoon; Peck, Kyong Ran

    2011-12-01

    Chronic active Epstein-Barr virus (CAEBV) infection is characterized by persistent infectious mononucleosis-like symptoms, an unusual pattern of Epstein-Barr virus (EBV) antibodies, detection of the EBV genome in affected tissues or peripheral blood, and chronic illness that cannot be attributed to any other known disease. This is the first reported Korean case of an immunocompetent adult with CAEBV-associated interstitial pneumonitis. A 28-year-old female was admitted with a fever that persisted for 3 weeks. She had multiple lymphadenopathy, hepatosplenomegaly, pancytopenia, and elevated serum aminotransferase levels. Serology for antibodies was positive and chest computed tomography showed diffuse ground glass opacities in both lungs. Histopathology of the lung tissue showed lymphocyte infiltration, and EBV DNA was detected in those lymphocytes using in situ hybridization with an EBV-encoded RNA probe. After 1 month of hospitalization, she improved without specific treatment.

  3. T-cell receptor gene rearrangement in Epstein-Barr virus infectious mononucleosis.

    PubMed

    Marbello, L; Riva, M; Veronese, S; Nosari, A M; Ravano, E; Colosimo, A; Paris, L; Morra, E

    2012-09-01

    This report describes the case of a previously healthy young man who presented with fever, pharyngitis, cervical lymphadenopathy, lymphocytosis, and severe thrombocytopenia. Serological tests for Epstein-Barr virus were diagnostic of a primary Epstein-Barr virus infectious mononucleosis but severe thrombocytopenia aroused the suspicion of a lymphoproliferative disease. T-cell receptor gene analysis performed on peripheral and bone marrow blood revealed a T-cell receptor γ-chain rearrangement without the evidence of malignancy using standard histologic and immunophenotype studies. Signs and symptoms of the infectious disease, blood count, and T-cell receptor gene rearrangement resolved with observation without the evidence of emergence of a lymphoproliferative disease. In the contest of a suspected lymphoproliferative disease, molecular results should be integrated with all available data for an appropriate diagnosis.

  4. Acute disseminated encephalomyelitis and thrombocytopenia following Epstein-Barr virus infection.

    PubMed

    Saeed, Muhammad; Dabbagh, Omar; Al-Muhaizae, Muhammad; Dhalaan, Hesham; Chedrawi, Aziza

    2014-11-01

    Epstein-Barr Virus (EBV) causes a broad spectrum of disease in humans with several clinical syndromes and is ubiquitous, infecting more than 95% of the world's population. Central Nervous System (CNS) disease alone associated with Epstein-Barr virus rarely occurs in previously healthy individuals. Systemic viral illness in children and complications are rare, but may occur. In few cases, it is associated with a variety of CNS and hematological complications like acute disseminated encephalomyelitis, transverse myelitis, neuropsychiatric syndrome, GBS, autoimmune thrombocytopenia and hemolytic anemia and they usually respond to immunotherapy. We report previously healthy boy, who presented with left sided weakness, headache and thrombocytopenia following EBV infection. The thrombocytopenia was resistant to intravenous immunoglobulin and methylprednisolone but responded well to Rituximab.

  5. M-protein-positive chronic active Epstein-Barr virus infection: features mimicking HIV-1 infection.

    PubMed

    Imashuku, Shinsaku; Azuma, Naoto; Kanegane, Hirokazu; Kasahara, Yoshihito

    2009-09-01

    Chronic active Epstein-Barr virus infection (CAEBV) is a unique and fatal lymphoproliferative disease (LPD), which often shows high serum IgG and/or IgE. The significance of such immunoglobulin abnormalities in CAEBV has not been fully evaluated and discussed. In addition, such clinical features mimic HIV-1 infection. We report here a case of CAEBV with M-protein detected which may shed a new light on the pathogenesis of this disease.

  6. Increasing Incidence of Severe Epstein-Barr Virus-Related Infectious Mononucleosis: Surveillance Study

    PubMed Central

    Tattevin, Pierre; Le Tulzo, Yves; Minjolle, Sophie; Person, Arnaud; Chapplain, Jean Marc; Arvieux, Cedric; Thomas, Remi; Michelet, Christian

    2006-01-01

    Older patients are more susceptible to severe Epstein-Barr virus (EBV)-related infectious mononucleosis (IM). This condition may increase in industrialized countries where primary EBV infection occurs later in life. Between 1990 and 2004, 38 patients were admitted to our department with EBV-related IM. Two patients died. The annual incidence increased significantly (r = 0.623; P = 0.013). PMID:16672427

  7. Acute renal failure: unusual complication of Epstein-Barr virus-induced infectious mononucleosis.

    PubMed

    Lei, P S; Lowichik, A; Allen, W; Mauch, T J

    2000-12-01

    A 17-year-old boy with juvenile rheumatoid arthritis presented with jaundice, confusion, hemolytic anemia, thrombocytopenia, and acute renal failure secondary to titer-confirmed acute Epstein-Barr virus (EBV). Renal biopsy specimen revealed interstitial nephritis with an inflammatory infiltrate composed of cytotoxic/suppressor T cells, and interstitial mononuclear cell nuclei expressed EBV encoded RNA-1 (EBER-1) mRNA. Methylprednisolone treatment resulted in rapid improvement.

  8. Genetic polymorphism of natural Epstein-Barr virus isolates from infectious mononucleosis patients and healthy carriers.

    PubMed Central

    Lung, M L; Chang, R S; Jones, J H

    1988-01-01

    We analyzed Epstein-Barr virus (EBV) genomes from lymphoblastoid cell lines isolated from patients with infectious mononucleosis and from healthy subjects from California, Hawaii, and Hong Kong between 1970 and 1987. Using genetic polymorphism as epidemiological markers, we found that several genotypes of EBV cocirculate in a community and that although most EBV strains isolated from California and Southern China may be differentiated genotypically, there was no specific association between genotype and disease or time of isolation. Images PMID:2901499

  9. Severe systemic autoimmune disease associated with Epstein-Barr virus infection.

    PubMed

    Sevilla, Julián; del Carmen Escudero, Maria; Jiménez, Raquel; González-Vicent, Marta; Manzanares, Javier; García-Novo, Dolores; Madero, Luis

    2004-12-01

    Infection with Epstein-Barr virus (EBV) has been associated with different autoimmune manifestations. The authors describe a girl who developed a severe systemic autoimmune disease with severe autoimmune hemolytic anemia, mild autoimmune thrombopenia, antineutrophil antibodies, and fatal autoimmune hepatitis after EBV infection. Despite immunosuppressive treatment and ultimately liver transplantation, this patient could not overcome her clinical condition and died. The etiopathogenesis of this complex disease and the association with EBV infection is discussed.

  10. Epstein-Barr virus-associated hemophagocytic syndrome in a patient with lupus nephritis.

    PubMed

    Isome, Masato; Suzuki, Junzo; Takahashi, Ai; Murai, Hiromichi; Nozawa, Ruriko; Suzuki, Shigeo; Kawasaki, Yukihiko; Suzuki, Hitoshi

    2005-02-01

    Hemophagocytic syndrome (HPS) is an unusual but severe illness associated with a variety of infections, as well as genetic, malignant tumors, and autoimmune diseases. We report an 11-year-old girl with systemic lupus erythematosus and nephritis who developed HPS associated with Epstein-Barr virus reactivation. In our patient, the onset of reactive HPS might be related to immunosuppressive treatment during the course of lupus nephritis.

  11. Epstein-Barr virus: general factors, virus-related diseases and measurement of viral load after transplant

    PubMed Central

    Gequelin, Luciana Cristina Fagundes; Riediger, Irina N.; Nakatani, Sueli M.; Biondo, Alexander W.; Bonfim, Carmem M.

    2011-01-01

    The Epstein-Barr virus is responsible for infectious mononucleosis syndrome and is also closely associated to several types of cancer. The main complication involving Epstein-Barr virus infection, both in recipients of hematopoietic stem cells and solid organs, is post-transplant lymphoproliferative disease. The importance of this disease has increased interest in the development of laboratory tools to improve post-transplant monitoring and to detect the disease before clinical evolution. Viral load analysis for Epstein-Barr virus through real-time polymerase chain reaction is, at present, the best tool to measure viral load. However, there is not a consensus on which sample type is the best for the test and what is its predictive value for therapeutic interventions. PMID:23049344

  12. Clinical and laboratory characteristics of infectious mononucleosis by Epstein-Barr virus in Mexican children

    PubMed Central

    2012-01-01

    Background Infectious mononucleosis (IM) or Mononucleosis syndrome is caused by an acute infection of Epstein-Barr virus. In Latin American countries, there are little information pertaining to the clinical manifestations and complications of this disease. For this reason, the purpose of this work was to describe the clinical and laboratory characteristics of infection by Epstein-Barr virus in Mexican children with infectious mononucleosis. Methods A descriptive study was carried out by reviewing the clinical files of patients less than 18 years old with clinical and serological diagnosis of IM by Epstein-Barr virus from November, 1970 to July, 2011 in a third level pediatric hospital in Mexico City. Results One hundred and sixty three cases of IM were found. The most frequent clinical signs were lymphadenopathy (89.5%), fever (79.7%), general body pain (69.3%), pharyngitis (55.2%), hepatomegaly (47.2%). The laboratory findings were lymphocytosis (41.7%), atypic lymphocytes (24.5%), and increased transaminases (30.9%), there were no rupture of the spleen and no deaths among the 163 cases. Conclusions Our results revealed that IM appeared in earlier ages compared with that reported in industrialized countries, where adolescents are the most affected group. Also, the order and frequency of the clinical manifestations were different in our country than in industrialized ones. PMID:22818256

  13. Acute kidney injury in symptomatic primary Epstein-Barr virus infectious mononucleosis: Systematic review.

    PubMed

    Moretti, Milena; Lava, Sebastiano A G; Zgraggen, Lorenzo; Simonetti, Giacomo D; Kottanattu, Lisa; Bianchetti, Mario G; Milani, Gregorio P

    2017-06-01

    Textbooks and reviews do not mention the association of symptomatic primary Epstein-Barr virus infectious mononucleosis with acute kidney injury in subjects without immunodeficiency or autoimmunity. Stimulated by our experience with two cases, we performed a review of the literature. The literature documents 38 cases (26 male and 12 female individuals ranging in age from 0.3 to 51, median 18 years) of symptomatic primary Epstein-Barr virus infectious mononucleosis complicated by acute kidney injury: 27 acute interstitial nephritides, 1 jaundice-associated nephropathy, 7 myositides and 3 hemolytic uremic syndromes. Acute kidney injury requiring renal replacement therapy was observed in 18 (47%) cases. Acute kidney injury did not resolve in one patient with acute interstitial nephritis. Two patients died because of systemic complications. The remaining 35 cases fully recovered. In individuals with acute symptomatic Epstein-Barr virus infectious mononucleosis, a relevant kidney injury is rare but the outcome potentially fatal. It results from interstitial nephritis, myositis-associated acute kidney injury, hemolytic uremic syndrome or jaundice-associated nephropathy. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Clinical and laboratory characteristics of infectious mononucleosis by Epstein-Barr virus in Mexican children.

    PubMed

    González Saldaña, Napoleón; Monroy Colín, Victor Antonio; Piña Ruiz, Georgina; Juárez Olguín, Hugo

    2012-07-20

    Infectious mononucleosis (IM) or Mononucleosis syndrome is caused by an acute infection of Epstein-Barr virus. In Latin American countries, there are little information pertaining to the clinical manifestations and complications of this disease. For this reason, the purpose of this work was to describe the clinical and laboratory characteristics of infection by Epstein-Barr virus in Mexican children with infectious mononucleosis. A descriptive study was carried out by reviewing the clinical files of patients less than 18 years old with clinical and serological diagnosis of IM by Epstein-Barr virus from November, 1970 to July, 2011 in a third level pediatric hospital in Mexico City. One hundred and sixty three cases of IM were found. The most frequent clinical signs were lymphadenopathy (89.5%), fever (79.7%), general body pain (69.3%), pharyngitis (55.2%), hepatomegaly (47.2%). The laboratory findings were lymphocytosis (41.7%), atypic lymphocytes (24.5%), and increased transaminases (30.9%), there were no rupture of the spleen and no deaths among the 163 cases. Our results revealed that IM appeared in earlier ages compared with that reported in industrialized countries, where adolescents are the most affected group. Also, the order and frequency of the clinical manifestations were different in our country than in industrialized ones.

  15. A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features.

    PubMed

    Kawamoto, Keisuke; Miyoshi, Hiroaki; Suzuki, Takaharu; Kozai, Yasuji; Kato, Koji; Miyahara, Masaharu; Yujiri, Toshiaki; Choi, Ilseung; Fujimaki, Katsumichi; Muta, Tsuyoshi; Kume, Masaaki; Moriguchi, Sayaka; Tamura, Shinobu; Kato, Takeharu; Tagawa, Hiroyuki; Makiyama, Junya; Kanisawa, Yuji; Sasaki, Yuya; Kurita, Daisuke; Yamada, Kyohei; Shimono, Joji; Sone, Hirohito; Takizawa, Jun; Seto, Masao; Kimura, Hiroshi; Ohshima, Koichi

    2018-06-01

    The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever ( P =0.005), but greater frequency of skin lesions ( P <0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease ( P <0.001 and P =0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis ( P =0.0087, P =0.0236, and P =0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival ( P =0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis ( P <0.001 and P =0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be

  16. Role of Viral miRNAs and Epigenetic Modifications in Epstein-Barr Virus-Associated Gastric Carcinogenesis.

    PubMed

    Giudice, Aldo; D'Arena, Giovanni; Crispo, Anna; Tecce, Mario Felice; Nocerino, Flavia; Grimaldi, Maria; Rotondo, Emanuela; D'Ursi, Anna Maria; Scrima, Mario; Galdiero, Massimiliano; Ciliberto, Gennaro; Capunzo, Mario; Franci, Gianluigi; Barbieri, Antonio; Bimonte, Sabrina; Montella, Maurizio

    2016-01-01

    MicroRNAs are short (21-23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses. The vast majority of viral miRNAs are encoded by the herpesviruses family. These DNA viruses including Epstein-Barr virus encode their own miRNAs and/or manipulate the expression of cellular miRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs.

  17. Efficient production of infectious viruses requires enzymatic activity of Epstein-Barr virus protein kinase.

    PubMed

    Murata, Takayuki; Isomura, Hiroki; Yamashita, Yoriko; Toyama, Shigenori; Sato, Yoshitaka; Nakayama, Sanae; Kudoh, Ayumi; Iwahori, Satoko; Kanda, Teru; Tsurumi, Tatsuya

    2009-06-20

    The Epstein-Barr virus (EBV) BGLF4 gene product is the only protein kinase encoded by the virus genome. In order to elucidate its physiological roles in viral productive replication, we here established a BGLF4-knockout mutant and a revertant virus. While the levels of viral DNA replication of the deficient mutant were equivalent to those of the wild-type and the revertant, virus production was significantly impaired. Expression of the BGLF4 protein in trans fully complemented the low yield of the mutant virus, while expression of a kinase-dead (K102I) form of the protein failed to restore the virus titer. These results demonstrate that BGLF4 plays a significant role in production of infectious viruses and that the kinase activity is crucial.

  18. Understanding the interplay between host immunity and Epstein-Barr virus in NPC patients

    PubMed Central

    Shen, Yong; Zhang, Suzhan; Sun, Ren; Wu, Tingting; Qian, Jing

    2015-01-01

    Epstein-Barr virus (EBV) has been used as a paradigm for studying host–virus interactions, not only because of its importance as a human oncogenic virus associated with several malignancies including nasopharyngeal carcinoma (NPC) but also owing to its sophisticated strategies to subvert the host antiviral responses. An understanding of the interplay between EBV and NPC is critical for the development of EBV-targeted immunotherapy. Here, we summarize the current knowledge regarding the host immune responses and EBV immune evasion mechanisms in the context of NPC. PMID:26038769

  19. Progress and Problems in Understanding and Managing Primary Epstein-Barr Virus Infections

    PubMed Central

    Odumade, Oludare A.; Hogquist, Kristin A.; Balfour, Henry H.

    2011-01-01

    Summary: Epstein-Barr virus (EBV) is a gammaherpesvirus that infects a large fraction of the human population. Primary infection is often asymptomatic but results in lifelong infection, which is kept in check by the host immune system. In some cases, primary infection can result in infectious mononucleosis. Furthermore, when host-virus balance is not achieved, the virus can drive potentially lethal lymphoproliferation and lymphomagenesis. In this review, we describe the biology of EBV and the host immune response. We review the diagnosis of EBV infection and discuss the characteristics and pathogenesis of infectious mononucleosis. These topics are approached in the context of developing therapeutic and preventative strategies. PMID:21233512

  20. Systemic lupus erythematosus associated with acute Epstein-Barr virus infection.

    PubMed

    Dror, Y; Blachar, Y; Cohen, P; Livni, N; Rosenmann, E; Ashkenazi, A

    1998-11-01

    Systemic lupus erythematosus (SLE) is a multisystem disease of unknown origin, characterized by a variety of autoimmune phenomena. Viruses have long been postulated to play a role in its pathogenesis. Several observations suggested a link between Epstein-Barr virus (EBV) and SLE. We describe a 14-year-old girl who presented with acute onset of SLE concurrently with clinical and laboratory findings consistent with EBV-induced infectious mononucleosis (IM). Evidence for acute EBV infection was confirmed by serological studies and detection of specific EBV antigens on kidney biopsy. This close association between EBV and SLE suggests a possible role of the virus in the pathogenesis of SLE in this patient.

  1. Long-term shedding of infectious epstein-barr virus after infectious mononucleosis.

    PubMed

    Fafi-Kremer, Samira; Morand, Patrice; Brion, Jean-Paul; Pavese, Patricia; Baccard, Monique; Germi, Raphaele; Genoulaz, Odile; Nicod, Sandrine; Jolivet, Michel; Ruigrok, Rob W H; Stahl, Jean-Paul; Seigneurin, Jean-Marie

    2005-03-15

    Epstein-Barr virus (EBV) DNA loads in peripheral blood mononuclear cells (PBMCs), plasma, and saliva, as well as infectivity of the virus in saliva, were evaluated in 20 patients for 6 months after the onset of infectious mononucleosis (IM). All patients displayed sustained high EBV DNA loads in the saliva, associated with a persistent infectivity of saliva at day 180. EBV DNA load in PBMCs decreased significantly from day 0 to day 180 (in spite of a viral rebound between day 30 and day 90 in 90% of the patients), and EBV DNA rapidly disappeared from plasma. These data show that patients with IM remain highly infectious during convalescence.

  2. Detection of Human Cytomegalovirus and Epstein-Barr Virus in Coronary Atherosclerotic Tissue

    PubMed Central

    Imbronito, Ana Vitória; Marcelino, Silvia Linardi; Grande, Sabrina Rosa; Nunes, Fabio Daumas; Romito, Giuseppe Alexandre

    2010-01-01

    Previous studies indicated that patients with atherosclerosis are predominantly infected by human cytomegalovirus (HCMV), but rarely infected by type 1 Epstein-Barr virus (EBV-1). In this study, atheromas of 30 patients who underwent aortocoronary bypass surgery with coronary endartherectomy were tested for the presence of these two viruses. HCMV occurred in 93.3% of the samples and EBV-1 was present in 50% of them. Concurrent presence of both pathogens was detected in 43.3% of the samples. PMID:24031529

  3. [Effect of the Epstein-Barr virus on the nervous system].

    PubMed

    Kononenko, V V

    2001-01-01

    On the basis of a comprehensive examination of 12 patients with verified Epstein-Barr virus (EBV) infection it has been shown that this infection can be accompanied by acute and chronic affections of the central and peripheral nervous system. The pathogenesis of chronic EBV-infection involves autoimmune disorders, neurosensitization, a hazard of an injury to the muscular tissue. Chronic EBV-infection calls for differential diagnosis with other slow virus infections, systemic tumor afflictions, systemic diseases of the connective tissue. Acyclovir or valacyclovir can be recommended as treatment of acute and chronic EBV-infection.

  4. Concomitant Epstein-Barr Virus-associated smooth muscle tumor and granulomatous inflammation of the liver.

    PubMed

    Can, Nhu Thuy; Grenert, James P; Vohra, Poonam

    2017-10-01

    Epstein-Barr Virus-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor typically seen in immunocompromised patients. Here, we report a case of EBV-SMT and associated granulomatous inflammation in the liver of a 32-year-old man with history of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). To our knowledge, an association of these two lesions has not been previously reported. We review the literature and discuss pathogenesis, differential diagnosis and immunohistochemical (IHC) stains helpful for the diagnosis of this rare entity. Finally, we consider possible explanations for the concomitant presence of these lesions. Published by Elsevier GmbH.

  5. Crohn's disease complicated by Epstein-Barr virus-driven haemophagocytic lymphohistiocytosis successfully treated with rituximab.

    PubMed

    Thompson, Grace; Pepperell, Dominic; Lawrence, Ian; McGettigan, Benjamin David

    2017-02-22

    We report a case of Epstein-Barr virus (EBV)-driven haemophagocytic lymphohistiocytosis (HLH) in a man with Crohn's disease treated with 6-mercaptopurine and adalimumab therapy who was successfully treated with rituximab therapy alone. This is the first published case in an adult patient with EBV-driven HLH in the setting of thiopurine use and inflammatory bowel disease to be successfully treated with rituximab therapy alone. Here, we will discuss putative immunological mechanisms which may contribute to this potentially life-threatening complication. 2017 BMJ Publishing Group Ltd.

  6. Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection.

    PubMed

    Hashimoto, Takahiro; Sakata, Yasushi; Fukushima, Kentaro; Maeda, Tetsuo; Arita, Yoh; Shioyama, Wataru; Nakaoka, Yoshikazu; Hori, Yumiko; Morii, Eiichi; Aozasa, Katsuyuki; Kanakura, Yuzuru; Yamauchi-Takihara, Keiko; Komuro, Issei

    2011-01-01

    A 45-year-old man with chronic active Epstein-Barr virus (EBV) infection (CAEBV) with natural killer cell type developed pulmonary arterial hypertension (PAH). After chemotherapy, he showed marked depression of the EBV DNA genome in the peripheral blood, but PAH sustained. He died of heart failure due to PAH, and the histo-pathological examination revealed pulmonary vascular abnormalities without lung disease on autopsy. Although the EBV DNA genome and the infiltrating lymphocytes were not detected in the lung, his clinical course suggested that his PAH might be caused by CAEBV. This is the first reported case of PAH associated CAEBV in an adult.

  7. A case of chronic active Epstein-Barr virus infection mimicking adult-onset Still's disease.

    PubMed

    Yoshioka, Katsunobu; Fukushima, Hiroko; Ishii, Naomi; Kita, Akiko; Hanioka, Yusuke; Minami, Mieko; Inoue, Takeshi; Yamagami, Keiko

    2013-01-01

    An 83-year-old man was diagnosed with adult-onset Still's disease (AOSD) based on clinical and laboratory findings. However, glucocorticoid had little effect. Epstein-Barr virus (EBV)-DNA was detected in peripheral blood, and autopsy findings confirmed a diagnosis of chronic active EBV infection (CAEBV). CAEBV mimics AOSD, and the presence of articular involvement and leukocytosis does not exclude the possibility of CAEBV. CAEBV should be included in the differential diagnosis of AOSD, and measurement of EBV-DNA is essential.

  8. Inhibitory effect of Epstein-Barr virus activation by Citrus fruits, a cancer chemopreventor.

    PubMed

    Iwase, Y; Takemura, Y; Ju-ichi, M; Kawaii, S; Yano, M; Okuda, Y; Mukainaka, T; Tsuruta, A; Okuda, M; Takayasu, J; Tokuda, H; Nishino, H

    1999-05-24

    To search useful compounds in Citrus fruit for cancer chemoprevention, we carried out a primary screening of extracts of fruit peels and seeds from 78 species of the genus Citrus and those from two Fortunella and one Poncirus species, which were closely related to the genus Citrus. These Citrus extracts inhibited the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) as a useful screening method for anti-tumor promoters. Our results indicated that Citrus containing substances may be inhibit susceptibility factors involved in the events leading to the development of cancer.

  9. Epstein-Barr virus-derived EBNA2 regulates STAT3 activation

    SciTech Connect

    Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako

    The Epstein-Barr virus (EBV)-encoded latency protein EBNA2 is a nuclear transcriptional activator that is essential for EBV-induced cellular transformation. Here, we show that EBNA2 interacts with STAT3, a signal transducer for an interleukin-6 family cytokine, and enhances the transcriptional activity of STAT3 by influencing its DNA-binding activity. Furthermore, EBNA2 cooperatively acts on STAT3 activation with LMP1. These data demonstrate that EBNA2 acts as a transcriptional coactivator of STAT3.

  10. Mononucleosis syndrome and coincidental human herpesvirus-7 and Epstein-Barr virus infection

    PubMed Central

    Chiu, H; Lee, C; Lee, P; Lin, K; Huang, L

    1998-01-01

    Two girls (a 5 year old and a 21 month old) experiencing mononucleosis syndrome with coincidental human herpesvirus (HHV)-7 and Epstein-Barr virus (EBV) infections are described. One patient had primary HHV-7 infection and reactivated EBV infection. The other had primary HHV-7 and EBV infections. These cases indicated that HHV-7 is capable of inducing infectious mononucleosis-like illness. Multiple herpesvirus infection in one of the patients also suggests that interaction among herpesviruses can occur in vivo. The consequence of this interaction may have clinical implications.

 PMID:9659100

  11. Pim kinases are upregulated during Epstein-Barr virus infection and enhance EBNA2 activity

    SciTech Connect

    Rainio, Eeva-Marja; Turku Graduate School of Biomedical Sciences, 20520 Turku; Ahlfors, Helena

    Latent Epstein-Barr virus (EBV) infection is strongly associated with B-cell proliferative diseases such as Burkitt's lymphoma. Here we show that the oncogenic serine/threonine kinases Pim-1 and Pim-2 enhance the activity of the viral transcriptional activator EBNA2. During EBV infection of primary B-lymphocytes, the mRNA expression levels of pim genes, especially of pim-2, are upregulated and remain elevated in latently infected B-cell lines. Thus, EBV-induced upregulation of Pim kinases and Pim-stimulated EBNA2 transcriptional activity may contribute to the ability of EBV to immortalize B-cells and predispose them to malignant growth.

  12. Geographic Population Structure in Epstein-Barr Virus Revealed by Comparative Genomics

    PubMed Central

    Chiara, Matteo; Manzari, Caterina; Lionetti, Claudia; Mechelli, Rosella; Anastasiadou, Eleni; Chiara Buscarinu, Maria; Ristori, Giovanni; Salvetti, Marco; Picardi, Ernesto; D’Erchia, Anna Maria; Pesole, Graziano; Horner, David S.

    2016-01-01

    Epstein-Barr virus (EBV) latently infects the majority of the human population and is implicated as a causal or contributory factor in numerous diseases. We sequenced 27 complete EBV genomes from a cohort of Multiple Sclerosis (MS) patients and healthy controls from Italy, although no variants showed a statistically significant association with MS. Taking advantage of the availability of ∼130 EBV genomes with known geographical origins, we reveal a striking geographic distribution of EBV sub-populations with distinct allele frequency distributions. We discuss mechanisms that potentially explain these observations, and their implications for understanding the association of EBV with human disease. PMID:27635051

  13. Increased frequency of Epstein-Barr virus excretion in patients with new daily persistent headaches.

    PubMed

    Diaz-Mitoma, F; Vanast, W J; Tyrrell, D L

    1987-02-21

    In a case-control study 27 (84%) of 32 patients with new daily persistent headaches (NDPH) and 8 (25%) of 32 controls had evidence of Epstein-Barr virus (EBV) "active" infection, as demonstrated by EBV excretion and/or early antigen titre above 1:32. 20 (62%) patients and 4 (12%) controls were excreting EBV in the oropharynx, as determined by a dot hybridisation assay. The mean titre of IgG antibodies to early antigen was significantly higher in patients than controls. EBV reactivation may be important in the pathogenesis of NDPH. Alternatively, patients with NDPH may be unusually prone to EBV reactivation.

  14. False Positive Immunoglobulin M Antibody to Cytomegalovirus in Child with Infectious Mononucleosis Caused by Epstein-Barr Virus Infection

    PubMed Central

    Shin, Jae Il; Lee, Jae Seung; Jang, Young Ho; Kim, Sung Hun; Lee, Kang Hyuk; Lee, Chang Hoon

    2009-01-01

    A 16-month-old boy was admitted because of cough that had lasted for 10 days. The patient showed severe hepatomegaly incidentally, and dual positivity of Immunoglobulin (Ig) M to Epstein-Barr virus (EBV) viral capsid antigen (VCA) and cytomegalovirus (CMV). On the basis of seroconversion to Epstein-Barr nuclear antigen (EBNA) Ig G positivity and reduced CMV Ig M titer with persistently negative CMV Ig G, a definite diagnosis of EBV-induced infectious mononucleosis was established 1 year 2 month later. PMID:19881978

  15. False positive immunoglobulin m antibody to cytomegalovirus in child with infectious mononucleosis caused by epstein-barr virus infection.

    PubMed

    Park, Jee Min; Shin, Jae Il; Lee, Jae Seung; Jang, Young Ho; Kim, Sung Hun; Lee, Kang Hyuk; Lee, Chang Hoon

    2009-10-31

    A 16-month-old boy was admitted because of cough that had lasted for 10 days. The patient showed severe hepatomegaly incidentally, and dual positivity of Immunoglobulin (Ig) M to Epstein-Barr virus (EBV) viral capsid antigen (VCA) and cytomegalovirus (CMV). On the basis of seroconversion to Epstein-Barr nuclear antigen (EBNA) Ig G positivity and reduced CMV Ig M titer with persistently negative CMV Ig G, a definite diagnosis of EBV-induced infectious mononucleosis was established 1 year 2 month later.

  16. Natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus infection.

    PubMed

    Ogata, Masao; Imamura, Tomoyuki; Mizunoe, Syunji; Ohtsuka, Eiichi; Kikuchi, Hiroshi; Nasu, Masaru

    2003-06-01

    We describe a 69-year-old female who developed natural killer cell-type body cavity lymphoma following chronic active Epstein-Barr virus (CAEBV) infection. Examination of the patient's pleural effusion revealed large abnormal lymphocytes, which were CD2(+), CD7(+), CD30(+), CD56(+), CD3(-), and CD4(-). No rearrangement of T cell receptor genes was detected. Clonal proliferation of Epstein-Barr virus (EBV)-infected cells in pleural effusion was demonstrated by Southern blot hybridization analysis. Human herpesvirus type-8 (HHV-8) DNA was not detected in these cells. The patient achieved a complete remission with combination chemotherapy. Prior to the clinical onset of lymphoma, high fever of unknown origin had persisted for 21 months. IgG antibodies to EBV-viral capsid antigen and to EBV-early antigens, types D and R were not high (1:160 and less than 1:10, respectively). Two months after the onset of fever, however, retrospective quantitative PCR assay revealed a high EBV DNA load in plasma, indicating that CAEBV infection had been the cause of the patient's recurrent fever. The remarkable features of this case are (i) the development of lymphoma following CAEBV infection that demonstrated a normal pattern of EBV-specific antibodies, (ii) the development of HHV-8-negative body cavity lymphoma, and (iii) the effectiveness of combination chemotherapy. Copyright 2003 Wiley-Liss, Inc.

  17. The curiously suspicious: a role for Epstein-Barr virus in lupus.

    PubMed

    Harley, J B; Harley, I T W; Guthridge, J M; James, J A

    2006-01-01

    While the events initiating the development of autoantibodies in systemic lupus erythematosus (SLE) have not yet been convincingly established, newly developed tools for molecular investigation make such an undertaking increasingly practical. Applied to the earliest events in the sequence culminating in lupus autoimmunity, we present a critical potential role for Epstein-Barr virus (EBV) in the development and perhaps perpetuation of SLE. The expected properties for an environmental risk factor for SLE are found in this virus and the human host response against it. Existing data show the molecular progression to autoimmunity observed in SLE patient sera, the discovery of the first autoimmune epitopes in the Sm and Ro autoantigen systems, and the possible emergence of these autoantibodies from the heterologous antibodies against Epstein-Barr nuclear antigen-1 (EBNA-1). Further, existing data demonstrate association of SLE with EBV infection, even preceding the development of autoimmunity. Finally, the data are consistent with a proposed model of lupus pathogenesis that begins with antibodies to EBNA-1, predisposing to immune responses that develop crossreactive autoantibodies that culminate in the development of SLE autoimmunity.

  18. Filaggrin gene polymorphism associated with Epstein-Barr virus-associated tumors in China.

    PubMed

    Yang, Yang; Liu, Wen; Zhao, Zhenzhen; Zhang, Yan; Xiao, Hua; Luo, Bing

    2017-08-01

    Mutations of filaggrin gene (FLG) have been identified as the cause of ichthyosis vulgaris, while recently FLG mutations were found to be associated with gastric cancer. This study aimed to investigate the association of filaggrin polymorphism with Epstein-Barr virus-associated tumors in China. A total of 200 patients with three types of tumors and 117 normal control samples were genotyped at three common FLG mutation loci (rs3126085, K4671X, R501X) by using Sequenom MassARRAY technique. The χ 2 test was used to evaluate the relationship between the mutation and the three kinds of tumors. A two-sided P value of <0.05 was considered statistically significant. The results showed that two single-nucleotide polymorphism (SNP) loci (rs3126085, K4671X) were significantly associated with nasopharyngeal carcinoma in genetic model. In addition, the two SNPs K4671X and rs3126085 were related to Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC), respectively. Furthermore, allele distributions in EBVaGC and EBVnGC were verified to be different in both SNP loci.

  19. Conjunctival tumor caused by Epstein-Barr virus-related infectious mononucleosis: Case report and review of literature.

    PubMed

    Vaivanijkul, Juntarut; Boonsiri, Kreopun

    2017-04-01

    The conjunctival tumor associated with Epstein-Barr virus related infectious mononucleosis is a rare ocular manifestation. Only a few cases have been reported in the literature. We reported this rare condition that presented in a 5-year-old boy.

  20. Broad cross-reactive T cell receptor repertoires recognizing dissimilar Epstein-Barr and influenza A virus epitopes

    PubMed Central

    Clute, Shalyn C.; Naumov, Yuri N.; Watkin, Levi B.; Aslan, Nuray; Sullivan, John L.; Thorley-Lawson, David A.; Luzuriaga, Katherine; Welsh, Raymond M.; Puzone, Roberto; Celada, Franco; Selin, Liisa K.

    2013-01-01

    Memory T cells cross-reactive with epitopes encoded by related or even unrelated viruses may alter the immune response and pathogenesis of infection by a process known as heterologous immunity. Because a challenge virus epitope may react with only a subset of the T cell repertoire in a cross-reactive epitope-specific memory pool, the vigorous cross-reactive response may be narrowly focused, or oligoclonal. We show here, by examining human T cell cross-reactivity between the HLA-A2-restricted influenza A virus-encoded M158-66 epitope (GILGFVFTL) and the dissimilar Epstein-Barr virus-encoded BMLF1280-288 epitope (GLCTLVAML), that under some conditions heterologous immunity can lead to a significant broadening rather than a narrowing of the T cell receptor repertoire. We suggest that dissimilar cross-reactive epitopes might generate a broad rather than narrow T cell repertoire if there is a lack of dominant high affinity clones, and this hypothesis is supported by computer simulation. PMID:21048112

  1. Fragment length polymorphisms among independent isolates of Epstein-Barr virus from immunocompromised and normal hosts.

    PubMed

    Katz, B Z; Niederman, J C; Olson, B A; Miller, G

    1988-02-01

    DNA restriction fragment length polymorphisms of Epstein-Barr virus (EBV) DNA were used as a molecular epidemiological tool to study multiple isolates of virus from the same and different individuals. We studied 35 EBV isolates: 19 from seven immunocompromised children and 16 from seven college students with mononucleosis. Analysis of the fragment length polymorphisms in this collection of isolates permitted several conclusions. Sites of polymorphism were most often encountered in regions with repetitive DNA. Epidemiologically unrelated patients harbored viruses that could be readily distinguished; by contrast, two infants and their mothers harbored similar viruses. Isolates from different sites in the same patient were similar. Variations between different clinical isolates of EBV mimic those found between different laboratory strains of the virus. Fragment length polymorphisms thus provide a useful marker for studying transmission and pathogenesis of EBV infections.

  2. Epstein-Barr virus strains and variations: Geographic or disease-specific variants?

    PubMed

    Neves, Marco; Marinho-Dias, Joana; Ribeiro, Joana; Sousa, Hugo

    2017-03-01

    The Epstein-Barr Virus (EBV) is associated with the development of several diseases, including infectious mononucleosis (IM), Burkitt's Lymphoma (BL), Nasopharyngeal Carcinoma, and other neoplasias. The publication of EBV genome 1984 led to several studies regarding the identification of different viral strains. Currently, EBV is divided into EBV type 1 (B95-8 strain) and EBV type 2 (AG876 strain), also known as type A and type B, which have been distinguished based upon genetic differences in the Epstein-Barr nuclear antigens (EBNAs) sequence. Several other EBV strains have been described in the past 10 years considering variations on EBV genome, and many have attempted to clarify if these variations are ethnic or geographically correlated, or if they are disease related. Indeed, there is an increasing interest to describe possible specific disease associations, with emphasis on different malignancies. These studies aim to clarify if these variations are ethnic or geographically correlated, or if they are disease related, thus being important to characterize the epidemiologic genetic distribution of EBV strains on our population. Here, we review the current knowledge on the different EBV strains and variants and its association with different diseases. J. Med. Virol. 89:373-387, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. [An adult with chronic active Epstein-Barr virus infection associated with repeated liver dysfunction].

    PubMed

    Endo, Tetsu; Mori, Yuki; Fukushi, Tsugumi; Yamaguchi, Kohei; Sato, Ken; Sakamoto, Juichi; Fukuda, Shinsaku; Wada, Ryuichi

    2010-08-01

    A 30-year-old woman with hepatitis for 5 months was admitted to our hospital. She had been given a diagnosis of liver dysfunction 2 years previously, and the hepatitis in this case was believed to be drug-induced. On admission, the patient was asymptomatic. Serologic tests for hepatitis A, B, and C were negative, and the laboratory results showed a WBC count of 7600/mm3 (lymphocytes, 85%), an AST level of 559 U/L, ALT level of 427 U/L, and EBV-DNA of 2.9x10(6) copies/microg DNA. Histopathological examination of the liver biopsy specimens revealed moderate lymphocyte infiltration in the sinusoids and positive Epstein-Barr-encoded RNA (EBER) -lymphocytes. Therefore, chronic active Epstein-Barr virus infection (CAEBV) was diagnosed. However, 9 months after the diagnosis she died of mycotic sepsis. We presume that the patient may have developed CAEBV at the prior diagnosis of liver dysfunction 2 years previously. Therefore, CAEBV associated with liver dysfunction should be considered during the differential diagnosis of patients showing persistent liver dysfunction.

  4. Computational analysis of EBNA1 ``druggability'' suggests novel insights for Epstein-Barr virus inhibitor design

    NASA Astrophysics Data System (ADS)

    Gianti, Eleonora; Messick, Troy E.; Lieberman, Paul M.; Zauhar, Randy J.

    2016-04-01

    The Epstein-Barr Nuclear Antigen 1 (EBNA1) is a critical protein encoded by the Epstein-Barr Virus (EBV). During latent infection, EBNA1 is essential for DNA replication and transcription initiation of viral and cellular genes and is necessary to immortalize primary B-lymphocytes. Nonetheless, the concept of EBNA1 as drug target is novel. Two EBNA1 crystal structures are publicly available and the first small-molecule EBNA1 inhibitors were recently discovered. However, no systematic studies have been reported on the structural details of EBNA1 "druggable" binding sites. We conducted computational identification and structural characterization of EBNA1 binding pockets, likely to accommodate ligand molecules (i.e. "druggable" binding sites). Then, we validated our predictions by docking against a set of compounds previously tested in vitro for EBNA1 inhibition (PubChem AID-2381). Finally, we supported assessments of pocket druggability by performing induced fit docking and molecular dynamics simulations paired with binding affinity predictions by Molecular Mechanics Generalized Born Surface Area calculations for a number of hits belonging to druggable binding sites. Our results establish EBNA1 as a target for drug discovery, and provide the computational evidence that active AID-2381 hits disrupt EBNA1:DNA binding upon interacting at individual sites. Lastly, structural properties of top scoring hits are proposed to support the rational design of the next generation of EBNA1 inhibitors.

  5. Presence of infective Epstein-Barr virus in the urine of patients with infectious mononucleosis.

    PubMed

    Landau, Z; Gross, R; Sanilevich, A; Friedmann, A; Mitrani-Rosenbaum, S

    1994-11-01

    The presence of Epstein-Barr virus (EBV) in the blood and urine of 20 patients with infectious mononucleosis (IM) was investigated together with the clinical course of the disease, and in 9 patients up to 2-7 months after recovery. EBV DNA, analyzed by the polymerase chain reaction (PCR), was detected in the blood of all 20 patients from the first sample obtained and detected between 3 to 42 days from the beginning of symptoms and up to 2-3 months after recovery. In the urine, EBV DNA was detected in 15 out of 16 (93%) patients in the first sample obtained and detected between 3 to 50 days during the clinical course of the disease. In four patients EBV DNA was detected in the urine up to 3 months after full recovery. Seventeen out of 26 (65%) urine samples including 3 which were obtained 2-7 months after recovery infected B cells as assessed by PCR. Nine out of 12 (75%) urine samples tested induced Epstein-Barr nuclear antigen (EBNA) in the infected B-cell line. In addition to the persistence of EBV in the blood of IM patients, these studies show for the first time the presence of infective EBV in the urine during the clinical course of the disease and up to 7 months after full clinical recovery.

  6. EVIDENCE OF EPSTEIN-BARR VIRUS ASSOCIATION WITH HEAD AND NECK CANCERS: A REVIEW.

    PubMed

    Prabhu, Soorebettu R; Wilson, David F

    2016-01-01

    Epstein-Barr virus (EBV) is ubiquitous: over 90% of the adult population is infected with this virus. EBV is capable of infecting both B lymphocytes and epithelial cells throughout the body including the head and neck region. Transmission occurs mainly by exchange of saliva. The infection is asymptomatic or mild in children but, in adolescents and young adults, it causes infectious mononucleosis, a self-limiting disease characterized by lethargy, sore throat, fever and lymphadenopathy. Once established, the virus often remains latent and people become lifelong carriers without experiencing disease. However, in some people, the latent virus is capable of causing malignant tumours, such as nasopharyngeal carcinoma and various B- and T-cell lymphomas, at sites including the head, neck and oropharyngeal region. As lymphoma is the second-most common malignant disease of the head, neck and oral region after squamous cell carcinoma, oral health care workers including dentists and specialists have a responsibility to carry out a thorough clinical examination of this anatomical region with a view to identifying and diagnosing lesions that may represent lymphomas. Early detection allows early treatment resulting in better prognosis. The focus of this review is on the morphology, transmission and carcinogenic properties of EBV and clinical and diagnostic aspects of a range of EBV-associated malignancies occurring in the head, neck and oral region. As carcinogenic agents, viruses contribute to a significant proportion of the global cancer burden: approximately 15% of all human cancers, worldwide, are attributable to viruses.1,2 Serologic and epidemiologic studies are providing mounting evidence of an etiologic association between viruses and head and neck malignancies.3 To update oral and maxillofacial surgeons and oral medicine specialists and raise awareness of this association, we recently reviewed the evidence of the etiologic role of human papillomavirus in oral disease.4

  7. Chromatin reorganisation in Epstein-Barr virus-infected cells and its role in cancer development.

    PubMed

    West, Michelle J

    2017-10-01

    The oncogenic Epstein-Barr virus (EBV) growth transforms B cells and drives lymphoma and carcinoma development. The virus encodes four key transcription factors (EBNA2, EBNA3A, EBNA3B and EBNA3C) that hijack host cell factors to bind gene control elements and reprogramme infected B cells. These viral factors predominantly target long-range enhancers to alter the expression of host cell genes that control B cell growth and survival and facilitate virus persistence. Enhancer and super-enhancer binding by these EBNAs results in large-scale reorganisation of three-dimensional enhancer-promoter architecture to drive the overexpression of oncogenes, the silencing of tumour suppressors and the modulation of transcription, cell-cycle progression, migration and adhesion. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  8. Epstein-Barr virus: a paradigm for persistent infection - for real and in virtual reality.

    PubMed

    Thorley-Lawson, David A; Duca, Karen A; Shapiro, Michael

    2008-04-01

    The really interesting thing about herpesviruses is that they can establish lifelong persistant infections in immunocompetent hosts. At first glance, they would seem to have very different ways of doing this. Here we will use as a model our current understanding of how the human herpesvirus Epstein-Barr virus establishes and maintains such an infection. We apply information from a wide range of sources including laboratory experimentation, clinical observation, animal models and a new computer simulation. We propose that the detailed mechanisms for establishing infection are dependent on the virus and tissues involved, but the strategy is the same - to persist in a long-lived cell type where the virus is invisible to the immune system and nonpathogenic.

  9. Immune deficiency as a risk factor in Epstein-Barr virus-induced malignant diseases.

    PubMed Central

    Purtilo, D T; Okano, M; Grierson, H L

    1990-01-01

    Epstein-Barr virus (EBV) is a ubiquitous DNA virus that normally infects silently, establishing lifelong latency. Substantial empirical observations support the view that immunodeficiency is permissive in EBV-induced lymphoproliferative diseases (LPD). Primary immune deficient patients such as those with X-linked lymphoproliferative disease and individuals with acquired immune deficiency secondary to immunosuppressive drugs for organ transplantation or individuals infected with human immunodeficiency virus are also at very high risk for lethal LPD. The importance of immunodeficiency and EBV in the development of head and neck carcinomas and uterine cervical carcinoma is less clear. Methods are available for detecting immunodeficiency and EBV genome and thus preventive strategies are being developed to preclude LPD from occurring. PMID:2176975

  10. Reproduction of Epstein-Barr Virus Infection and Pathogenesis in Humanized Mice

    PubMed Central

    2014-01-01

    Epstein-Barr virus (EBV) is etiologically associated with a variety of diseases including lymphoproliferative diseases, lymphomas, carcinomas, and autoimmune diseases. Humans are the only natural host of EBV and limited species of new-world monkeys can be infected with the virus in experimental conditions. Small animal models of EBV infection, required for evaluation of novel therapies and vaccines for EBV-associated diseases, have not been available. Recently the development of severely immunodeficient mouse strains enabled production of humanized mice in which human immune system components are reconstituted and express their normal functions. Humanized mice can serve as infection models for human-specific viruses such as EBV that target cells of the immune system. This review summarizes recent studies by the author's group addressing reproduction of EBV infection and pathogenesis in humanized mice. PMID:24605074

  11. Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors

    PubMed Central

    Hui, Kwai Fung; Tam, Kam Pui

    2017-01-01

    Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers. PMID:29160853

  12. Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors.

    PubMed

    Hui, Kwai Fung; Tam, Kam Pui; Chiang, Alan Kwok Shing

    2017-11-21

    Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers.

  13. Plasma cortisol levels and reactivation of latent Epstein-Barr virus in response to examination stress.

    PubMed

    Glaser, R; Pearl, D K; Kiecolt-Glaser, J K; Malarkey, W B

    1994-01-01

    In this study, we explored the possibility that glucocorticoid hormones, known to increase under stress, might be one component of the mechanism involved in induction of latent Epstein Barr virus (EBV). We obtained blood samples from 45 male medical students during examinations and approximately 3-4 weeks before the examinations (baseline) and measured antibody titers to EBV and plasma cortisol levels. We found reproducible changes in EBV, virus capsid antigen (VCA) antibody titers, with higher antibody titers observed in the examination blood samples consistent with the reactivation of latent virus. However, we found no evidence that day and night plasma cortisol values across the sampling points changed significantly from baseline to examinations. Therefore, academic stress did not elevate cortisol levels, but increases in EBV VCA antibody titers were still observed. The data suggest in these subjects that other neuropeptides or hormones were involved in the induction of latent EBV.

  14. Regulation of Telomere Homeostasis during Epstein-Barr virus Infection and Immortalization.

    PubMed

    Kamranvar, Siamak A; Masucci, Maria G

    2017-08-09

    The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect B-lymphocytes in vitro and transform the infected cells into autonomously proliferating immortal cell lines underlies the association of this human gamma-herpesvirus with a broad variety of lymphoid and epithelial cell malignancies. Current evidence suggests that both telomerase-dependent and -independent pathways of telomere elongation are activated in the infected cells during the early and late phases of virus-induced immortalization. Here we review the interaction of EBV with different components of the telomere maintenance machinery and the mechanisms by which the virus regulates telomere homeostasis in proliferating cells. We also discuss how these viral strategies may contribute to malignant transformation.

  15. Antibody to the rheumatoid arthritis nuclear antigen. Its relationship to in vivo Epstein-Barr virus infection.

    PubMed

    Catalano, M A; Carson, D A; Niederman, J C; Feorino, P; Vaughan, J H

    1980-05-01

    Most patients with seropositive rheumatoid arthritis, and a variable but lesser percentage of normal subjects, have precipitating antibodies to a nuclear antigen, rheumatoid arthritis nuclear antigen, present in Epstein-Barr virus-infected human B lymphoblastoid cells. We have used a sensitive indirect immunofluorescence assay for antibody to rheumatoid arthritis nuclear antigen in a study of patients with infectious mononucleosis and healthy control subjects. Of 110 sera from normal, college-age cadets, 58 were from individuals without prior Epstein-Barr virus infection, as indicated by the lack of antibody to viral capsid antigen. All of these also lacked activity to rheumatoid arthritis nuclear antigen. 52 sera were positive for antibody to viral capsid antigen, and antibody to rheumatoid arthritis nuclear antigen was present in 26 (50%) of these. In 67 sequential sera from 11 college-age students with infectious mononucleosis who became positive for antibody to rheumatoid arthritis nuclear antigen, only 2 were positive during the 1 mo. Thereafter the incidence and titers increased progressively through the 1st yr after infection. This time-course resembled that for the development of antibody to Epstein-Barr nuclear antigen, another transformation antigen in Epstein-Barr virus-infected B lymphocytes. The development of positivity for both was much later than that of antibody to the structural viral capsid antigen, which in the current study was always positive by 1 wk. Thus, antibody to rheumatoid arthritis nuclear antigen is present in a large proportion of normal individuals and can now be clearly ascribed, from both in vivo and in vitro studies, to prior infection with Epstein-Barr virus.

  16. Adult systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease: A case report.

    PubMed

    Wang, Youping; Liu, Xinyue; Chen, Yan

    2015-09-01

    Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (EBV + T-LPD) occurs mainly in Asia and South America and is extremely rare in adults. The disease is characterized by a clonal proliferation of EBV-infected T cells with a cytotoxic immunophenotype and is associated with a poor clinical outcome and can be life-threatening. The majority of the patients have evidence of systemic disease, often with lymph node, liver and spleen involvement. The present study describes a case of adult systemic EBV + T-LPD with high fever, systemic lymphadenopathy, hepatosplenomegaly, nose-pharynx neoplasm, pancytopenia, EB virus infection and proliferative bone marrow, with the aim of improving the understanding of the condition.

  17. Space Flight-Induced Reactivation of Latent Epstein-Barr Virus

    NASA Technical Reports Server (NTRS)

    Stowe, Raymond P.; Barrett, Alan D. T.; Pierson, Duane L.

    2001-01-01

    Reactivation of latent Epstein-Barr virus (EBV) may be an important threat to crew health during extended space missions. Decreased cellular immune function has been reported both during and after space flight. Preliminary studies have demonstrated increased EBV shedding in saliva as well as increased antibody titers to EBV lytic proteins. We hypothesize that the combined effects of microgravity along with associated physical and psychological stress will decrease EBV-specific T-cell immunity and reactivate latent EBV in infected B-lymphocytes. If increased virus production and clonal expansion of infected B-lymphocytes are detected, then pharmacological measures can be developed and instituted prior to onset of overt clinical disease. More importantly, we will begin to understand the basic mechanisms involved in stress-induced reactivation of EBV in circulating B-lymphocytes.

  18. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection.

    PubMed

    Chijioke, Obinna; Müller, Anne; Feederle, Regina; Barros, Mario Henrique M; Krieg, Carsten; Emmel, Vanessa; Marcenaro, Emanuela; Leung, Carol S; Antsiferova, Olga; Landtwing, Vanessa; Bossart, Walter; Moretta, Alessandro; Hassan, Rocio; Boyman, Onur; Niedobitek, Gerald; Delecluse, Henri-Jacques; Capaul, Riccarda; Münz, Christian

    2013-12-26

    Primary infection with the human oncogenic Epstein-Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion that predisposes for the development of distinct EBV-associated lymphomas. Why some individuals experience this symptomatic primary EBV infection, whereas the majority acquires the virus asymptomatically, remains unclear. Using a mouse model with reconstituted human immune system components, we show that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis mainly because of a loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Detection of cell-free Epstein-Barr virus DNA in serum during acute infectious mononucleosis.

    PubMed

    Gan, Y J; Sullivan, J L; Sixbey, J W

    1994-08-01

    Infectious Epstein-Barr virus (EBV) is shed from the oropharynx of infected hosts intermittently throughout life, but in the peripheral circulation the viral genome characteristically maintains itself in a noninfectious, cell-associated form. Sera from 125 persons with heterophil-positive acute infectious mononucleosis or EBV-associated nasopharyngeal carcinoma or who were healthy virus carriers were examined for evidence of cell-free viral DNA. EBV DNA suggesting viremia was detected in 11 (27%) of 41 infectious mononucleosis patients by polymerase chain reaction analysis but infrequently in healthy seropositive carriers and patients with nasopharyngeal carcinoma. In serial samples examined from 2 patients, serum EBV DNA was detected over a 3-day interval. Viral DNA was found in concert with one serologic marker of acute infection, EBV-specific polymeric IgA, that could affect patterns of viral spread and clinical symptomatology.

  20. Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection

    PubMed Central

    Chijioke, Obinna; Müller, Anne; Feederle, Regina; Barros, Mario Henrique M.; Krieg, Carsten; Emmel, Vanessa; Marcenaro, Emanuela; Leung, Carol S.; Antsiferova, Olga; Landtwing, Vanessa; Bossart, Walter; Moretta, Alessandro; Hassan, Rocio; Boyman, Onur; Niedobitek, Gerald; Delecluse, Henri-Jacques; Capaul, Riccarda; Münz, Christian

    2014-01-01

    SUMMARY Primary infection with the human oncogenic Epstein Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion, which predisposes for the development of distinct EBV-associated lymphomas. It remains unclear why some individuals experience this symptomatic primary EBV infection, while the majority acquires the virus asymptomatically. Using a mouse model with reconstituted human immune system components, we show here that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis, mainly due to loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies. PMID:24360958

  1. Perspectives of Phage-Eukaryotic Cell Interactions to Control Epstein-Barr Virus Infections.

    PubMed

    Górski, Andrzej; Międzybrodzki, Ryszard; Jończyk-Matysiak, Ewa; Weber-Dąbrowska, Beata; Bagińska, Natalia; Borysowski, Jan

    2018-01-01

    Recently, leading medical journals emphasized the importance of further studies on the potential application of bacterial viruses (phages) for the treatment of antibiotics-resistant infections outlining the present status of the therapy and perspectives for the future. Furthermore, a leading scientific journal pointed to the recent progress in research on phage interactions with eukaryotic cells (especially cells of the immune system) and potential implications of their results for our broader understanding of the role of phages - not only as "bacteria eaters" - but also as an important part of our body defense protecting against external and internal pathogenic invaders (as suggested previously). This illustrates how our understanding of the actual role and potential of phages is expanding and how worldwide interest in their use in medicine is growing. In this article we envision how this advancement of our knowledge about phages could be translated into the progress in combating herpesvirus infections especially those caused by Epstein-Barr virus (EBV).

  2. The role of Epstein-Barr virus in systemic lupus erythematosus.

    PubMed

    McClain, M T; Harley, J B; James, J A

    2001-10-01

    Systemic lupus erythematosus (SLE) is a devastating autoimmune disease with no known cure. Lupus patients suffer from a myriad of clinical symptoms which variably include arthritis, pleuritis, pericarditis, vasculitis, and nephritis. The underlying mechanisms behind these clinical findings and the etiologic events preceding and causing disease onset, however, remain largely unknown. For many years, investigators have suspected that Epstein-Barr virus might somehow be involved in the etiology and/or pathogenesis of systemic lupus. Numerous studies have examined this possibility from various angles and have arrived at different conclusions. This work reviews these historical papers in the context of new results and presents a hypothetical role for this virus as an etiological environmental trigger for SLE.

  3. Chaetocin reactivates the lytic replication of Epstein-Barr virus from latency via reactive oxygen species.

    PubMed

    Zhang, Shilun; Yin, Juan; Zhong, Jiang

    2017-01-01

    Oxidative stress, regarded as a negative effect of free radicals in vivo, takes place when organisms suffer from harmful stimuli. Some viruses can induce the release of reactive oxygen species (ROS) in infected cells, which may be closely related with their pathogenicity. In this report, chaetocin, a fungal metabolite reported to have antimicrobial and cytostatic activity, was studied for its effect on the activation of latent Epstein-Barr virus (EBV) in B95-8 cells. We found that chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration (50 nmol L -1 ). The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine (NAC), an ROS inhibitor, suppressed chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that chaetocin reactivates latent EBV primarily via ROS pathways.

  4. Epstein-Barr Virus Hijacks DNA Damage Response Transducers to Orchestrate Its Life Cycle.

    PubMed

    Hau, Pok Man; Tsao, Sai Wah

    2017-11-16

    The Epstein-Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways. The consequences of DDR inactivation lead to genomic instability and promote cellular transformation. This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation.

  5. Incidence of Epstein-Barr Virus in Astronaut Saliva During Spaceflight

    NASA Technical Reports Server (NTRS)

    Payne, Deborah A.; Mehta, Satish K.; Tyring, Stephen K.; Stowe, Raymond P.; Pierson, Duane L.

    1998-01-01

    Astronauts experience psychological and physical stresses that may result in re-activation of latent viruses during spaceflight, potentially increasing the risk of disease among crew members. The shedding of Epstein-Barr virus (EBV) in the saliva of astronauts will increase during spaceflight. A total of 534 saliva specimens were collected from 11 EBV-seropositive astronauts before, during, and after four space shuttle missions. The presence of EBV DNA in saliva, assessed by polymerase chain reaction (PCR), was used to determine shedding patterns before, during, and after spaceflight. EBV DNA was detected more frequently before flight than during (p less than 0.001) or after (p less than 0.01) flight. No significant difference between the in-flight and postflight periods was detected in the frequency of occurrence of EBV DNA. The increased frequency of shedding of EBV before flight suggests that stress levels may be greater before launch than during or after spaceflight.

  6. Epstein-Barr virus-encoded EBNA-5 binds to Epstein-Barr virus-induced Fte1/S3a protein

    SciTech Connect

    Kashuba, Elena; Yurchenko, Mariya; Szirak, Krisztina

    Epstein-Barr virus (EBV) transforms resting human B cells into immortalized immunoblasts. EBV-encoded nuclear antigens EBNA-5 (also called EBNA-LP) is one of the earliest viral proteins expressed in freshly infected B cells. We have recently shown that EBNA-5 binds p14ARF, a nucleolar protein that regulates the p53 pathway. Here, we report the identification of another protein with partially nucleolar localization, the v-fos transformation effector Fte-1 (Fte-1/S3a), as an EBNA-5 binding partner. In transfected cells, Fte-1/S3a and EBNA-5 proteins showed high levels of colocalization in extranucleolar inclusions. Fte-1/S3a has multiple biological functions. It enhances v-fos-mediated cellular transformation and is part of themore » small ribosomal subunit. It also interacts with the transcriptional factor CHOP and apoptosis regulator poly(ADP-ribose) polymerase (PARP). Fte-1/S3a is regularly expressed at high levels in both tumors and cancer cell lines. Its high expression favors the maintenance of malignant phenotype and undifferentiated state, whereas its down-regulation is associated with cellular differentiation and growth arrest. Here, we show that EBV-induced B cell transformation leads to the up-regulation of Fte-1/S3a. We suggest that EBNA-5 through binding may influence the growth promoting, differentiation inhibiting, or apoptosis regulating functions of Fte-1/S3a.« less

  7. Subcellular distribution and life cycle of Epstein-Barr virus in keratinocytes of oral hairy leukoplakia.

    PubMed Central

    Rabanus, J. P.; Greenspan, D.; Petersen, V.; Leser, U.; Wolf, H.; Greenspan, J. S.

    1991-01-01

    The authors investigated the life cycle of Epstein-Barr virus (EBV) in keratinocytes of oral hairy leukoplakia by combining immunohistochemistry. DNA in situ hybridization, and lectin histochemistry with electron microscopy. Diffuse-staining components of the EBV early antigen complex (EA-D), EBV 150-kd capsid antigen (VCA), EBV membrane antigen (gp350/220), and double-stranded DNA were labeled with monoclonal antibodies. An EBV-DNA probe was used to locate EBV DNA. Wheat-germ agglutinin (WGA) was employed to distinguish Golgi-associated compartments. The authors found EBV proteins and EBV DNA only in keratinocytes with apparent viral assembly. In situ hybridization showed EBV DNA in free corelike material and in electron-dense cores of mature nucleocapsids. Monoclonal antibodies to nonspecific double-stranded DNA attached to the same structures and to marginated chromatin. Components of EA-D were dispersed throughout the nuclei but accumulated near condensed chromatin and in 'punched-out' regions of the chromatin. Epstein-Barr virus 150-kd capsid antigen was found only in the nuclei, where it appeared preferentially on mature nucleocapsids. As yet unexplained arrays of intranuclear particles that remained unlabeled with all EBV-specific probes reacted intensely with an antiserum against common papillomavirus antigen. Gp350/220 was detectable in various cellular membrane compartments and was highly concentrated on EBV envelopes in peripheral Golgi-associated secretory vesicles. It was less abundant on the extracellular EBV, indicating that viral membrane antigen partly dissociates from the mature virus. Combined lectin-binding histochemistry and electron microscopy demonstrated for the first time that EBV is processed in the Golgi apparatus, which eventually releases the virus by fusion with the plasma membrane. These results provide insight into the biologic events that occur during complete EBV replication in vivo. Images Figure 1 Figure 2 Figure 3 Figure 4

  8. Advances in Virus-Directed Therapeutics against Epstein-Barr Virus-Associated Malignancies

    PubMed Central

    Ghosh, Sajal K.; Perrine, Susan P.; Faller, Douglas V.

    2012-01-01

    Epstein-Barr virus (EBV) is the causal agent in the etiology of Burkitt's lymphoma and nasopharyngeal carcinoma and is also associated with multiple human malignancies, including Hodgkin's and non-Hodgkin's lymphoma, and posttransplantation lymphoproliferative disease, as well as sporadic cancers of other tissues. A causal relationship of EBV to these latter malignancies remains controversial, although the episomic EBV genome in most of these cancers is clonal, suggesting infection very early in the development of the tumor and a possible role for EBV in the genesis of these diseases. Furthermore, the prognosis of these tumors is invariably poor when EBV is present, compared to their EBV-negative counterparts. The physical presence of EBV in these tumors represents a potential “tumor-specific” target for therapeutic approaches. While treatment options for other types of herpesvirus infections have evolved and improved over the last two decades, however, therapies directed at EBV have lagged. A major constraint to pharmacological intervention is the shift from lytic infection to a latent pattern of gene expression, which persists in those tumors associated with the virus. In this paper we provide a brief account of new virus-targeted therapeutic approaches against EBV-associated malignancies. PMID:22500168

  9. The Microenvironment in Epstein-Barr Virus-Associated Malignancies.

    PubMed

    Tan, Geok Wee; Visser, Lydia; Tan, Lu Ping; van den Berg, Anke; Diepstra, Arjan

    2018-04-13

    The Epstein–Barr virus (EBV) can cause a wide variety of cancers upon infection of different cell types and induces a highly variable composition of the tumor microenvironment (TME). This TME consists of both innate and adaptive immune cells and is not merely an aspecific reaction to the tumor cells. In fact, latent EBV-infected tumor cells utilize several specific mechanisms to form and shape the TME to their own benefit. These mechanisms have been studied largely in the context of EBV+ Hodgkin lymphoma, undifferentiated nasopharyngeal carcinoma, and EBV+ gastric cancer. This review describes the composition, immune escape mechanisms, and tumor cell promoting properties of the TME in these three malignancies. Mechanisms of susceptibility which regularly involve genes related to immune system function are also discussed, as only a small proportion of EBV-infected individuals develops an EBV-associated malignancy.

  10. The Epstein-Barr Virus Episome Maneuvers between Nuclear Chromatin Compartments during Reactivation

    PubMed Central

    Moquin, Stephanie A.; Thomas, Sean; Whalen, Sean; Warburton, Alix; Fernandez, Samantha G.; McBride, Alison A.; Pollard, Katherine S.

    2017-01-01

    ABSTRACT The human genome is structurally organized in three-dimensional space to facilitate functional partitioning of transcription. We learned that the latent episome of the human Epstein-Barr virus (EBV) preferentially associates with gene-poor chromosomes and avoids gene-rich chromosomes. Kaposi's sarcoma-associated herpesvirus behaves similarly, but human papillomavirus does not. Contacts on the EBV side localize to OriP, the latent origin of replication. This genetic element and the EBNA1 protein that binds there are sufficient to reconstitute chromosome association preferences of the entire episome. Contacts on the human side localize to gene-poor and AT-rich regions of chromatin distant from transcription start sites. Upon reactivation from latency, however, the episome moves away from repressive heterochromatin and toward active euchromatin. Our work adds three-dimensional relocalization to the molecular events that occur during reactivation. Involvement of myriad interchromosomal associations also suggests a role for this type of long-range association in gene regulation. IMPORTANCE The human genome is structurally organized in three-dimensional space, and this structure functionally affects transcriptional activity. We set out to investigate whether a double-stranded DNA virus, Epstein-Barr virus (EBV), uses mechanisms similar to those of the human genome to regulate transcription. We found that the EBV genome associates with repressive compartments of the nucleus during latency and with active compartments during reactivation. This study advances our knowledge of the EBV life cycle, adding three-dimensional relocalization as a novel component to the molecular events that occur during reactivation. Furthermore, the data add to our understanding of nuclear compartments, showing that disperse interchromosomal interactions may be important for regulating transcription. PMID:29142137

  11. Epigenetic Alterations in Epstein-Barr Virus-Associated Diseases.

    PubMed

    Niller, Hans Helmut; Banati, Ferenc; Salamon, Daniel; Minarovits, Janos

    2016-01-01

    Latent Epstein-Bar virus genomes undergo epigenetic modifications which are dependent on the respective tissue type and cellular phenotype. These define distinct viral epigenotypes corresponding with latent viral gene expression profiles. Viral Latent Membrane Proteins 1 and 2A can induce cellular DNA methyltransferases, thereby influencing the methylation status of the viral and cellular genomes. Therefore, not only the viral genomes carry epigenetic modifications, but also the cellular genomes adopt major epigenetic alterations upon EBV infection. The distinct cellular epigenotypes of EBV-infected cells differ from the epigenotypes of their normal counterparts. In Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) significant changes in the host cell methylome with a strong tendency towards CpG island hypermethylation are observed. Hypermethylated genes unique for EBVaGC suggest the existence of an EBV-specific "epigenetic signature". Contrary to the primary malignancies carrying latent EBV genomes, lymphoblastoid cells (LCs) established by EBV infection of peripheral B cells in vitro are characterized by a massive genome-wide demethylation and a significant decrease and redistribution of heterochromatic histone marks. Establishing complete epigenomes of the diverse EBV-associated malignancies shall clarify their similarities and differences and further clarify the contribution of EBV to the pathogenesis, especially for the epithelial malignancies, NPC and EBVaGC.

  12. Designing an effective vaccine to prevent Epstein-Barr virus-associated diseases: challenges and opportunities.

    PubMed

    Dasari, Vijayendra; Bhatt, Kunal H; Smith, Corey; Khanna, Rajiv

    2017-04-01

    Epstein-Barr virus (EBV) is a ubiquitous herpesvirus associated with a number of clinical manifestations. Primary EBV infection in young adolescents often manifests as acute infectious mononucleosis and latent infection is associated with multiple lymphoid and epithelial cancers and autoimmune disorders, particularly multiple sclerosis. Areas covered: Over the last decade, our understanding of pathogenesis and immune regulation of EBV-associated diseases has provided an important platform for the development of novel vaccine formulations. In this review, we discuss developmental strategies for prophylactic and therapeutic EBV vaccines which have been assessed in preclinical and clinical settings. Expert commentary: Major roadblocks in EBV vaccine development include no precise understanding of the clinical correlates of protection, uncertainty about adjuvant selection and the unavailability of appropriate animal models. Recent development of new EBV vaccine formulations provides exciting opportunities for the formal clinical assessment of novel formulations.

  13. Immune-mediated neuropathy with Epstein-Barr virus-positive T-cell lymphoproliferative disease.

    PubMed

    Hattori, Takaaki; Arai, Ayako; Yokota, Takanori; Imadome, Ken-Ichi; Tomimitsu, Hiroyuki; Miura, Osamu; Mizusawa, Hidehiro

    2015-01-01

    A 47-year-old man with Epstein-Barr virus (EBV)-positive T/NK- cell lymphoproliferative disease (EBV-T/NK-LPD) developed acute-onset weakness. A nerve conduction study showed a conduction block in both the proximal and most distal segments. Although the patient's neuropathy transiently responded to intravenous immunoglobulin, it was progressive for at least 25 days until the start of prednisolone (PSL) administration, after which it remarkably improved. The neuropathy further improved after allogeneic bone marrow transplantation (BMT). The present patient's clinical course is not consistent with that of typical Guillain-Barré syndrome. This case suggests that EBV-T/NK-LPD can cause progressive immune-mediated neuropathy as a result of chronic EBV antigen presentation and can be treated with PSL and BMT.

  14. Primary immunodeficiencies predisposed to Epstein-Barr virus-driven haematological diseases.

    PubMed

    Parvaneh, Nima; Filipovich, Alexandra H; Borkhardt, Arndt

    2013-09-01

    Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, maintains lifelong subclinical persistent infections in humans. In the circulation, EBV primarily infects the B cells, and protective immunity is mediated by EBV-specific cytotoxic T cells (CTLs) and natural killer (NK) cells. However, EBV has been linked to several devastating diseases, such as haemophagocytic lymphohistiocytosis (HLH) and lymphoproliferative diseases in the immunocompromised host. Some types of primary immunodeficiencies (PIDs) are characterized by the development of EBV-associated complications as their predominant clinical feature. The study of such genetic diseases presents an ideal opportunity for a better understanding of the biology of the immune responses against EBV. Here, we summarize the range of PIDs that are predisposed to EBV-associated haematological diseases, describing their clinical picture and pathogenetic mechanisms. © 2013 John Wiley & Sons Ltd.

  15. Advances in Understanding the Pathogenesis of Epstein-Barr Virus-Associated Lymphoproliferative Disorders.

    PubMed

    Yang, Xi; Nishida, Naonori; Zhao, Xiaodong; Kanegane, Hirokazu

    2015-10-01

    Epstein-Barr virus (EBV) was discovered 50 years ago from an african Burkitt lymphoma cell line. EBV-associated lymphoproliferative disorders (LPDs) are life- threatening diseases, especially in children. In this article, we review EBV-associated LPDs, especially in the area of primary immunodeficiency disease (PID). We searched PubMed for publications with key words including EBV infection, lymphoma, LPDs and PID, and selected the manuscripts written in English that we judged to be relevant to the topic of this review.On the basis of the data in the literature, we grouped the EBV-associated LPDs into four categories: nonmalignant disease, malignant disease, acquired immunodeficiency disease and PID. Each category has its own risk factor for LPD development. EBV-associated LPD is a complex disease, creating new challenges for diagnosis and treatment.

  16. Recent Concise Viewpoints of Chronic Active Epstein-Barr Virus Infection.

    PubMed

    Okano, Motohiko

    2015-01-01

    Chronic active Epstein-Barr virus infection (CAEBV) is characterized mainly by prolonged or intermittent fever, lymphadenopathy and hepatosplenomegaly without definite underlying diseases at the diagnosis. Patients with CAEBV also may have various life-threatening conditions including hematological, neurological, pulmonary, cardiac, digestive tract, ocular and/or dermal disorders. Additionally, during the course of illness, they often develop hematological malignancies such as T cell, NK cell or B cell lymphoproliferative disorder (LPD) and/or lymphoma. No causative pathogenetic mechanisms have been sufficiently clarified, and additionally no promising efficacious treatment was demonstrated except for the hematopoietic stem cell transplantation (HSCT) in cases who develop T cell or NK cell LPD or lymphoma. This minireview outlines the recent development for the comprehensive viewpoints of CAEBV mainly regarding to virological, immunological, pathological and therapeutical progresses.

  17. [A case of chronic active Epstein-Barr virus infection with a pharyngeal ulcer].

    PubMed

    Nagano, Hiromi; Iuchi, Hiroyuki; Yoshifuku, Kosuke; Morizono, Kensuke; Kurono, Yuichi

    2013-07-01

    Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and hepatosplenomegaly. A 44-year-old women visited our ENT clinic with a four-month history of fever and throat pain. She was diagnosed as having CAEBV based on the findings of fever, liver dysfunction, lymphadenopathy, pharyngeal ulcer, the titer for IgG to the EBV capsid and pathological findings. The whole-blood EBV DNA levels were high and above 3.7 x 10(3) copies/mL. After administration of intravenous predonine (1000 mg/day for 3 days) and oral predonine (1.5 mg/kg. 60 mg/day), the liver dysfunction and pharyngeal ulcer improved. Since the prognosis is poor in adult cases of CAEBV, chemotherapy is scheduled for this case.

  18. Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection.

    PubMed

    Fukuda, Yutaka; Momoi, Nobuo; Akaihata, Mitsuko; Nagasawa, Katsutoshi; Mitomo, Masaki; Aoyagi, Yoshimichi; Endoh, Kisei; Hosoya, Mitsuaki

    2015-08-01

    Chronic active Epstein-Barr virus (EBV) infection (CAEBV), characterized by persistent infectious mononucleosis-like symptoms, can lead to cardiovascular complications including coronary artery aneurysm or myocarditis. Here, we present the case of an 11-year-old boy with pulmonary arterial hypertension (PAH) and junctional ectopic tachycardia associated with CAEBV. The patient did not have any major symptoms attributed to CAEBV, such as fever, lymphadenopathy or splenomegaly when the PAH developed. Mild liver dysfunction was found at the first examination, and it persisted. Two years after the PAH symptoms appeared, CAEBV was evident, based on deteriorated liver function, hepatosplenomegaly, and coronary artery aneurysms. CAEBV should be considered as a cause of secondary PAH, particularly when liver dysfunction coexists. © 2015 Japan Pediatric Society.

  19. PCR array analysis of gene expression profiles in chronic active Epstein-Barr virus infection.

    PubMed

    Murakami, Masanao; Hashida, Yumiko; Imajoh, Masayuki; Maeda, Akihiko; Kamioka, Mikio; Senda, Yasutaka; Sato, Tetsuya; Fujieda, Mikiya; Wakiguchi, Hiroshi; Daibata, Masanori

    2014-07-01

    To determine the host cellular gene expression profiles in chronic active Epstein-Barr virus infection (CAEBV), peripheral blood samples were obtained from three patients with CAEBV and investigated using a PCR array analysis that focused on T-cell/B-cell activation. We identified six genes with expression levels that were tenfold higher in CAEBV patients compared with those in healthy controls. These results were verified by quantitative reverse transcription-PCR. We identified four highly upregulated genes, i.e., IL-10, IL-2, IFNGR1, and INHBA. These genes may be involved in inflammatory responses and cell proliferation, and they may contribute to the development and progression of CAEBV. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  20. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection.

    PubMed

    Kimura, H; Hoshino, Y; Kanegane, H; Tsuge, I; Okamura, T; Kawa, K; Morishima, T

    2001-07-15

    Thirty patients with chronic active Epstein-Barr virus (CAEBV) infection were analyzed. The study group included 18 male and 12 female patients, ranging in age from 5 to 31 years with a mean age of 14.2 years. Not all patients had high titers of EBV-specific antibodies, but all patients had high viral loads in their peripheral blood (more than 10(2.5) copies/microg DNA). Fifty percent of the patients displayed chromosomal aberrations, and 79% had monoclonality of EBV. Patients were divided into 2 clinically distinct groups, based on whether the predominantly infected cells in their peripheral blood were T cells or natural killer (NK) cells. Over a 68-month period of observation, 10 patients died from hepatic failure, malignant lymphoma, or other causes. Patients with T-cell CAEBV had a shorter survival time than those with NK-cell type of disease.

  1. Viral interleukin-10 in chronic active Epstein-Barr virus infection.

    PubMed

    Kanegane, H; Wakiguchi, H; Kanegane, C; Kurashige, T; Tosato, G

    1997-07-01

    Viral interleukin-10 (IL-10), a product of the Epstein-Barr virus (EBV) replication gene BCRF1, shares extensive structural and functional similarity with the human cytokine IL-10. Both viral and human IL-10 inhibit T cell growth and interferon-gamma production. With two ELISAs, one that recognized both human and viral (total) IL-10 and the other specific for viral IL-10, IL-10 was measured in serum or plasma from 34 patients with chronic active EBV infection (CAEBV) and from 15 healthy controls. Of the patients, 56% had measurable total IL-10 and 29% had measurable viral IL-10. In contrast, total IL-10 was detectable in only 2 of 15 controls and viral IL-10 was undetectable. Thus, many patients with CAEBV have abnormally high levels of circulating IL-10 that may contribute to disease pathogenesis by inhibiting host immunity.

  2. Spontaneous Regression of Pulmonary Nodules Presenting as Epstein-Barr Virus-related Atypical Infectious Mononucleosis.

    PubMed

    Shinozuka, Jun; Awaguni, Hitoshi; Tanaka, Shin-Ichiro; Makino, Shigeru; Maruyama, Rikken; Inaba, Tohru; Imashuku, Shinsaku

    2016-07-01

    Pulmonary nodules associated with Epstein-Barr virus (EBV)-related atypical infectious mononucleosis have rarely been described. A 12-year-old Japanese boy, upon admission, revealed multiple small round nodules (a total of 7 nodules in 4 to 8 mm size) in the lungs on computed tomography. The hemorrhagic pharyngeal tonsils with hot signals on 18F-fluorodeoxyglucose-positron emission tomography-computed tomography were biopsied revealing the presence of EBV-encoded small nuclear RNA (EBER)-positive cells; however, no lymphoma was noted. The patient was diagnosed as having atypical EBV-infectious mononucleosis associated with primary EBV infection. Pulmonary nodules markedly reduced in numbers and sizes spontaneously over a 2-year period. Differential diagnosis of pulmonary nodules in childhood should include atypical EBV infection.

  3. Acute Gastritis and Splenic Infarction Caused by Epstein-Barr Virus

    PubMed Central

    Jeong, Ji Eun; Kim, Kyung Moon; Shim, Jae Won; Kim, Deok Soo; Shim, Jung Yeon; Park, Moon Soo; Park, Soo Kyung

    2018-01-01

    Epstein-Barr virus (EBV) infection can be presented with various clinical manifestations and different levels of severity when infected. Infectious mononucleosis, which is most commonly caused by EBV infection in children and adolescents, is a clinical syndrome characterized by fatigue, malaise, fever, sore throat, and generalized lymphadenopathy. But rarely, patients with infectious mononucleosis may present with gastrointestinal symptoms and complicated by gastritis, splenic infarction, and splenic rupture. We encountered a 16-year-old girl who presented with fever, fatigue, and epigastric pain. Splenic infarction and EBV-associated gastritis were diagnosed by using esophagogastroduodenoscopy and abdominal computed tomography. Endoscopy revealed a generalized hyperemic nodular lesion in the stomach, and the biopsy findings were chronic gastritis with erosion and positive in situ hybridization for EBV. As splenic infarction and acute gastritis are rare in infectious mononucleosis and are prone to be overlooked, we must consider these complications when an infectious mononucleosis patient presents with gastrointestinal symptom. PMID:29713613

  4. Bromodomain and extraterminal inhibitors block the Epstein-Barr virus lytic cycle at two distinct steps.

    PubMed

    Keck, Kristin M; Moquin, Stephanie A; He, Amanda; Fernandez, Samantha G; Somberg, Jessica J; Liu, Stephanie M; Martinez, Delsy M; Miranda, Jj L

    2017-08-11

    Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle. BET inhibitors prevent expression of the viral immediate-early protein BZLF1. JQ1 alters transcription of genes controlled by the host protein BACH1, and BACH1 knockdown reduces BZLF1 expression. BET proteins also localize to the lytic origin of replication (OriLyt) genetic elements, and BET inhibitors prevent viral late gene expression. There JQ1 reduces BRD4 recruitment during reactivation to preclude replication initiation. This represents a rarely observed dual mode of action for drugs.

  5. Progress, Prospects, and Problems in Epstein-Barr Virus Vaccine Development

    PubMed Central

    Balfour, Henry H.

    2014-01-01

    Epstein-Barr virus (EBV) is responsible for a farrago of acute and chronic human diseases including cancer. A prophylactic vaccine could reduce this disease burden. Several EBV vaccines have been given to humans but none has been sufficiently studied to establish safety and efficacy. EBV vaccine development has been hampered by the lack of an animal model other than subhuman primates, proprietary issues, selection of an appropriate adjuvant, and failure to reach consensus on what an EBV vaccine could or should actually achieve. A recent conference at the U.S. National Institutes of Health emphasizing the global importance of EBV vaccine and advocating a phase 3 trial to prevent infectious mononucleosis should encourage research that could eventually lead to its licensure. PMID:24632197

  6. Prolonged hepatitis and jaundice: a rare complication of paediatric Epstein-Barr virus infection.

    PubMed

    Tan, Zhen Han; Phua, Kong Boo; Ong, Christina; Kader, Ajmal

    2015-07-01

    We herein report the case of a 14-year-old girl with Epstein-Barr virus (EBV) infectious mononucleosis who developed prolonged hepatitis and jaundice. At presentation, she had tender hepatomegaly with a markedly deranged liver function test. Abdominal ultrasonography showed hepatomegaly and a thickened gallbladder wall. During the subsequent 11 weeks, her transaminases showed two further peaks, which corresponded with clinical deterioration. Her highest alanine transaminase level was 1,795 µ/L and total bilirubin level was 154 µmol/L. She recovered fully with conservative management. EBV-related liver involvement is typically mild and self-limiting. We believe that tender hepatomegaly and gallbladder thickening may be important predictors of significant liver involvement. Although multiple transaminase peaks may occur, we do not consider this an indication for antiviral or immunosuppressive therapy. In the absence of strong evidence supporting the use of any specific therapy, we recommend a conservative approach for an immunocompetent patient.

  7. Successful Treatment of Pediatric Epstein-Barr Virus-positive Aggressive Natural Killer-Cell Leukemia.

    PubMed

    Kim, Bo Kyung; Hong, Kyung Taek; Kang, Hyoung Jin; An, Hong Yul; Choi, Jung Yoon; Hong, Che Ry; Park, Kyung Duk; Lee, Dong Soon; Shin, Hee Young

    2018-06-08

    Epstein-Barr virus (EBV)-positive aggressive natural killer-cell leukemia (ANKL) is a rare malignancy of mature natural killer cells, with a very poor survival rate. Patients have a rapidly declining clinical course and a poor prognosis, with a median survival of only a few months. Herein, we describe a 16-year-old boy who was diagnosed with EBV-positive ANKL and successfully treated using combination chemotherapy and a subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT). The patient is disease free 4 years and 9 months after alloHSCT. Thus, combination chemotherapy followed by alloHSCT seems to be a promising therapeutic option for EBV-positive ANKL.

  8. Acute Epstein-Barr virus infection presenting as severe gastroenteritis without infectious mononucleosis-like manifestations.

    PubMed

    Fujiwara, Mikio; Miyamoto, Shin'ichi; Iguchi, Kouta; Matsunaka, Toshihiro; Sakashita, Hiromi; Tsuruyama, Tatsuaki; Kanegane, Hirokazu; Marusawa, Hiroyuki; Nakase, Hiroshi; Chiba, Tsutomu

    2009-12-01

    Primary Epstein-Barr virus (EBV) infection is usually a self-limiting disease. Although it is sometimes accompanied by severe complications such as thrombocytopenia, hemolytic anemia, and splenic rupture, predominantly gastrointestinal complications are rarely reported. We studied an unusual case of primary EBV infection associated with severe hemorrhagic gastroenteritis. EBV infection was confirmed in the biopsy specimen by demonstrating the presence of EBV DNA by polymerase chain reaction, and of EBV-encoded small RNA (EBER)-positive cells by in-situ hybridization. Our patient was suspected of having primary EBV infection from the serological findings-EBV-viral capsid antigen IgM (+) and EBV nuclear antigen (-)-but he did not show typical clinical features of infectious mononucleosis such as lymph node swelling, pharyngitis, liver dysfunction, and splenomegaly. A definite diagnosis of primary EBV infection was made using biopsy specimens by demonstrating the presence of EBV DNA and EBER-positive cells.

  9. Severe thrombocytopenia as a complication of acute Epstein-Barr virus infection.

    PubMed

    Likic, Robert; Kuzmanic, Dusko

    2004-01-31

    Severe thrombocytopenia is an extremely rare complication of acute Epstein-Barr virus (EBV) infection. EBV infection usually causes hematological abnormalities, mainly atypical lymphocytosis, which is a feature of infectious mononucleosis, and uncomplicated cases often present with mild decreases in platelet counts. Our otherwise healthy, 21-year-old male Caucasian patient had thrombocytopenia and bleeding diathesis with platelet counts of 8 x 10(9)/L without other signs and symptoms of infectious mononucleosis. We commenced treatment with intravenous methylprednisolone before the acute EBV infection was serologically confirmed. Platelet counts initially rose and then fell after we stopped administrating corticosteroids. Repeated administration of methylprednisolone was followed by full recovery of the platelet count and normalization of formerly elevated transaminases. EBV infection may happen in children, adolescents and adults and this differential diagnosis should be considered in every patient presenting with acute thrombocytopenia.

  10. Chest pain in a young patient: an unusual complication of Epstein-Barr virus.

    PubMed

    Raman, Lavanya; Rathod, Krishnaraj Sinhji; Banka, Rajesh

    2014-03-31

    A 29-year-old man presented with sudden left-sided pleuritic chest pain on a background of sore throat during the preceding week. On examination he had tender cervical lymphadenopathy, he was tachycardic and had a 24 mm Hg blood pressure difference between the left and right arms. Bloods revealed deranged liver function tests and a lymphocytosis. His D-dimer was raised, hence he was treated for presumed pulmonary embolism before imaging was available. Monospot test was positive. He subsequently had both a CT pulmonary angiogram and a CT angiogram of the aorta to exclude pulmonary embolism and aortic dissection. The CT revealed splenomegaly with a large subdiaphragmatic haematoma secondary to splenic rupture. This had likely caused referred pain through diaphragmatic irritation. He was taken to theatre for urgent splenectomy. The unifying diagnosis was infectious mononucleosis complicated by spontaneous splenic rupture secondary to Epstein-Barr virus infection.

  11. Possible autoimmune hepatitis induced after chronic active Epstein-Barr virus infection.

    PubMed

    Wada, Yoshiko; Sato, Chikako; Tomita, Kyoko; Ishii-Aso, Rika; Haga, Hiroaki; Okumoto, Kazuo; Nishise, Yuko; Watanabe, Hisayoshi; Saito, Takafumi; Ueno, Yoshiyuki

    2014-02-01

    Chronic active Epstein-Barr virus infection (CAEBV) can be manifested in a variety of systemic conditions, including interstitial pneumonia, malignant lymphoma, and coronary aneurysm. Sometimes it may be associated with hepatic failure, although the mechanism underlying CAEBV-related hepatotoxicity remains unclear. We encountered a case of autoimmune hepatitis (AIH) associated with CAEBV. A 61-year-old male was referred to our hospital because of abnormal liver enzyme levels after initial diagnosis of CAEBV had been made by laboratory tests and liver biopsy. On admission, positivity for anti-nuclear antibody was evident, and examination of the liver biopsy specimen showed findings compatible with AIH. Steroid administration was initiated, and the liver function parameters subsequently improved. Although phenotypic changes in liver biopsy specimens are rare in this condition, the present case could provide clues to the possible pathogenesis of AIH.

  12. Evaluation of Epstein-Barr Virus infection in hypopharyngeal carcinomas from 37 Japanese patients.

    PubMed

    Zhou, L; Miyagi, Y; Hiroshi, E; Tanaka, Y; Aoki, I; Tsukuda, M

    1998-06-01

    Thirty-seven biopsy specimens from primary sites, 18 surgically removed metastatic neck nodes, and 18 surgically removed primary sites from 37 patients with hypopharyngeal carcinoma (HPC) were evaluated for the presence of Epstein-Barr Virus (EBV) infection by in situ hybridization (ISH) and polymerase chain reaction (PCR). Although some of normal lymphocytes in 6 of 18 metastatic nodes were positive by ISH, there were no positive results from HPC tumor cells themselves. Our results indicate that EBV-infected non-neoplastic cells such as lymphocytes can be a cause of false positivity, if a study were conducted with PCR alone. Because ISH for EBV-encoded early RNAs was highly sensitive, even more sensitive than PCR from paraffin-embedded samples in our study, this method should be the first choice for identification of EBV infection to avoid false positives.

  13. Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1.

    PubMed

    Kvansakul, Marc; Wei, Andrew H; Fletcher, Jamie I; Willis, Simon N; Chen, Lin; Roberts, Andrew W; Huang, David C S; Colman, Peter M

    2010-12-23

    Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes.

  14. Hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus in the central nervous system.

    PubMed

    Magaki, Shino; Ostrzega, Nora; Ho, Elliot; Yim, Catherine; Wu, Phillis; Vinters, Harry V

    2017-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare immune hyperactivation syndrome which may be primary (genetic) or secondary to various immune-related conditions including infection, immunodeficiency, and malignancies. Rapid diagnosis and treatment are essential because it can be associated with significant morbidity and mortality. Epstein-Barr virus (EBV) is a known infectious cause of acquired HLH, but EBV-associated HLH involving the central nervous system is rare and not well characterized neuropathologically. We report a case of fatal EBV-associated HLH with severe involvement of the central nervous system showing florid hemophagocytosis in the choroid plexus, with extensive neuron loss and gliosis in the cerebrum, cerebellum, and brainstem. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Unilateral laterothoracic exanthema with coincident evidence of Epstein Barr virus reactivation: exploration of a possible link.

    PubMed

    Scheinfeld, Noah

    2007-07-13

    Unilateral laterothoracic exanthem (ULE) was first described in 1962 in the United States and comprehensively elaborated in 1992. Although ULE most commonly occurs in children, ULE can occur in adults. ULE may or may not be preceded by a viral prodrome and is marked by coalescing erythematous papules predominately on one side of the body. ULE usually lasts 4-6 weeks but can last as little as 2 weeks. It has inconsistently been linked to viral infection, in particular parvovirus B-19. I note ULE in an adult with concurrent reactivation of Epstein Barr virus (EBV) that lasted 4 weeks. The role of the reactivation of EBV in human disease and ULE is explored.

  16. PARP1 restricts Epstein Barr Virus lytic reactivation by binding the BZLF1 promoter.

    PubMed

    Lupey-Green, Lena N; Moquin, Stephanie A; Martin, Kayla A; McDevitt, Shane M; Hulse, Michael; Caruso, Lisa B; Pomerantz, Richard T; Miranda, Jj L; Tempera, Italo

    2017-07-01

    The Epstein Barr virus (EBV) genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type, and in other herpesviruses, loss of CTCF binding at specific regions correlates with viral reactivation. Here, we demonstrate that binding of PARP1, an important cofactor of CTCF, at the BZLF1 lytic switch promoter restricts EBV reactivation. Knockdown of PARP1 in the Akata-EBV cell line significantly increases viral copy number and lytic protein expression. Interestingly, CTCF knockdown has no effect on viral reactivation, and CTCF binding across the EBV genome is largely unchanged following reactivation. Moreover, EBV reactivation attenuates PARP activity, and Zta expression alone is sufficient to decrease PARP activity. Here we demonstrate a restrictive function of PARP1 in EBV lytic reactivation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal.

    PubMed

    Serafini, Barbara; Scorsi, Eleonora; Rosicarelli, Barbara; Rigau, Valérie; Thouvenot, Eric; Aloisi, Francesca

    2017-06-15

    Rebound of disease activity in multiple sclerosis patients after natalizumab withdrawal is a potentially life-threatening event. To verify whether highly destructive inflammation after natalizumab withdrawal is associated with Epstein-Barr virus (EBV) reactivation in central nervous system infiltrating B-lineage cells and cytotoxic immunity, we analyzed post-mortem brain tissue from a patient who died during a fulminating MS relapse following natalizumab withdrawal. Numerous EBV infected B cells/plasma cells and CD8+ T cells infiltrated all white matter lesions; the highest frequency of EBV lytically infected cells and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions. These results may encourage switching to B-cell depleting therapy after natalizumab discontinuation. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Progression of understanding for the role of Epstein-Barr virus and management of nasopharyngeal carcinoma.

    PubMed

    Nakanishi, Yosuke; Wakisaka, Naohiro; Kondo, Satoru; Endo, Kazuhira; Sugimoto, Hisashi; Hatano, Miyako; Ueno, Takayoshi; Ishikawa, Kazuya; Yoshizaki, Tomokazu

    2017-09-01

    Nasopharyngeal carcinoma (NPC) is very common in southern China and Southeast Asia. In regions where NPC is endemic, undifferentiated subtypes constitute most cases and are invariably associated with Epstein-Barr virus (EBV) infection, whereas the differentiated subtype is more common in other parts of the world. Undifferentiated NPC is a unique malignancy with regard to its epidemiology, etiology, and clinical presentation. Clinically, NPC is highly invasive and metastatic, but sensitive to both chemotherapy and radiotherapy (RT). Overall prognosis has dramatically improved over the past three decades because of advances in management, including the improvement of RT technology, the broader application of chemotherapy, and more accurate disease staging. Despite the excellent local control with modern RT, distant failure remains a challenging problem. Advances in molecular technology have helped to elucidate the molecular pathogenesis of NPC. This article reviews the contribution of EBV gene products to NPC pathogenesis and the current management of NPC.

  19. Cholecystitis and nephrotic syndrome complicating Epstein-Barr virus primary infection.

    PubMed

    Rodà, Diana; Huici, Malka; Ricart, Sílvia; Vila, Jordi; Fortuny, Clàudia; Alsina, Laia

    2017-02-01

    Epstein-Barr virus (EBV) infection results in a spectrum of clinical manifestations. The host immune response to EBV plays a key role in the extent and degree of clinical features, which in children under 4 years of age are usually mild, non-specific and self-limiting. A 2-year-old boy in whom no known immune disorder could be found presented with acute acalculous cholecystitis, renal dysfunction with massive proteinuria, ascites, pleural effusion, minimal peripheral oedema and a severe systemic inflammatory response. Improvement occurred after initiation of corticosteroids and antiviral treatment with gancyclovir. In severely symptomatic or complicated EBV infection, a primary immunodeficiency must be suspected. If a primary immunodeficiency has been ruled out, the correct management of severe EBV infection in the immunocompetent host remains controversial.

  20. Enzyme-linked immunosorbent assay for detection of antibodies to Epstein-Barr virus antigens.

    PubMed

    Voevodin, A F; Pácsa, A S

    1983-01-01

    Enzyme-Linked Immunosorbent Assay (ELISA) was standardized for measurement of antibody activity of reference human and baboon (Papio hamadryas) sera to soluble Epstein-Barr virus (EBV) antigens. A comparison with the immunofluorescent (IF) method showed that ELISA detects antibody specifically and sensitivity. In ELISA, Herpesvirus Papio (HVP) nuclear antigen (HUPNA) positive baboon serum reacted with EBV nuclear antigen (EBNA), as a further indication of the antigenic similarity between HVP and EBV. Forty-two baboon sera were tested with EBV antigens in both ELISA and IF test. The results showed an agreement between the two methods and also that by the use of EBV antigens, ELISA measures anti-HVP activity of baboon sera. ELISA did not reveal significant difference in antibody activity of 23 baboons with lymphoma and that of 24 healthy baboons. Results provide further data that ELISA can be used effectively in the field of EBV serology.

  1. Production of thyrotropin receptor antibodies in acute phase of infectious mononucleosis due to Epstein-Barr virus primary infection: a case report of a child.

    PubMed

    Nagata, Keiko; Okuno, Keisuke; Ochi, Marika; Kumata, Keisuke; Sano, Hitoshi; Yoneda, Naohiro; Ueyama, Jun-Ichi; Matsushita, Michiko; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Kanzaki, Susumu; Hayashi, Kazuhiko

    2015-01-01

    Various autoantibodies have been reported to be detected during the progression of infectious mononucleosis. We observed a case of infectious mononucleosis due to Epstein-Barr virus primary infection for 2 months, and noticed the transiently increased titer of thyrotropin receptor autoantibodies detected at the acute phase on the 3rd day after admission. At that time, real-time quantitative PCR also revealed the mRNA expressions of an immediate early lytic gene, BZLF1, and a latent gene, EBNA2. The expression of BZLF1 mRNA means that Epstein-Barr virus infects lytically, and EBNA2 protein has an important role in antibody production as well as the establishment of Epstein-Barr virus latency. These results suggest that Epstein-Barr virus lytic infection is relevant to thyrotropin receptor autoantibody production. Thyrotropin receptor autoantibodies stimulate thyroid follicular cells to produce excessive thyroid hormones and cause Graves' disease. Recently, we reported the thyrotropin receptor autoantibody production from thyrotropin receptor autoantibody-predisposed Epstein-Barr virus-infected B cells by the induction of Epstein-Barr virus lytic infection in vitro. This case showed in vivo findings consistent with our previous reports, and is important to consider the pathophysiology of Graves' disease and one of the mechanisms of autoimmunity.

  2. Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility: A multiethnic study.

    PubMed

    Langer-Gould, Annette; Wu, Jun; Lucas, Robyn; Smith, Jessica; Gonzales, Edlin; Amezcua, Lilyana; Haraszti, Samantha; Chen, Lie Hong; Quach, Hong; James, Judith A; Barcellos, Lisa F; Xiang, Anny H

    2017-09-26

    To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis. Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth. Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups ( p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics ( p = 0.004) but not in blacks ( p = 0.95) or whites ( p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics ( p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics. The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations. © 2017 American Academy of Neurology.

  3. Epstein-Barr virus in systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis—association and causation.

    PubMed

    Lossius, Andreas; Johansen, Jorunn N; Torkildsen, Øivind; Vartdal, Frode; Holmøy, Trygve

    2012-12-01

    Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if so, by which mechanisms the virus may contribute. In this review, we discuss possible viral and immunological mechanisms that might explain associations between EBV and autoimmune diseases and whether these associations represent causes or effects of inflammation and autoimmunity.

  4. Virus-specific cytotoxic T cells in chronic active Epstein-Barr virus infection.

    PubMed

    Shibayama, Haruna; Imadome, Ken-Ichi; Onozawa, Erika; Tsuzura, Akiho; Miura, Osamu; Koyama, Takatoshi; Arai, Ayako

    2017-01-01

    Chronic active Epstein-Barr virus infection (CAEBV) is a disease characterized by clonally proliferating and activated EBV-infected T or NK cells accompanied by chronic inflammation and T- or NK-cell neoplasms. However, the mechanism for developing CAEBV has not been clarified to date. Because the decreased number or inactivation of EBV-specific cytotoxic T lymphocytes (CTLs) resulted in the development of EBV-positive B-cell neoplasms, we investigated the number of CTLs in CAEBV patients using the tetrameric complexes of HLA-restricted EBV-specific peptides. Among the seven patients examined, EBV-specific CTLs were detected in the peripheral blood mononuclear cells (PBMCs) of four cases but were not detected in three cases. The ratio of EBV-specific CTLs in PBMCs tended to be higher in the patients with active disease than in those with inactive disease. In two patients in whom EBV-specific CTLs had not been detected, CTLs appeared after the eradication of EBV-infected T cells by allogeneic bone marrow transplantation. These results suggested that the failure of CTLs had a role in developing CAEBV, although the induction number and function of EBV-specific CTLs might vary in each patient.

  5. [Epstein-Barr virus infection with severe consequences. EBV, haemophagocytic lymphohistiocytosis and Hodgkin lymphoma with Down syndrome].

    PubMed

    Kuitert, Pieter C J; Abbink, Floor C H; Broers, Chantal J M; van der Valk, Paul; van Furth, A Marceline; van der Kuip, Martijn

    2014-01-01

    Over 90% of the population is infected with the Epstein-Barr virus (EBV). Following primary infection, the virus remains latent in B-lymphocytes. In isolated cases, especially in immunocompromised patients, the Epstein-Barr virus can result in a chronic active infection (CAEBV). We describe an 11-year-old boy with Down syndrome who was admitted because of fever of unknown origin during several periods. Serological findings (high VCA-IgG and absent EBNA-IgG) were suggestive of CAEBV, which was confirmed by the high circulating EBV viral load. During admission the clinical picture worsened and our patient developed pancytopenia, which led us to diagnose concurrent haemophagocytic lymphohistiocytosis and Hodgkin lymphoma. CAEBV is the result of deficiency in cellular immunity, which in this patient could possibly be attributed to deficiencies in the immune system associated with Down syndrome. CAEBV is difficult to treat, and it can come with life-threatening complications such as haemophagocytic lymphohistiocytosis.

  6. Systemic Epstein-Barr Virus-positive T-Cell Lymphoproliferative Disease of Childhood With Good Response to Steroid Therapy.

    PubMed

    Kim, Do-Hoon; Kim, Myungshin; Kim, Yonggoo; Han, Kyungja; Han, Eunhee; Lee, Jae Wook; Chung, Nack-Gyun; Cho, Bin

    2017-11-01

    Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood is a rare disease and has a very fulminant clinical course with high mortality. A 21-month-old female patient was referred to our hospital with a 1 week history of fever and was subsequently diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood. After starting treatment with dexamethasone, she showed early defervescence and improvement of laboratory parameters, and has remained disease-free after stopping steroid treatment, although longer follow-up is necessary. Our report underscores the possibility that this disease entity may be heterogenous in terms of prognosis.

  7. Central nervous system complications and neuroradiological findings in children with chronic active Epstein-Barr virus infection.

    PubMed

    Ishikawa, Nobutsune; Kawaguchi, Hiroshi; Nakamura, Kazuhiro; Kobayashi, Masao

    2013-02-01

    Although many neurological complications have been described in acute Epstein-Barr virus infection, few reports have discussed the central nervous system complications in chronic active Epstein-Barr virus (CAEBV) infection. We retrospectively surveyed the medical records of 14 patients with CAEBV infection in our institute. Neuroradiological studies were performed in 10 of these patients. Five had no neurological symptoms, whereas two presented with posterior reversible encephalopathy syndrome, one presented with basal ganglia calcification, and one presented with falx cerebri hemorrhage. Although both of the posterior reversible encephalopathy syndrome cases developed epilepsy several years after recovering from prolonged neurological deterioration, the others had no neurological sequelae. This study revealed that various central nervous system complications may occur during the clinical course in pediatric CAEBV patients. © 2012 The Authors. Pediatrics International © 2012 Japan Pediatric Society.

  8. L-asparaginase induced complete remission in Epstein-Barr virus positive, multidrug resistant, cutaneous T-cell lymphoma.

    PubMed

    Obama, K; Tara, M; Niina, K

    1999-06-01

    A 30-year-old man was admitted to our hospital with subcutaneous tumors and a high fever. Based on biomicroscopic findings of the tumor, the patient was diagnosed as having diffuse, medium, well-differentiated malignant lymphoma. Immunochemical analysis showed that CD3, CD4, CD25, and TCR beta were positive, and in situ hybridization revealed Epstein-Barr virus-encoded small RNAs in the nuclei of the lymphoma cells. Despite the patient's resistance to multidrug therapy, complete remission was achieved using L-asparaginase. This case is unique because of its peculiar clinical course and a possible association with the Epstein-Barr virus. L-asparaginase may be an important treatment in other patients who exhibit some of these characteristics.

  9. Early Disseminated Lyme Disease Causing False-Positive Serology for Primary Epstein-Barr Virus Infection: Report of 2 Cases.

    PubMed

    Pavletic, Adriana J; Marques, Adriana R

    2017-07-15

    False-positive serology for Lyme disease was reported in patients with acute infectious mononucleosis. Here we describe 2 patients with early disseminated Lyme disease who were misdiagnosed with infectious mononucleosis based on false-positive tests for primary Epstein-Barr virus infection. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  10. Histopathologic and immunohistological evaluation of anaplastic large cell lymphoma with Epstein-Barr virus in an orangutan (Pongo pygmaeus).

    PubMed

    Bak, Eun-Jung; Jho, Yeonsook; Woo, Gye-Hyeong

    2015-02-01

    An 18-month-old female orangutan (Pongo pygmaeus) died after exhibiting fever, cough, and rapid breathing. Based on serological, virological, histopathological and immunohistochemical examination, anaplastic large cell lymphoma was confirmed. To the best of our knowledge, this is the first report of anaplastic large cell lymphoma associated with Epstein-Barr virus (EBV) in an orangutan. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Clinically severe Epstein-Barr virus encephalitis with mild cerebrospinal fluid abnormalities in an immunocompetent adolescent: a case report.

    PubMed

    Engelmann, Ilka; Nasser, Hala; Belmiloudi, Soufien; Le Guern, Rémi; Dewilde, Anny; Vallée, Louis; Hober, Didier

    2013-06-01

    A 15-year-old boy developed Epstein-Barr virus (EBV) encephalitis, a rare complication of infectious mononucleosis. The severe clinical picture and the marked neuroimaging changes were in contrast with mild cerebrospinal fluid abnormalities: leukocyte count was normal and protein level was only slightly elevated. EBV DNA was detected in cerebrospinal fluid by polymerase chain reaction. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report.

    PubMed

    Ameli, Fereshteh; Ghafourian, Firouzeh; Masir, Noraidah

    2014-08-27

    Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is an extremely rare disorder and classically arises following primary acute or chronic active Epstein-Barr virus infection. It is characterized by clonal proliferation of Epstein-Barr virus-infected T-cells with an activated cytotoxic phenotype. This disease has a rapid clinical course and is more frequent in Asia and South America, with relatively few cases being reported in Western countries. The clinical and pathological features of the disease overlap with other conditions including infectious mononucleosis, chronic active Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis and natural killer cell malignancies. We describe the rare case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease in a 16-year-old Malay boy. He presented with a six-month history of fever and cough, with pulmonary and mediastinal lymphadenopathy and severe pancytopenia. Medium- to large-sized, CD8+ and Epstein-Barr virus-encoded RNA-positive atypical lymphoid cells were present in the bone marrow aspirate. He subsequently developed fatal virus-associated hemophagocytic syndrome and died due to sepsis and multiorgan failure. Although systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is a disorder which is rarely encountered in clinical practice, our case report underlines the importance of a comprehensive diagnostic approach in the management of this disease. A high level of awareness of the disease throughout the diagnosis process for young patients who present with systemic illness and hemophagocytic syndrome may be of great help for the clinical diagnosis of this disease.

  13. Association between human papilloma virus/Epstein-Barr virus coinfection and oral carcinogenesis.

    PubMed

    Jiang, Ru; Ekshyyan, Oleksandr; Moore-Medlin, Tara; Rong, Xiaohua; Nathan, Sean; Gu, Xin; Abreo, Fleurette; Rosenthal, Eben L; Shi, Mingxia; Guidry, Joseph T; Scott, Rona S; Hutt-Fletcher, Lindsey M; Nathan, Cherie-Ann O

    2015-01-01

    The recent epidemic of head and neck squamous cell carcinomas associated with human papilloma virus (HPV) has not addressed its association with lymphoid tissue in the oropharynx or the potential role of Epstein-Barr virus (EBV)/HPV coinfection. The prevalence of HPV and EBV infection/coinfection and CD21 mRNA expression were determined in normal and cancerous tissues from the oropharynx using in situ hybridization (ISH), p16, and quantitative reverse transcriptase PCR (qRT-PCR). The effects of coinfection on tumorigenicity were evaluated using proliferation and invasion assays. Normal oropharynx, tonsil, non-cancer base of tongue (BOT), and BOT from sleep apnea patients demonstrated EBV positivity ranging from 7% to 36% depending on the site and methods of detection used (qRT-PCR or ISH). Among non-malignant BOT samples, HPV positivity was noted only in 20%. The percent of tonsil and BOT cancers positive for HPV (up to 63% and 80%, respectively) or coinfected with HPV/EBV (up to 25% and 70%, respectively) were both significantly associated with cancer status. Notably, HPV/EBV coinfection was observed only in malignant tissue originating in lymphoid-rich oropharynx sites (tonsil, BOT). CD21 mRNA (the major EBV attachment receptor) was detected in tonsil and BOT epithelium, but not in soft-palate epithelium. Coinfected cell lines showed a significant increase in invasiveness (P < 0.01). There is a high prevalence of HPV/EBV infection and coinfection in BOT and tonsil cancers, possibly reflecting their origins in lymphoid-rich tissue. In vitro, cells modeling coinfection have an increased invasive potential. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. LMP1-Induced Sumoylation Influences the Maintenance of Epstein-Barr Virus Latency through KAP1

    PubMed Central

    Moss, Charles Randall; Whitehurst, Christopher B.; Moody, Cary A.

    2015-01-01

    ABSTRACT As a herpesvirus, Epstein-Barr virus (EBV) establishes a latent infection that can periodically undergo reactivation, resulting in lytic replication and the production of new infectious virus. Latent membrane protein-1 (LMP1), the principal viral oncoprotein, is a latency-associated protein implicated in regulating viral reactivation and the maintenance of latency. We recently found that LMP1 hijacks the SUMO-conjugating enzyme Ubc9 via its C-terminal activating region-3 (CTAR3) and induces the sumoylation of cellular proteins. Because protein sumoylation can promote transcriptional repression, we hypothesized that LMP1-induced protein sumoylation induces the repression of EBV lytic promoters and helps maintain the viral genome in its latent state. We now show that with inhibition of LMP1-induced protein sumoylation, the latent state becomes less stable or leakier in EBV-transformed lymphoblastoid cell lines. The cells are also more sensitive to viral reactivation induced by irradiation, which results in the increased production and release of infectious virus, as well as increased susceptibility to ganciclovir treatment. We have identified a target of LMP1-mediated sumoylation that contributes to the maintenance of latency in this context: KRAB-associated protein-1 (KAP1). LMP1 CTAR3-mediated sumoylation regulates the function of KAP1. KAP1 also binds to EBV OriLyt and immediate early promoters in a CTAR3-dependent manner, and inhibition of sumoylation processes abrogates the binding of KAP1 to these promoters. These data provide an additional line of evidence that supports our findings that CTAR3 is a distinct functioning regulatory region of LMP1 and confirm that LMP1-induced sumoylation may help stabilize the maintenance of EBV latency. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) plays an important role in the maintenance of viral latency. Previously, we documented that LMP1 targets cellular proteins to be modified by a

  15. Viral Causes of Lymphoma: The History of Epstein-Barr Virus and Human T-Lymphotropic Virus 1.

    PubMed

    Esau, Daniel

    2017-01-01

    In 1964, Epstein, Barr, and Achong published a report outlining their discovery of viral particles in lymphoblasts isolated from a patient with Burkitt lymphoma. The Epstein-Barr virus (EBV) was the first human cancer virus to be described, and its discovery paved the way for further investigations into the oncogenic potential of viruses. In the decades following the discovery of EBV, multinational research efforts led to the discovery of further viral causes of various human cancers. Lymphomas are perhaps the cancer type that is most closely associated with oncogenic viruses: infection with EBV, human T-lymphotropic virus 1 (HTLV-1), human immunodeficiency virus (HIV), Kaposi sarcoma-associated herpesvirus/human herpesvirus 8, and hepatitis C virus have all been associated with lymphomagenesis. Lymphomas have also played an important role in the history of oncoviruses, as both the first human oncovirus (EBV) and the first human retrovirus (HTLV-1) were discovered through isolates taken from patients with unique lymphoma syndromes. The history of the discovery of these 2 key oncoviruses is presented here, and their impact on further medical research, using the specific example of HIV research, is briefly discussed.

  16. Transcriptome-wide analysis of alternative RNA splicing events in Epstein-Barr virus-associated gastric carcinomas.

    PubMed

    Armero, Victoria E S; Tremblay, Marie-Pier; Allaire, Andréa; Boudreault, Simon; Martenon-Brodeur, Camille; Duval, Cyntia; Durand, Mathieu; Lapointe, Elvy; Thibault, Philippe; Tremblay-Létourneau, Maude; Perreault, Jean-Pierre; Scott, Michelle S; Bisaillon, Martin

    2017-01-01

    Multiple human diseases including cancer have been associated with a dysregulation in RNA splicing patterns. In the current study, modifications to the global RNA splicing landscape of cellular genes were investigated in the context of Epstein-Barr virus-associated gastric cancer. Global alterations to the RNA splicing landscape of cellular genes was examined in a large-scale screen from 295 primary gastric adenocarcinomas using high-throughput RNA sequencing data. RT-PCR analysis, mass spectrometry, and co-immunoprecipitation studies were also used to experimentally validate and investigate the differential alternative splicing (AS) events that were observed through RNA-seq studies. Our study identifies alterations in the AS patterns of approximately 900 genes such as tumor suppressor genes, transcription factors, splicing factors, and kinases. These findings allowed the identification of unique gene signatures for which AS is misregulated in both Epstein-Barr virus-associated gastric cancer and EBV-negative gastric cancer. Moreover, we show that the expression of Epstein-Barr nuclear antigen 1 (EBNA1) leads to modifications in the AS profile of cellular genes and that the EBNA1 protein interacts with cellular splicing factors. These findings provide insights into the molecular differences between various types of gastric cancer and suggest a role for the EBNA1 protein in the dysregulation of cellular AS.

  17. Human Papillomavirus Promotes Epstein-Barr Virus Maintenance and Lytic Reactivation in Immortalized Oral Keratinocytes

    PubMed Central

    Makielski, Kathleen R.; Lee, Denis; Lorenz, Laurel D.; Nawandar, Dhananjay M.; Chiu, Ya- Fang; Kenney, Shannon C.; Lambert, Paul F.

    2016-01-01

    Epstein-Barr virus and human papillomaviruses are human tumor viruses that infect and replicate in upper aerodigestive tract epithelia and cause head and neck cancers. The productive phases of both viruses are tied to stratified epithelia highlighting the possibility that these viruses may affect each other’s life cycles. Our lab has established an in vitro model system to test the effects of EBV and HPV co-infection in stratified squamous oral epithelial cells. Our results indicate that HPV increases maintenance of the EBV genome in the co-infected cells and promotes lytic reactivation of EBV in upper layers of stratified epithelium. Expression of the HPV oncogenes E6 and E7 were found to be necessary and sufficient to account for HPV-mediated lytic reactivation of EBV. Our findings indicate that HPV increases the capacity of epithelial cells to support the EBV life cycle, which could in turn increase EBV-mediated pathogenesis in the oral cavity. PMID:27179345

  18. Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

    PubMed

    Descamps, V; Mahe, E; Houhou, N; Abramowitz, L; Rozenberg, F; Ranger-Rogez, S; Crickx, B

    2003-05-01

    Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome.

  19. Reactivation of Latent Epstein-Barr Virus; A Comparison After Gamma Rays and Proton Treatment

    NASA Technical Reports Server (NTRS)

    Mehta, Satish K.; Plante, Ianik; Bloom, David C.; Stowe, Raymond; Renner, Ashlie; Wu, Honglu; Crucian, Brian; Pierson, Duane L.

    2017-01-01

    Among different unique stressors astronauts are exposed to during spaceflight, cosmic radiation constitutes an important one that leads to various health effects. In particular, space radiation may contribute to decreased immunity, which has been observed in astronauts during short and long duration missions, as evidenced by several changes in cellular immunity and plasma cytokines levels. Reactivation of latent herpes viruses, either directly from radiation or resulting from perturbation in the immune system, is also observed in astronauts. While EBV is one of the eight human herpes viruses known to infect more than 90% human adults and stays latent for the life of the host without normally causing adverse effects of reactivation, increased reactivation in astronauts is well-documented, though the mechanism of this increase is not understood. In this work, we have studied the effect of two different types of radiations, Cs-137 gamma and 150-MeV proton on the reactivation rates of the Epstein - Barr virus (EBV) in vitro in EBV latent cell lines at doses of 0.1, 0.5, 1.0 and 2.0 Gy. While we find that both types of radiations reactivated latent EBV in vitro, we observe that at equivalent doses, early response is stronger for protons but with time, the reactivation induced by gamma rays is more persistent. These differences between the protons and gamma rays curves in latent virus reactivation challenge the common paradigm that protons and gamma rays have similar biological effects.

  20. Structure of a trimeric variant of the Epstein-Barr virus glycoprotein B

    SciTech Connect

    Backovic, Marija; Longnecker, Richard; Jardetzky, Theodore S

    Epstein-Barr virus (EBV) is a herpesvirus that is associated with development of malignancies of lymphoid tissue. EBV infections are life-long and occur in >90% of the population. Herpesviruses enter host cells in a process that involves fusion of viral and cellular membranes. The fusion apparatus is comprised of envelope glycoprotein B (gB) and a heterodimeric complex made of glycoproteins H and L. Glycoprotein B is the most conserved envelope glycoprotein in human herpesviruses, and the structure of gB from Herpes simplex virus 1 (HSV-1) is available. Here, we report the crystal structure of the secreted EBV gB ectodomain, which formsmore » 16-nm long spike-like trimers, structurally homologous to the postfusion trimers of the fusion protein G of vesicular stomatitis virus (VSV). Comparative structural analyses of EBV gB and VSV G, which has been solved in its pre and postfusion states, shed light on gB residues that may be involved in conformational changes and membrane fusion. Also, the EBV gB structure reveals that, despite the high sequence conservation of gB in herpesviruses, the relative orientations of individual domains, the surface charge distributions, and the structural details of EBV gB differ from the HSV-1 protein, indicating regions and residues that may have important roles in virus-specific entry.« less

  1. Elevated stress hormone levels relate to Epstein-Barr virus reactivation in astronauts

    NASA Technical Reports Server (NTRS)

    Stowe, R. P.; Pierson, D. L.; Barrett, A. D.

    2001-01-01

    OBJECTIVE: The objective of this study was to determine the effects of stress and spaceflight on levels of neuroendocrine hormones and Epstein-Barr virus (EBV)-specific antibodies in astronauts. METHODS: Antiviral antibody titers and stress hormones were measured in plasma samples collected from 28 astronauts at their annual medical exam (baseline), 10 days before launch (L-10), landing day (R+0), and 3 days after landing (R+3). Urinary stress hormones were also measured at L-10 and R+0. RESULTS: Significant increases (p <.01) in EBV virus capsid antigen antibodies were found at all three time points (L-10, R+0, and R+3) as compared with baseline samples. Anti-EBV nuclear antigen antibodies were significantly decreased at L-10 (p <.05) and continued to decrease after spaceflight (R+0 and R+3, p <.01). No changes were found in antibodies to the nonlatent measles virus. The 11 astronauts who showed evidence of EBV reactivation had significant increases in urinary epinephrine and norepinephrine as compared with astronauts without EBV reactivation. CONCLUSION: These findings indicate that physical and psychological stresses associated with spaceflight resulted in decreased virus-specific T-cell immunity and reactivation of EBV.

  2. Epstein-Barr virus and human diseases: recent advances in diagnosis.

    PubMed Central

    Okano, M; Thiele, G M; Davis, J R; Grierson, H L; Purtilo, D T

    1988-01-01

    Since the discovery of Epstein-Barr virus (EBV) from a cultured Burkitt's lymphoma cell line in 1964, the virus has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis. During the recent decade, EBV has been etiologically implicated in a broad spectrum of human diseases. The precise role of this virus in these diseases is not well understood, but clearly, defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells. As a result, a growing number of cases of EBV-associated B-cell proliferative diseases or lymphoma have been noted in patients with primary and acquired immunodeficiencies. These lymphoproliferative diseases and others, such as chronic mononucleosis syndrome, are leading to new areas of investigation which are providing information regarding the pathogenetic mechanisms of EBV-induced diseases. The early accurate diagnosis of EBV infection can be achieved by performing EBV-specific serology, detecting for EBV-determined nuclear antigen in tissues, establishing spontaneous lymphoid cell lines, and using molecular hybridization techniques for demonstrating the presence of viral genome in affected lesions. Images PMID:2848624

  3. A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis.

    PubMed

    Balfour, Henry H; Holman, Carol J; Hokanson, Kristin M; Lelonek, Meghan M; Giesbrecht, Jill E; White, Dana R; Schmeling, David O; Webb, Chiu-Ho; Cavert, Winston; Wang, David H; Brundage, Richard C

    2005-11-01

    Characterizing virus-host interactions during self-limited infectious mononucleosis could explain how Epstein-Barr virus (EBV) replication is normally controlled and provide insight into why certain immunocompromised patients fail to contain it. University students had an average of 7 clinical and virologic evaluations during acute infectious mononucleosis. EBV was quantified in 697 samples of oral wash fluid, whole blood, peripheral blood mononuclear cells (PBMCs), and plasma by a real-time (TaqMan) polymerase chain reaction (qEBV) assay developed in our laboratory. Twenty of 25 subjects had serologically confirmed primary EBV infection. EBV was cleared from whole blood by a first-order process with a median half-life of 3 days, and its quantity was associated with severity of illness (r2=0.82). Oral shedding persisted at a median of >or=1x104 copies/mL for 32 weeks and was unrelated to severity of illness. Subjects with nonprimary EBV infection shed virus intermittently, and median quantities for all samples became undetectable within 4 weeks. Using a novel qEBV assay, we demonstrated that young adults with primary EBV infection rapidly cleared virus from blood but not from the oropharynx. High oral concentrations of EBV in asymptomatic persons who have resumed normal activities support the concept that infectious mononucleosis is most likely acquired by kissing.

  4. Epstein-Barr virus latency switch in human B-cells: a physico-chemical model.

    PubMed

    Werner, Maria; Ernberg, Ingemar; Zou, Jiezhi; Almqvist, Jenny; Aurell, Erik

    2007-08-31

    The Epstein-Barr virus is widespread in all human populations and is strongly associated with human disease, ranging from infectious mononucleosis to cancer. In infected cells the virus can adopt several different latency programs, affecting the cells' behaviour. Experimental results indicate that a specific genetic switch between viral latency programs, reprograms human B-cells between proliferative and resting states. Each of these two latency programs makes use of a different viral promoter, Cp and Qp, respectively. The hypothesis tested in this study is that this genetic switch is controlled by both human and viral transcription factors; Oct-2 and EBNA-1. We build a physico-chemical model to investigate quantitatively the dynamical properties of the promoter regulation and experimentally examine protein level variations between the two latency programs. Our experimental results display significant differences in EBNA-1 and Oct-2 levels between resting and proliferating programs. With the model we identify two stable latency programs, corresponding to a resting and proliferating cell. The two programs differ in robustness and transcriptional activity. The proliferating state is markedly more stable, with a very high transcriptional activity from its viral promoter. We predict the promoter activities to be mutually exclusive in the two different programs, and our relative promoter activities correlate well with experimental data. Transitions between programs can be induced, by affecting the protein levels of our transcription factors. Simulated time scales are in line with experimental results. We show that fundamental properties of the Epstein-Barr virus involvement in latent infection, with implications for tumor biology, can be modelled and understood mathematically. We conclude that EBNA-1 and Oct-2 regulation of Cp and Qp is sufficient to establish mutually exclusive expression patterns. Moreover, the modelled genetic control predict both mono- and bistable

  5. Analysis of Epstein-Barr Virus Genomes and Expression Profiles in Gastric Adenocarcinoma.

    PubMed

    Borozan, Ivan; Zapatka, Marc; Frappier, Lori; Ferretti, Vincent

    2018-01-15

    Epstein-Barr virus (EBV) is a causative agent of a variety of lymphomas, nasopharyngeal carcinoma (NPC), and ∼9% of gastric carcinomas (GCs). An important question is whether particular EBV variants are more oncogenic than others, but conclusions are currently hampered by the lack of sequenced EBV genomes. Here, we contribute to this question by mining whole-genome sequences of 201 GCs to identify 13 EBV-positive GCs and by assembling 13 new EBV genome sequences, almost doubling the number of available GC-derived EBV genome sequences and providing the first non-Asian EBV genome sequences from GC. Whole-genome sequence comparisons of all EBV isolates sequenced to date (85 from tumors and 57 from healthy individuals) showed that most GC and NPC EBV isolates were closely related although American Caucasian GC samples were more distant, suggesting a geographical component. However, EBV GC isolates were found to contain some consistent changes in protein sequences regardless of geographical origin. In addition, transcriptome data available for eight of the EBV-positive GCs were analyzed to determine which EBV genes are expressed in GC. In addition to the expected latency proteins (EBNA1, LMP1, and LMP2A), specific subsets of lytic genes were consistently expressed that did not reflect a typical lytic or abortive lytic infection, suggesting a novel mechanism of EBV gene regulation in the context of GC. These results are consistent with a model in which a combination of specific latent and lytic EBV proteins promotes tumorigenesis. IMPORTANCE Epstein-Barr virus (EBV) is a widespread virus that causes cancer, including gastric carcinoma (GC), in a small subset of individuals. An important question is whether particular EBV variants are more cancer associated than others, but more EBV sequences are required to address this question. Here, we have generated 13 new EBV genome sequences from GC, almost doubling the number of EBV sequences from GC isolates and providing the

  6. Epstein-Barr virus-induced infectious mononucleosis after two separate episodes of virus-associated hemophagocytic syndrome.

    PubMed

    Ohno, Tatsuharu; Ueda, Yo; Kishimoto, Wataru; Arimoto-Miyamoto, Kazue; Takeoka, Tomoharu; Tsuji, Masaaki

    2009-01-01

    A 24-year-old man, who had suffered previous two episodes of non- Epstein-Barr virus (EBV)-associated hemophagocytic syndrome (HPS) at the ages of 16 and 18, developed EBV-induced infectious mononucleosis. His antibody pattern to EBV highlighted the initial infection. The disease took a self-limited course without developing into HPS. No reactivation of EBV infection was noted over the following 6 years. The patient may have attained immune competency in adulthood, which was somehow impaired during his adolescence.

  7. Pathogenic Role of Exosomes in Epstein-Barr Virus (EBV)-Associated Cancers

    PubMed Central

    Teow, Sin-Yeang; Liew, Kitson; Khoo, Alan Soo-Beng; Peh, Suat-Cheng

    2017-01-01

    Exosomes are 40- to 100-nm membrane-bound small vesicles that carry a great variety of cellular cargoes including proteins, DNA, messenger RNAs (mRNAs), and microRNAs (miRNAs). These nanovesicles are detected in various biological fluids such as serum, urine, saliva, and seminal fluids. Exosomes serve as key mediators in intercellular communication by facilitating the transfer and exchange of cellular components from cells to cells. They contain various pathogenic factors whereby their adverse effects have been implicated in multiple viral infections and cancers. Interestingly, accumulating evidences showed that exosomes derived from tumour viruses or oncoviruses, exacerbate virus-associated cancers by remodelling the tumour microenvironment. In this review, we summarize the contributing factors of Epstein-Barr virus (EBV) products-containing exosomes in viral pathogenesis and their potential implications in EBV-driven malignancies. Understanding the biological role of these exosomes in the disease would undoubtedly boost the development of a more comprehensive strategy to combat EBV-associated cancers and to better predict the therapeutic outcomes. Furthermore, we also highlight the potentials and challenges of EBV products-containing exosomes being employed as diagnostic markers and therapeutic targets for EBV-related cancers. Since these aspects are rather underexplored, we attempt to underline interesting areas that warrant further investigations in the future. PMID:29104494

  8. Infektion mit Epstein-Barr-Virus und Tumor-Entstehung beim Menschen

    NASA Astrophysics Data System (ADS)

    Kirchner, H.

    1981-08-01

    The Epstein-Barr Virus (EBV) is the only infectious agent for which a close association with human malignant tumors has been clearly demonstrated. These tumors are one type of nasopharyngeal carcinoma which is frequent in parts of East Asia and the Burkitt lymphoma which predominantly occurs in parts of Africa and New Guinea. Nonetheless, the EBV is the causative agent of infectious mononucleosis (IM), a benign, self-limiting lymphoproliferative disease of adolescents. The major difference between the countries in which the EBV-induced tumors occur and those in which IM occurs is the late primary EBV infection in the latter, whereas primary infection with EBV occurs in the first year of life in the former. All theories of viral carcinogenesis have to explain the long latency period between primary infection and tumor growth and how an ubiquitous virus may be oncogenic. Thus, invariably, one has to assume a role of cofactors, which may be of cytogenetic nature or may be represented by additional infections or by chemical agents. Since most modern theories of carcinogenesis consider a multi-step development of tumors, the theory that infection with an ubiquitous virus at the right time of life represents one step to carcinogenesis seems to be tenable.

  9. Asymmetric Arginine dimethylation of Epstein-Barr virus nuclear antigen 2 promotes DNA targeting

    SciTech Connect

    Gross, Henrik; Barth, Stephanie; Palermo, Richard D.

    The Epstein-Barr virus (EBV) growth-transforms B-lymphocytes. The virus-encoded nuclear antigen 2 (EBNA2) is essential for transformation and activates gene expression by association with DNA-bound transcription factors such as RBPJkappa (CSL/CBF1). We have previously shown that EBNA2 contains symmetrically dimethylated Arginine (sDMA) residues. Deletion of the RG-repeat results in a reduced ability of the virus to immortalise B-cells. We now show that the RG repeat also contains asymmetrically dimethylated Arginines (aDMA) but neither non-methylated (NMA) Arginines nor citrulline residues. We demonstrate that only aDMA-containing EBNA2 is found in a complex with DNA-bound RBPJkappa in vitro and preferentially associates with the EBNA2-responsivemore » EBV C, LMP1 and LMP2A promoters in vivo. Inhibition of methylation in EBV-infected cells results in reduced expression of the EBNA2-regulated viral gene LMP1, providing additional evidence that methylation is a prerequisite for DNA-binding by EBNA2 via association with the transcription factor RBPJkappa.« less

  10. Epstein-Barr virus infection and nasopharyngeal carcinoma: the other side of the coin.

    PubMed

    Perri, Francesco; Della Vittoria Scarpati, Giuseppina; Giuliano, Mario; D'Aniello, Carmine; Gnoni, Antonio; Cavaliere, Carla; Licchetta, Antonella; Pisconti, Salvatore

    2015-11-01

    Oncogenic viruses may have a significant impact on the therapeutic management of several malignancies besides their well-known role in tumor pathogenesis. Epstein-Barr virus (EBV) induces neoplastic transformation of epithelial cells of the nasopharynx by various molecular mechanisms mostly involving activation of oncogenes and inactivation of tumor-suppressor genes. EBV infection can also induce the expression of several immunogenic peptides on the plasma membrane of the infected cells. Importantly, these virus-related antigens may be used as targets for antitumor immunotherapy-based treatment strategies. Two different immunotherapy strategies, namely adoptive and active immunotherapy, have been developed and strongly improved in the recent years. Furthermore, EBV infection may influence the use of targeted therapies for nasopharyngeal carcinoma (NPC) considering that the presence of EBV can induce important modifications in cell signaling. As an example, latent membrane protein type 1 is a viral transmembrane protein mainly involved in the cancerogenesis process, which can also mediate overexpression of the epidermal growth factor receptor (EGFR) in NPC cells, rendering them more sensitive to anti-EGFR therapy. Finally, EBV may induce epigenetic changes in the infected cells, such as DNA hypermethylation and histone deacetylation, that can sustain tumor growth and can thus be considered potential targets for novel therapies. In conclusion, EBV infection can modify important biological features of NPC cells, rendering them more vulnerable to both immunotherapy and targeted therapy.

  11. Epigenetic dysregulation of epstein-barr virus latency and development of autoimmune disease.

    PubMed

    Niller, Hans Helmut; Wolf, Hans; Ay, Eva; Minarovits, Janos

    2011-01-01

    Epstein-Barr virus (EBV) is ahumanherpesvirus thatpersists in the memory B-cells of the majority of the world population in a latent form. Primary EBV infection is asymptomatic or causes a self-limiting disease, infectious mononucleosis. Virus latency is associated with a wide variety of neoplasms whereof some occur in immune suppressed individuals. Virus production does not occur in strict latency. The expression of latent viral oncoproteins and nontranslated RNAs is under epigenetic control via DNA methylation and histone modifications that results either in a complete silencing of the EBV genome in memory B cells, or in a cell-type dependent usage of a couple of latency promoters in tumor cells, germinal center B cells and lymphoblastoid cells (LCL, transformed by EBV in vitro). Both, latent and lytic EBV proteins elicit a strong immune response. In immune suppressed and infectious mononucleosis patients, an increased viral load can be detected in the blood. Enhanced lytic replication may result in new infection- and transformation-events and thus is a risk factor both for malignant transformation and the development of autoimmune diseases. An increased viral load or a changed presentation of a subset of lytic or latent EBV proteins that cross-react with cellular antigens may trigger pathogenic processes through molecular mimicry that result in multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

  12. A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders

    PubMed Central

    Gwizdek, Katarzyna; Michalski, Marek; Wojnicz, Romuald

    2016-01-01

    The Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae virus family. EBV infection can cause infectious mononucleosis (IM) in the lytic phase of EBV’s life cycle. Past EBV infection is associated with lymphomas, and may also result in certain allergic and autoimmune diseases. Although potential mechanisms of autoimmune diseases have not been clearly elucidated, both genetic and environmental factors, such as infectious agents, are considered to be responsible for their development. In addition, EBV modifies the host immune response. The worldwide prevalence of autoimmune diseases shows how common this pathogen is. Normally, the virus stays in the body and remains dormant throughout life. However, this is not always the case, and a serious EBV-related illness may develop later in life. This explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms. Based on the present studies, EBV infection can cause autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren’s syndrome, and autoimmune hepatitis. The EBV has also been reported in patients with autoimmune thyroid disorders. Although EBV is not the only agent responsible for the development of autoimmune thyroid diseases, it can be considered a contributory factor. PMID:27833448

  13. A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders.

    PubMed

    Dittfeld, Anna; Gwizdek, Katarzyna; Michalski, Marek; Wojnicz, Romuald

    2016-01-01

    The Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae virus family. EBV infection can cause infectious mononucleosis (IM) in the lytic phase of EBV's life cycle. Past EBV infection is associated with lymphomas, and may also result in certain allergic and autoimmune diseases. Although potential mechanisms of autoimmune diseases have not been clearly elucidated, both genetic and environmental factors, such as infectious agents, are considered to be responsible for their development. In addition, EBV modifies the host immune response. The worldwide prevalence of autoimmune diseases shows how common this pathogen is. Normally, the virus stays in the body and remains dormant throughout life. However, this is not always the case, and a serious EBV-related illness may develop later in life. This explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms. Based on the present studies, EBV infection can cause autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren's syndrome, and autoimmune hepatitis. The EBV has also been reported in patients with autoimmune thyroid disorders. Although EBV is not the only agent responsible for the development of autoimmune thyroid diseases, it can be considered a contributory factor.

  14. Humanized Mouse Models of Epstein-Barr Virus Infection and Associated Diseases

    PubMed Central

    Fujiwara, Shigeyoshi; Matsuda, Go; Imadome, Ken-Ichi

    2013-01-01

    Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of the adult population of the world. EBV is associated with a variety of diseases including infectious mononucleosis, lymphoproliferative diseases, malignancies such as Burkitt lymphoma and nasopharyngeal carcinoma, and autoimmune diseases including rheumatoid arthritis (RA). EBV in nature infects only humans, but in an experimental setting, a limited species of new-world monkeys can be infected with the virus. Small animal models, suitable for evaluation of novel therapeutics and vaccines, have not been available. Humanized mice, defined here as mice harboring functioning human immune system components, are easily infected with EBV that targets cells of the hematoimmune system. Furthermore, humanized mice can mount both cellular and humoral immune responses to EBV. Thus, many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytic lymphohistiocytosis and erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice. Here we summarize recent achievements in the field of humanized mouse models of EBV infection and show how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus. PMID:25436886

  15. Quantitative multi-target RNA profiling in Epstein-Barr virus infected tumor cells.

    PubMed

    Greijer, A E; Ramayanti, O; Verkuijlen, S A W M; Novalić, Z; Juwana, H; Middeldorp, J M

    2017-03-01

    Epstein-Barr virus (EBV) is etiologically linked to multiple acute, chronic and malignant diseases. Detection of EBV-RNA transcripts in tissues or biofluids besides EBV-DNA can help in diagnosing EBV related syndromes. Sensitive EBV transcription profiling yields new insights on its pathogenic role and may be useful for monitoring virus targeted therapy. Here we describe a multi-gene quantitative RT-PCR profiling method that simultaneously detects a broad spectrum (n=16) of crucial latent and lytic EBV transcripts. These transcripts include (but are not restricted to), EBNA1, EBNA2, LMP1, LMP2, BARTs, EBER1, BARF1 and ZEBRA, Rta, BGLF4 (PK), BXLF1 (TK) and BFRF3 (VCAp18) all of which have been implicated in EBV-driven oncogenesis and viral replication. With this method we determine the amount of RNA copies per infected (tumor) cell in bulk populations of various origin. While we confirm the expected RNA profiles within classic EBV latency programs, this sensitive quantitative approach revealed the presence of rare cells undergoing lytic replication. Inducing lytic replication in EBV tumor cells supports apoptosis and is considered as therapeutic approach to treat EBV-driven malignancies. This sensitive multi-primed quantitative RT-PCR approach can provide broader understanding of transcriptional activity in latent and lytic EBV infection and is suitable for monitoring virus-specific therapy responses in patients with EBV associated cancers. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Compartmentalization and transmission of multiple epstein-barr virus strains in asymptomatic carriers.

    PubMed

    Sitki-Green, Diane; Covington, Mary; Raab-Traub, Nancy

    2003-02-01

    Infection with the Epstein-Barr virus (EBV) is often subclinical in the presence of a healthy immune response; thus, asymptomatic infection is largely uncharacterized. This study analyzed the nature of EBV infection in 20 asymptomatic immunocompetent hosts over time through the identification of EBV strain variants in the peripheral blood and oral cavity. A heteroduplex tracking assay specific for the EBV gene LMP1 precisely identified the presence of multiple EBV strains in each subject. The strains present in the peripheral blood and oral cavity were often completely discordant, indicating the existence of distinct infections, and the strains present and their relative abundance changed considerably between time points. The possible transmission of strains between the oral cavity and peripheral blood compartments could be tracked within subjects, suggesting that reactivation in the oral cavity and subsequent reinfection of B lymphocytes that reenter the periphery contribute to the maintenance of persistence. In addition, distinct virus strains persisted in the oral cavity over many time points, suggesting an important role for epithelial cells in the maintenance of persistence. Asymptomatic individuals without tonsillar tissue, which is believed to be an important source of virus for the oral cavity, also exhibited multiple strains and a cyclic pattern of transmission between compartments. This study revealed that the majority of patients with infectious mononucleosis were infected with multiple strains of EBV that were also compartmentalized, suggesting that primary infection involves the transmission of multiple strains. Both the primary and carrier states of infection with EBV are more complex than previously thought.

  17. Prognostic value of serum Epstein-Barr virus antibodies in patients with nasopharyngeal carcinoma and undetectable pretreatment Epstein-Barr virus DNA.

    PubMed

    Yao, Ji-Jin; Lin, Li; Jin, Ya-Nan; Wang, Si-Yang; Zhang, Wang-Jian; Zhang, Fan; Zhou, Guan-Qun; Cheng, Zhi-Bin; Qi, Zhen-Yu; Sun, Ying

    2017-08-01

    Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC). Serum IgA antibodies against early antigen (EA-IgA) and viral capsid antigen (VCA-IgA) are the most commonly used to screen for NPC in endemic areas. However, the prognostic value of serum EA-IgA and VCA-IgA in patients with NPC is less clear. We hypothesize that serum EA-IgA and VCA-IgA levels have prognostic impact for survival outcomes in NPC patients with undetectable pretreatment EBV (pEBV) DNA. In this series, 334 patients with non-metastatic NPC and undetectable pEBV DNA were included. Serum EA-IgA and VCA-IgA were determined by ELISA. After analysis, serum EA-IgA and VCA-IgA loads correlated positively with T, N, and overall stage (all P < 0.05). Serum EA-IgA was not associated with survival outcome in univariable analyses. But patients with serum VCA-IgA >1:120 had significantly inferior 5-year progression-free survival (80.4% vs 89.6%, P = 0.025), distant metastasis-free survival (88.4% vs 94.8%, P = 0.050), and locoregional relapse-free survival (88.4% vs 95.6%, P = 0.023; log-rank test). Multivariable analyses revealed that N stage was the only independent prognostic factor (all P < 0.05), but the VCA-IgA became insignificant. Further analyses revealed that serum VCA-IgA was not an independent prognostic factor in early N (N0-1) or advanced N (N2-3) stage NPC. In summary, although both EA-IgA and VCA-IgA correlate strongly with TNM stage, our analyses do not suggest that these antibodies are prognostic biomarkers in patients with NPC and undetectable pEBV DNA. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  18. Epstein-Barr Virus-associated lymphoproliferative disorders: experimental and clinical developments

    PubMed Central

    Geng, Lingyun; Wang, Xin

    2015-01-01

    Epstein-Barr Virus (EBV), the first human virus related to oncogenesis, was initially identified in a Burkitt lymphoma cell line in 1964. EBV infects over 90% of the world’s population. Most infected people maintain an asymptomatic but persistent EBV infection lifelong. However, in some individuals, EBV infection has been involved in the development of cancer and autoimmune disease. Nowadays, oncogenic potential of EBV has been intensively studied in a wide range of human neoplasms, including Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), etc. EBV encodes a series of viral protein and miRNAs, promoting its persistent infection and the transformation of EBV-infected cells. Although the exact role of EBV in the oncogenesis remains to be clarified, novel diagnostic and targeted therapeutic approaches are encouraging for the management of EBV-related malignancies. This review mainly focuses on the experimental and clinical advances of EBV-associated lymphoproliferative disorders. PMID:26628948

  19. [Lymphocytic Clonal Expansion in Adult Patients with Epstein-Barr Virus-Associated Lymphoproliferative Disease].

    PubMed

    Zhong, Feng-Luan; Zhang, Hong-Yu; Zhang, Qian; Feng, Jia; Zhang, Wen-Li; Xu, Lei; Xu, Hai-Chan; Wen, Juan-Juan; Meng, Qing-Xiang

    2017-12-01

    To explore the lymphocytic clonal expansion in adult patients with Epstein-Barr virus-associated lymphoproliferative diseases (EBV+LPD), and to investigate the experimental methods for EBV+LPD cells so as to provide a more objective measure for the diagnosis, classification and prognosis in the early stage of this disease. Peripheral blood samples from 5 patients with EBV+LPD, 4 patients with adult infectious mononucleosis(IM) as negative control and 3 patients with acute NK-cell leukemia(ANKL) as positive control were collected. Prior to immunochemotherapy, viral loads and clonality were analysed by flow cytometry (FCM), T cell receptor gene rearrangement (TCR) was detected by real-time polymerase chain reaction (RT-PCR), and diversity of EB virus terminal repeat (EBV-TR) was detected by Southern blot. FCM showed only 1 case with clonal TCRVβ in 5 patients with EBV+LPD, TCR clonal expansion could be detected both in patients with IM(4 of 4) and 4 patients with EBV+LPD(4 of 5), Out of patients with EBV+LPD, 1 patient displayed a monoclonal band and 2 patients showed oligoclonal bands when detecting EBV-TR by southen blot. Detecting the diversity of EBV-TR by Southern blot may be the most objective way to reflex clonal transformation of EBV+LPD, which is of great benefit to the diagnosis, classification and prognosis in the early stage of this disease.

  20. Host genetics of Epstein-Barr virus infection, latency and disease.

    PubMed

    Houldcroft, Charlotte J; Kellam, Paul

    2015-03-01

    Epstein-Barr virus (EBV) infects 95% of the adult population and is the cause of infectious mononucleosis. It is also associated with 1% of cancers worldwide, such as nasopharyngeal carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma. Human and cancer genetic studies are now major forces determining gene variants associated with many cancers, including nasopharyngeal carcinoma and Hodgkin's lymphoma. Host genetics is also important in infectious disease; however, there have been no large-scale efforts towards understanding the contribution that human genetic variation plays in primary EBV infection and latency. This review covers 25 years of studies into host genetic susceptibility to EBV infection and disease, from candidate gene studies, to the first genome-wide association study of EBV antibody response, and an EBV-status stratified genome-wide association study of Hodgkin's lymphoma. Although many genes are implicated in EBV-related disease, studies are often small, not replicated or followed up in a different disease. Larger, appropriately powered genomic studies to understand the host response to EBV will be needed to move our understanding of the biology of EBV infection beyond the handful of genes currently identified. Fifty years since the discovery of EBV and its identification as a human oncogenic virus, a glimpse of the future is shown by the first whole-genome and whole-exome studies, revealing new human genes at the heart of the host-EBV interaction. © 2014 The Authors Reviews in Medical Virology published by John Wiley & Sons Ltd.

  1. Current research on chronic active Epstein-Barr virus infection in Japan.

    PubMed

    Fujiwara, Shigeyoshi; Kimura, Hiroshi; Imadome, Ken-ichi; Arai, Ayako; Kodama, Eiichi; Morio, Tomohiro; Shimizu, Norio; Wakiguchi, Hiroshi

    2014-04-01

    Epstein-Barr virus (EBV) infection is usually asymptomatic and persists lifelong. Although EBV-infected B cells have the potential for unlimited proliferation, they are effectively removed by the virus-specific cytotoxic T cells, and EBV-associated lymphoproliferative disease develops only in immunocompromised hosts. Rarely, however, individuals without apparent immunodeficiency develop chronic EBV infection with persistent infectious mononucleosis-like symptoms. These patients have high EBV-DNA load in the peripheral blood and systemic clonal expansion of EBV-infected T cells or natural killer (NK) cells. Their prognosis is poor with life-threatening complications including hemophagocytic lymphohistiocytosis, organ failure, and malignant lymphomas. The term "chronic active EBV infection" (CAEBV) is now generally used for this disease. The geographical distribution of CAEBV is markedly uneven and most cases have been reported from Japan and other East Asian countries. Here we summarize the current understanding of CAEBV and describe the recent progress of CAEBV research in Japan. © 2014 Japan Pediatric Society.

  2. Fatal chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis.

    PubMed

    Chiba, Tetsuhiro; Goto, Shigemasa; Yokosuka, Osamu; Imazeki, Fumio; Tanaka, Masamichi; Fukai, Kenichi; Takahashi, Yoko; Tsujimura, Hideki; Saisho, Hiromitsu

    2004-02-01

    We report a 22-year-old female who presented with pyrexia, pancytopenia and liver dysfunction. The patient showed mild liver dysfunction with low-grade fever and mild hepatosplenomegaly 6 years previously, and autoimmune hepatitis (AIH) was diagnosed based on the examination of the laboratory data and liver biopsy. On admission, both markers of Epstein-Barr virus (EBV) and in-situ hybridisation from a liver biopsy specimen indicated chronic active EBV infection (CAEBV). The patient was administered an immunosuppressive agent and antiviral drug added to steroid therapy, but ultimately died from liver failure and virus-associated haemophagocytosis 10 months after the definite diagnosis. Retrospective examination of the serum at the diagnosis of AIH revealed extremely high titres of antibody to EBV, and EBV-DNA was also detectable by polymerase chain reaction. These results suggest the possibility that the patient may already have suffered from CAEBV at the initial diagnosis. We presume that hepatic involvement of CAEBV should be considered as differential diagnosis in cases showing liver dysfunction with clinical and biochemical features observed in AIH.

  3. Chronic active Epstein-Barr virus infection in an adult with no detectable immune deficiency.

    PubMed

    de Boer, M; Mol, M J T M; Bogman, M J J T; Galama, J M D; Raymakers, R A P

    2003-11-01

    Epstein-Barr virus (EBV) establishes lifelong latent infection. In some patients the host-virus balance is disturbed, resulting in a chronic active EBV infection. The following case illustrates the difficulty in diagnosing and treating chronic EBV infection. A 30-year-old woman was referred because of recurrent swellings of lymphatic tissue of both eyelids, orbit and lymph nodes and general malaise since the age of 19. In the past, repeated biopsies showed MALT lymphoma and nonspecific lymphoid infiltrations. Now, a biopsy of an axillary lymph node showed paracortical hyperplasia with a polymorphous polyclonal lymphoid proliferation, and large numbers of EBV-encoded small RNA (EBER) positive cells, consistent with EBV infection. Laboratory investigation showed a high EBV viral load. No evidence of immunodeficiency was found. Chronic active EBV infection (CAEBV) was diagnosed. Treatment with high-dose acyclovir did not significantly reduce the viral load. Rituximab was given in an attempt to reduce the amount of EBV-infected B lymphocytes. However, soon after the second dose the patient died of a sub-arachnoidal haemorrhage. This case report illustrates CAEBV as a rare manifestation of EBV-induced disease, which will be detected more frequently with the use of EBV-EBER hybridisation of lymph nodes and polymerase chain reaction (PCR) for EBV DNA. The prognosis is poor with no established therapeutic strategies.

  4. Human cytomegalovirus and Epstein-Barr virus type 1 in periodontal abscesses.

    PubMed

    Saygun, I; Yapar, M; Ozdemir, A; Kubar, A; Slots, J

    2004-04-01

    Recent studies have linked herpesviruses to severe types of periodontal disease, but no information exists on their relationship to periodontal abscesses. The present study determined the presence of human cytomegalovirus (HCMV) and Epstein-Barr virus type 1 (EBV-1) in periodontal abscesses and the effect of treatment on the subgingival occurrence of these viruses. Eighteen adults with periodontal abscesses participated in the study. Subgingival samples were collected from each patient with sterile curettes from an abscess-affected site and a healthy control site. HCMV and EBV-1 were identified by polymerase chain reaction at the time of the abscess and at 4 months after surgical and systemic doxycycline therapy. HCMV was detected in 66.7% of periodontal abscess sites and in 5.6% of healthy sites (P=0.002). EBV-1 occurred in 72.2% of abscess sites but not in any healthy site (P<0.001). HCMV and EBV-1 co-infection was identified in 55.6% of the abscess sites. Posttreatment, HCMV and EBV-1 were not found in any study site. HCMV and EBV-1 genomes are commonly found in periodontal abscesses. These data favor a model in which a herpesvirus infection of the periodontium impairs the host defense and serves as a platform for the entrance of bacterial pathogens into gingival tissue with subsequent risk of abscess development.

  5. Epstein-Barr virus reactivation associated with diminished cell-mediated immunity in antarctic expeditioners

    NASA Technical Reports Server (NTRS)

    Mehta, S. K.; Pierson, D. L.; Cooley, H.; Dubow, R.; Lugg, D.

    2000-01-01

    Epstein-Barr virus (EBV) reactivation and cell-mediated immune (CMI) responses were followed in 16 Antarctic expeditioners during winter-over isolation at 2 Australian National Antarctic Research Expedition stations. Delayed-type hypersensitivity (DTH) skin testing was used as an indicator of the CMI response, that was evaluated 2 times before winter isolation and 3 times during isolation. At all 5 evaluation times, 8 or more of the 16 subjects had a diminished CMI response. Diminished DTH was observed on every test occasion in 4/16 subjects; only 2/16 subjects exhibited normal DTH responses for all 5 tests. A polymerase chain reaction (PCR) assay was used to detect EBV DNA in saliva specimens collected before, during, and after the winter isolation. EBV DNA was present in 17% (111/642) of the saliva specimens; all 16 subjects shed EBV in their saliva on at least 1 occasion. The probability of EBV shedding increased (P = 0.013) from 6% before or after winter isolation to 13% during the winter period. EBV appeared in saliva during the winter isolation more frequently (P < 0.0005) when DTH response was diminished than when DTH was normal. The findings indicate that the psychosocial, physical, and other stresses associated with working and living in physical isolation during the Antarctic winter result in diminished CMI and an accompanying increased reactivation and shedding of latent viruses.

  6. Epstein-Barr Virus Reactivation Associated with Diminished Cell-Mediated Immunity in Antarctic Expeditioners

    NASA Technical Reports Server (NTRS)

    Pierson, Duane L.; Mehta, Satish K.; Cooley, Helen; Dubow, Robin; Lugg, Desmond

    1999-01-01

    Reactivation of Epstein-Barr virus (EBV) and cell-mediated immune (CMI) responses were followed in 16 Antarctic expeditioners during winter-over isolation at two Australian National Antarctic Research Expedition stations. Delayed-type hypersensitivity skin testing was used as an indicator of the CMI response, which was evaluated two times before winter isolation and three times during isolation. At all five evaluation times, 8 or more of the 16 subjects had a diminished. CMI response. Diminished CMI was observed on every test occasion in 4/16 subjects; only 2/16 subjects exhibited normal CMI responses for all five tests. A polymerase chain reaction (PCR) assay was used to detect EBV DNA in saliva specimens collected before, after, and during the winter isolation. EBV DNA was present in 17% (111/642) of the saliva specimens; all 16 subjects shed EBV in their saliva on at least one occasion. The probability of EBV shedding increased (p=0.013) from 6% before or after winter isolation to 13% during the winter period. EBV appeared in saliva during the winter isolation more frequently (p<0.0005) when CMI responsiveness was diminished than when CMI status was normal. The findings indicate that the psychosocial, physical, and other stresses associated with working and living in physical isolation during the Antarctic winter results in diminished CMI and an accompanying increased reactivation and shedding of latent viruses.

  7. Systemic Epstein-Barr virus infection associated with membranous nephropathy in children.

    PubMed

    Araya, C E; González-Peralta, R P; Skoda-Smith, S; Dharnidharka, V R

    2006-03-01

    Epstein-Barr virus (EBV) infection can cause diverse renal manifestations ranging from microscopic hematuria to acute renal failure. Membranous nephropathy (MN) is an uncommon and usually secondary cause of nephrotic syndrome in children, and has been reported after chronic infections and antigenemia. We report two pediatric cases of secondary MN associated with acute and chronic systemic EBV infection. Patient 1 had a liver transplant for cirrhosis due to biliary atresia and developed chronic EB viremia. Membranous nephropathy occurred 3 years later and with aggressive therapy has partially subsided, in temporal association with a drop in blood EBV PCR levels. The other patient had a primary immunodeficiency and developed a lymphoproliferative disorder attributed to EBV. Nephrotic syndrome developed at initial presentation and was associated with MN on biopsy. The patient cleared the virus from blood, which was associated with eventual resolution of the MN. We postulate that EB viremia in patients lacking a fully competent immune system, but without a renal allograft, may create a susceptible environment for chronic systemic EB antigenemia that can then lead to immune-complex MN in the kidney. The association of EBV with renal histological changes consistent with MN has been suggested but not directly described before.

  8. Computer-Aided Design of an Epitope-Based Vaccine against Epstein-Barr Virus

    PubMed Central

    Alonso-Padilla, Julio

    2017-01-01

    Epstein-Barr virus is a very common human virus that infects 90% of human adults. EBV replicates in epithelial and B cells and causes infectious mononucleosis. EBV infection is also linked to various cancers, including Burkitt's lymphoma and nasopharyngeal carcinomas, and autoimmune diseases such as multiple sclerosis. Currently, there are no effective drugs or vaccines to treat or prevent EBV infection. Herein, we applied a computer-aided strategy to design a prophylactic epitope vaccine ensemble from experimentally defined T and B cell epitopes. Such strategy relies on identifying conserved epitopes in conjunction with predictions of HLA presentation for T cell epitope selection and calculations of accessibility and flexibility for B cell epitope selection. The T cell component includes 14 CD8 T cell epitopes from early antigens and 4 CD4 T cell epitopes, targeted during the course of a natural infection and providing a population protection coverage of over 95% and 81.8%, respectively. The B cell component consists of 3 experimentally defined B cell epitopes from gp350 plus 4 predicted B cell epitopes from other EBV envelope glycoproteins, all mapping in flexible and solvent accessible regions. We discuss the rationale for the formulation and possible deployment of this epitope vaccine ensemble. PMID:29119120

  9. Epstein-Barr virus growth/latency III program alters cellular microRNA expression

    SciTech Connect

    Cameron, Jennifer E.; Tulane Cancer Center, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL79, New Orleans, LA 70112; Fewell, Claire

    The Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cancers. Initial EBV infection alters lymphocyte gene expression, inducing cellular proliferation and differentiation as the virus transitions through consecutive latency transcription programs. Cellular microRNAs (miRNAs) are important regulators of signaling pathways and are implicated in carcinogenesis. The extent to which EBV exploits cellular miRNAs is unknown. Using micro-array analysis and quantitative PCR, we demonstrate differential expression of cellular miRNAs in type III versus type I EBV latency including elevated expression of miR-21, miR-23a, miR-24, miR-27a, miR-34a, miR-146a and b, and miR-155. In contrast, miR-28 expression was found to be lowermore » in type III latency. The EBV-mediated regulation of cellular miRNAs may contribute to EBV signaling and associated cancers.« less

  10. Stress-induced reactivation of Epstein-Barr virus in astronauts

    NASA Technical Reports Server (NTRS)

    Stowe, R. P.; Pierson, D. L.; Feeback, D. L.; Barrett, A. D.

    2000-01-01

    Herpesviruses are leading causes of infectious blindness and death in immunocompromised individuals. Impaired cellular immunity, which is known to result in increased frequency and severity of herpesvirus infections, has been demonstrated both during and after spaceflight. Therefore, we examined whether Epstein-Barr virus (EBV), a well-characterized latent herpesvirus, undergoes reactivation in astronauts. Sera from Shuttle astronauts, taken before and after spaceflight, were examined for evidence of EBV reactivation. The geometric mean antibody titer to EBV viral capsid antigen (VCA) was significantly increased prior to flight compared to baseline (p = 0. 0001). After spaceflight, evidence of acute lytic replication was found in which 8- to 64-fold increases in EBV early antigen (EA) antibodies occurred without significant increases in antibodies to measles virus. Additionally, stress-induced shifts in circulating leukocytes and elevated levels of urinary cortisol and epinephrine were found. Overall, significant increases in EA or high VCA/EA antibody titers were found in 8 of 23 (35%) male astronauts and 3 of 5 (60%) female astronauts. These results indicate that stress reactivates EBV prior to flight and suggest that acute lytic replication of EBV occurs during spaceflight. Copyright 2000 S. Karger AG, Basel.

  11. Interleukin 28B gene polymorphisms and Epstein-Barr virus-associated lymphoproliferative diseases.

    PubMed

    Akay, Ela; Patel, Mauli; Conibear, Tim; Chaggar, Turren; Haque, Tanzina

    2014-01-01

    Single-nucleotide polymorphisms (SNPs) near the interleukin (IL) 28B gene encoding a type III interferon (IFN-λ) are the most important genetic predictors of treatment response to hepatitis C virus (HCV). This retrospective study was undertaken to determine any association between IL28B SNPs and the development of viraemia in Epstein-Barr virus (EBV)-driven acute infectious mononucleosis (IM) and post-transplant lymphoproliferative disease (PTLD). Genomic DNA extracted from plasma from 45 EBV seropositive controls and 46 acute IM, 23 non-PTLD (transplant) and 21 PTLD patients was tested by PCR for 2 SNPs within IL28B. EBV DNA levels were tested in IM and PTLD samples by a real-time quantitative PCR. No significant differences were seen in SNP frequencies at rs12979860 and rs8099917 in IM and PTLD patients compared to EBV seropositive controls and transplant patients. EBV DNA levels were lower in IM and PTLD patients with CC (a favourable genotype in HCV) at rs12979860 compared to non-CC genotypes (p = 0.055). Acute IM patients with CC had significantly lower levels of EBV DNA in plasma compared to those with non-CC genotypes (p = 0.011). Genotype CC may influence anti-viral responses of IFN-λ, thereby allowing better control of EBV viraemia during lymphoproliferation, particularly in IM.

  12. Acute hepatitis: a rare complication of Epstein-Barr virus (EBV) infection.

    PubMed

    Uluğ, Mehmet; Celen, Mustafa Kemal; Ayaz, Celal; Geyik, Mehmet Faruk; Hoşoğlu, Salih

    2010-10-28

    Infectious Mononucleosis (IM), a benign lymphoproliferative disease, is the best known clinical syndrome caused by Epstein-Barr Virus (EBV). It usually resolves over a period of weeks or months without sequelae but may occasionally be complicated by a wide variety of neurologic, hematologic, hepatic, respiratory, and psychological complications. In this report we describe a patient with acute hepatitis following EBV-IM in a previously healthy woman. A 26-year-old woman who presented with fever, generalized weakness, nausea, sore throat, yellowing of skin, and a generalized skin rash was admitted to our clinic. Tonsillar enlargement, pharyngeal erythema, palatal petechiae, lymphadenopathy, and jaundice were noted. Significant atypical lymphocytes ( > 10%) were seen on the peripheral blood smear. Liver function tests such as ALT: 303 U/L, AST: 172 U/L, ALP: 193 U/L and total bilirubin: 7.3 mg/dl were elevated. Serological tests for EBV infection were consistent with acute infection (EBV virus capsid antigen was reactive with IgM and IgG antibodies). The Monospot test was also positive. On the seventh day, liver function tests and bilirubin had risen to peak level and platelets were decreased. The patient was managed supportively and her critical condition improved and was finally stabilized. Although the prognosis for IM is very favorable, a variety of acute complications may occur.

  13. Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency.

    PubMed

    Dheekollu, Jayaraju; Malecka, Kimberly; Wiedmer, Andreas; Delecluse, Henri-Jacques; Chiang, Alan K S; Altieri, Dario C; Messick, Troy E; Lieberman, Paul M

    2017-01-31

    Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection.

  14. From Conventional to Next Generation Sequencing of Epstein-Barr Virus Genomes.

    PubMed

    Kwok, Hin; Chiang, Alan Kwok Shing

    2016-02-24

    Genomic sequences of Epstein-Barr virus (EBV) have been of interest because the virus is associated with cancers, such as nasopharyngeal carcinoma, and conditions such as infectious mononucleosis. The progress of whole-genome EBV sequencing has been limited by the inefficiency and cost of the first-generation sequencing technology. With the advancement of next-generation sequencing (NGS) and target enrichment strategies, increasing number of EBV genomes has been published. These genomes were sequenced using different approaches, either with or without EBV DNA enrichment. This review provides an overview of the EBV genomes published to date, and a description of the sequencing technology and bioinformatic analyses employed in generating these sequences. We further explored ways through which the quality of sequencing data can be improved, such as using DNA oligos for capture hybridization, and longer insert size and read length in the sequencing runs. These advances will enable large-scale genomic sequencing of EBV which will facilitate a better understanding of the genetic variations of EBV in different geographic regions and discovery of potentially pathogenic variants in specific diseases.

  15. Visualization of episomal and integrated Epstein-Barr virus DNA by fiber fluorescence in situ hybridization.

    PubMed

    Reisinger, Jürgen; Rumpler, Silvia; Lion, Thomas; Ambros, Peter F

    2006-04-01

    For many Epstein-Barr virus (EBV)-associated malignancies, it is still a matter of controversy whether infected cells harbor episomal or chromosomally integrated EBV genomes or both. It is well established that the expression of EBV genes per se carries oncogenic potential, but the discrimination between episomal and integrated forms is of great relevance because integration events can contribute to the oncogenic properties of EBV, whereas host cells that exclusively harbor viral episomes may not carry the risks mediated by chromosomal integration. This notion prompted us to establish a reliable technique that not only allows to unequivocally discriminate episomal from integrated EBV DNA, but also provides detailed insights into the genomic organization of the virus. Here, we show that dynamic molecular combing of host cell DNA combined with fluorescence in situ hybridization (FISH) using EBV-specific DNA probes facilitate unambiguous discrimination of episomal from integrated viral DNA. Furthermore, the detection of highly elongated internal repeat 1 (IR1) sequences provides evidence that this method permits detection of major genomic alterations within the EBV genome. Thus, fiber FISH may also provide valuable insights into the genomic organization of viral genomes other than EBV.

  16. An update: Epstein-Barr virus and immune evasion via microRNA regulation.

    PubMed

    Zuo, Lielian; Yue, Wenxin; Du, Shujuan; Xin, Shuyu; Zhang, Jing; Liu, Lingzhi; Li, Guiyuan; Lu, Jianhong

    2017-06-01

    Epstein-Barr virus (EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans. To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that microRNAs (miRNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes miRNAs for immune evasion. EBV encodes miRNAs targeting both viral and host genes involved in the immune response. The miRNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4 + and CD8 + T cell response of infected cells. These reports strongly indicate that EBV miRNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host miRNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated miRNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment. During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of miRNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.

  17. Mathematical modelling the age dependence of Epstein-Barr virus associated infectious mononucleosis.

    PubMed

    Huynh, Giao T; Adler, Frederick R

    2012-09-01

    Most people get Epstein-Barr virus (EBV) infection at young age and are asymptomatic. Primary EBV infection in adolescents and young adults, however, often leads to infectious mononucleosis (IM) with symptoms including fever, fatigue and sore throat that can persist for months. Expansion in the number of CD8(+) T cells, especially against EBV lytic proteins, are the main cause of these symptoms. We propose a mathematical model for the regulation of EBV infection within a host to address the dependence of IM on age. This model tracks the number of virus, infected B cell and epithelial cell and CD8(+) T-cell responses to the infection. We use this model to investigate three hypotheses for the high incidence of IM in teenagers and young adults: saliva and antibody effects that increase with age, high cross-reactive T-cell responses and a high initial viral load. The model supports the first two of these hypotheses and suggests that variation in host antibody responses and the complexity of the pre-existing cross-reactive T-cell repertoire, both of which depend on age, may play important roles in the etiology of IM.

  18. Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children

    PubMed Central

    Jayasooriya, Shamanthi; de Silva, Thushan I.; Njie-jobe, Jainaba; Sanyang, Chilel; Leese, Alison M.; Bell, Andrew I.; McAulay, Karen A.; Yanchun, Peng; Long, Heather M.; Dong, Tao; Whittle, Hilton C.; Rickinson, Alan B.; Rowland-Jones, Sarah L.; Hislop, Andrew D.; Flanagan, Katie L.

    2015-01-01

    Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14–18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms. PMID:25816224

  19. Epstein- Barr Virus: Clinical and Epidemiological Revisits and Genetic Basis of Oncogenesis

    PubMed Central

    Ali, Abdelwahid Saeed; Al-Shraim, Mubarak; Al-Hakami, Ahmed Musa; Jones, Ian M

    2015-01-01

    Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancies PMID:26862355

  20. Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease.

    PubMed

    Middeldorp, Jaap M

    2015-01-01

    Epstein-Barr virus (EBV) is widely distributed in the world and associated with a still increasing number of acute, chronic, malignant and autoimmune disease syndromes. Humoral immune responses to EBV have been studied for diagnostic, pathogenic and protective (vaccine) purposes. These studies use a range of methodologies, from cell-based immunofluorescence testing to antibody-diversity analysis using immunoblot and epitope analysis using recombinant or synthetic peptide-scanning. First, the individual EBV antigen complexes (VCA , MA, EA(D), EA(R) and EBNA) are defined at cellular and molecular levels, providing a historic overview. The characteristic antibody responses to these complexes in health and disease are described, and differences are highlighted by clinical examples. Options for EBV vaccination are briefly addressed. For a selected number of immunodominant proteins, in particular EBNA1, the interaction with human antibodies is further detailed at the epitope level, revealing interesting insights for structure, function and immunological aspects, not considered previously. Humoral immune responses against EBV-encoded tumour antigens LMP1, LMP2 and BARF1 are addressed, which provide novel options for targeted immunotherapy. Finally, some considerations on EBV-linked autoimmune diseases are given, and mechanisms of antigen mimicry are briefly discussed. Further analysis of humoral immune responses against EBV in health and disease in carefully selected patient cohorts will open new options for understanding pathogenesis of individual EBV-linked diseases and developing targeted diagnostic and therapeutic approaches.

  1. Status of Epstein-Barr Virus Coinfection with Helicobacter pylori in Gastric Cancer

    PubMed Central

    Singh, Shyam

    2017-01-01

    Epstein-Barr virus is a ubiquitous human herpesvirus whose primary infection causes mononucleosis, Burkett's lymphoma, nasopharyngeal carcinoma, autoimmune diseases, and gastric cancer (GC). The persistent infection causes malignancies in lymph and epithelial cells. Helicobacter pylori causes gastritis in human with chronic inflammation. This chronic inflammation is thought to be the cause of genomic instability. About 45%-word population have a probability of having both pathogens, namely, H. pylori and EBV. Approximately 180 per hundred thousand population is developing GC along with many gastric abnormalities. This makes GC the third leading cause of cancer-related death worldwide. Although lots of research are carried out individually for EBV and H. pylori, still there are very few reports available on coinfection of both pathogens. Recent studies suggested that EBV and H. pylori coinfection increases the occurrence of GC as well as the early age of GC detection comparing to individual infection. The aim of this review is to present status on coinfection of both pathogens and their association with GC. PMID:28421114

  2. Epstein Barr virus-positive mucocutaneous ulcer of the colon associated Hodgkin lymphoma in Crohn's disease.

    PubMed

    Moran, Neil R; Webster, Bradley; Lee, Kenneth M; Trotman, Judith; Kwan, Yiu-Lam; Napoli, John; Leong, Rupert W

    2015-05-21

    Epstein Barr virus (EBV) positive mucocutaneous ulcers (EBVMCU) form part of a spectrum of EBV-associated lymphoproliferative disease. They have been reported in the setting of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin and gastrointestinal tract (GIT). Case reports and series to date suggest a benign natural history responding to conservative management, particularly in the GIT. We report an unusual case of EBVMCU in the colon, arising in the setting of immunosuppression in the treatment of Crohn's disease, with progression to Hodgkin lymphoma 18 mo after cessation of infliximab. The patient presented with multiple areas of segmental colonic ulceration, histologically showing a polymorphous infiltrate with EBV positive Reed-Sternberg-like cells. A diagnosis of EBVMCU was made. The ulcers failed to regress upon cessation of infliximab and methotrexate for 18 mo. Following commencement of prednisolone for her Crohn's disease, the patient developed widespread Hodgkin lymphoma which ultimately presented as a life-threatening lower GIT bleed requiring emergency colectomy. This is the first report of progression of EBVMCU to Hodgkin lymphoma, in the setting of ongoing iatrogenic immunosuppression and inflammatory bowel disease.

  3. Serological diagnosis of Epstein-Barr virus infection: Problems and solutions

    PubMed Central

    De Paschale, Massimo; Clerici, Pierangelo

    2012-01-01

    Serological tests for antibodies specific for Epstein-Barr virus (EBV) antigens are frequently used to define infection status and for the differential diagnosis of other pathogens responsible for mononucleosis syndrome. Using only three parameters [viral capsid antigen (VCA) IgG, VCA IgM and EBV nuclear antigen (EBNA)-1 IgG],it is normally possible to distinguish acute from past infection: the presence of VCA IgM and VCA IgG without EBNA-1 IgG indicates acute infection, whereas the presence of VCA IgG and EBNA-1 IgG without VCA IgM is typical of past infection. However, serological findings may sometimes be difficult to interpret as VCA IgG can be present without VCA IgM or EBNA-1 IgG in cases of acute or past infection, or all the three parameters may be detected simultaneously in the case of recent infection or during the course of reactivation. A profile of isolated EBNA-1 IgG may also create some doubts. In order to interpret these patterns correctly, it is necessary to determine IgG avidity, identify anti-EBV IgG and IgM antibodies by immunoblotting, and look for heterophile antibodies, anti-EA (D) antibodies or viral genome using molecular biology methods. These tests make it possible to define the status of the infection and solve any problems that may arise in routine laboratory practice. PMID:24175209

  4. Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant.

    PubMed

    Rouce, Rayne H; Louis, Chrystal U; Heslop, Helen E

    2014-11-01

    Epstein-Barr virus (EBV) reactivation can cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplant. Delays in reconstitution of EBV-specific T lymphocyte activity can lead to life-threatening EBV lymphoproliferative disease (EBV-PTLD). This review highlights recent advances in the understanding of pathophysiology, risk factors, diagnosis, and management of EBV viremia and PTLD. During the past decade, early detection strategies, such as serial measurement of EBV-DNA load, have helped identify high-risk patients and diagnose early lymphoproliferation. The most significant advances have come in the form of innovative treatment options, including manipulation of the balance between outgrowing EBV-infected B cells and the EBV cytotoxic T lymphocyte response, and targeting infected B cells with monoclonal antibodies, chemotherapy, unmanipulated donor lymphocytes, and donor or more recently third-party EBV cytotoxic T lymphocytes. Defining criteria for preemptive therapy remains a challenge. EBV reactivation is a significant complication after stem cell transplant. Continued improvements in risk stratification and treatment options are required to improve the morbidity and mortality caused by EBV-associated diseases. Current approaches use rituximab to deplete B cells or adoptive transfer of EBV cytotoxic T lymphocyte to reconstitute immunity. The availability of rapid EBV-specific T cell products offers the possibility of improved outcomes.

  5. Characterization of skin blister fluids from children with Epstein-Barr virus-associated lymphoproliferative disease.

    PubMed

    Wada, Taizo; Toma, Tomoko; Miyazawa, Hanae; Koizumi, Eiko; Shirahashi, Tetsujiro; Matsuda, Yusuke; Yachie, Akihiro

    2018-04-01

    Epstein-Barr virus (EBV)-associated T- or natural killer (NK)-cell lymphoproliferative disease (LPD) is a heterogeneous group of disorders characterized by chronic proliferation of EBV-infected lymphocytes. Patients may present with severe skin manifestations, including hypersensitivity to mosquito bites (HMB) and hydroa vacciniforme (HV)-like eruption, which are characterized by blister formation and necrotic ulceration. Skin biopsy specimens show inflammatory reactions comprising EBV-infected lymphocytes. However, blister fluids have not been fully assessed in patients with this disease. Blister fluids were collected from three patients with EBV-associated LPD: two with HMB and one with HV. Immunophenotyping of blister lymphocytes and measurement of tumor necrosis factor (TNF)-α in blister fluids were performed. The patients with HMB and HV exhibited markedly increased percentages of NK and γδ T cells, respectively, in both peripheral blood and blister fluids. These NK and γδ T cells strongly expressed the activation marker human leukocyte antigen-DR and were considered to be cellular targets of EBV infections. TNF-α was highly elevated in all blister fluids. Severe local skin reactions of EBV-associated LPD may be associated with infiltrating EBV-infected lymphocytes and a high TNF-α concentration in blister fluids. © 2018 Japanese Dermatological Association.

  6. Prevalence of human papillomavirus and Epstein-Barr virus in salivary gland diseases.

    PubMed

    Lin, Frank Cheau-Feng; Chen, Pei-Liang; Tsao, Tang-Yi; Li, Chia-Ru; Jeng, Kee-Ching; Tsai, Stella Chin-Shaw

    2014-10-01

    The roles of human papillomavirus (HPV) and Epstein-Barr virus (EBV) in head and neck neoplasms have been well reported, but little is known about their relationship with salivary gland tumours. This study investigated the presence of HPV and EBV in salivary gland diseases. The presence of HPV 16/18 and EBV was analysed in archival pathological specimens collected from patients who had undergone surgery for salivary gland diseases. HPV 16/18 DNA was detected using nested polymerase chain reaction (PCR) and further confirmed with immunohistochemistry. EBV DNA was detected using real-time PCR. A total of 61 pathological specimens were examined: 39.5% (15/38) of pleomorphic adenomas, 33.3% (3/9) of Warthin's tumours, 33.3% (one of 3) of mucoepidermoid carcinomas, and 25.0% (one of 4) of benign lymphoepithelial lesions were positive for high-risk HPV 16/18. Only two Warthin's tumours were positive for EBV. The infectious nature of salivary gland neoplasms was revealed by the high prevalence of HPV infection, and the specific presence of EBV in Warthin's tumours, suggesting a potential role for HPV and EBV in salivary gland diseases. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  7. Acute or chronic life-threatening diseases associated with Epstein-Barr virus infection.

    PubMed

    Okano, Motohiko; Gross, Thomas G

    2012-06-01

    Infectious mononucleosis (IM) is one of the representative, usually benign, acute diseases associated with primary Epstein-Barr virus (EBV) infection. IM is generally self-limiting and is characterized mostly by transient fever, lymphadenopathy and hepatosplenomegaly. However, very rarely primary EBV infection results in severe or fatal conditions such as hemophagocytic lymphohistiocytosis together with fulminant hepatitis designated as severe or fatal IM or EBV-associated hemophagocytic lymphohistiocytosis alone. In addition, chronic EBV-associated diseases include Burkitt's lymphoma, undifferentiated nasopharyngeal carcinoma, Hodgkin lymphoma, T-cell lymphoproliferative disorder (LPD)/lymphoma, natural killer-cell LPD including leukemia or lymphoma, gastric carcinoma, pyothorax-associated lymphoma and senile B-cell LPD as well as chronic active EBV infection and LPD/lymphoma in patients with immunodeficiency. The number of chronic life-threatening diseases linked to the EBV infection is increasingly reported and many of these diseases have a poor prognosis. This review will focus on the historical, pathogenetic, diagnostic, therapeutic and prophylactic issues of EBV-associated life-threatening diseases.

  8. Severe Epstein-Barr virus infection in primary immunodeficiency and the normal host.

    PubMed

    Worth, Austen J J; Houldcroft, Charlotte J; Booth, Claire

    2016-11-01

    Epstein-Barr virus (EBV) infection is ubiquitous in humans, but the majority of infections have an asymptomatic or self-limiting clinical course. Rarely, individuals may develop a pathological EBV infection with a variety of life threatening complications (including haemophagocytosis and malignancy) and others develop asymptomatic chronic EBV viraemia. Although an impaired ability to control EBV infection has long been recognised as a hallmark of severe T-cell immunodeficiency, the advent of next generation sequencing has identified a series of Primary Immunodeficiencies in which EBV-related pathology is the dominant feature. Chronic active EBV infection is defined as chronic EBV viraemia associated with systemic lymphoproliferative disease, in the absence of immunodeficiency. Descriptions of larger cohorts of patients with chronic active EBV in recent years have significantly advanced our understanding of this clinical syndrome. In this review we summarise the current understanding of the pathophysiology and natural history of these diseases and clinical syndromes, and discuss approaches to the investigation and treatment of severe or atypical EBV infection. © 2016 John Wiley & Sons Ltd.

  9. Emerging Roles of Small Epstein-Barr Virus Derived Non-Coding RNAs in Epithelial Malignancy

    PubMed Central

    Lung, Raymond Wai-Ming; Tong, Joanna Hung-Man; To, Ka-Fai

    2013-01-01

    Latent Epstein-Barr virus (EBV) infection is an etiological factor in the progression of several human epithelial malignancies such as nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma. Reports have shown that EBV produces several viral oncoproteins, yet their pathological roles in carcinogenesis are not fully elucidated. Studies on the recently discovered of EBV-encoded microRNAs (ebv-miRNAs) showed that these small molecules function as post-transcriptional gene regulators and may play a role in the carcinogenesis process. In NPC and EBV positive gastric carcinoma (EBVaGC), 22 viral miRNAs which are located in the long alternative splicing EBV transcripts, named BamH1 A rightward transcripts (BARTs), are abundantly expressed. The importance of several miR-BARTs in carcinogenesis has recently been demonstrated. These novel findings enhance our understanding of the oncogenic properties of EBV and may lead to a more effective design of therapeutic regimens to combat EBV-associated malignancies. This article will review the pathological roles of miR-BARTs in modulating the expression of cancer-related genes in both host and viral genomes. The expression of other small non-coding RNAs in NPC and the expression pattern of miR-BARTs in rare EBV-associated epithelial cancers will also be discussed. PMID:23979421

  10. Hemophagocytic lymphohistiocytosis caused by primary Epstein-Barr virus in patient with Crohn's disease.

    PubMed

    Virdis, Francesco; Tacci, Sara; Messina, Federico; Varcada, Massimo

    2013-11-27

    We present a case of a 19-year-old man with a 6-year history of Crohn's disease (CD), previously treated with 6-mercaptopurine, who was admitted to our department for Epstein-Barr virus (EBV) infection and subsequently developed a hemophagocytic lymphohistiocytosis (HLH). HLH is a rare disease which causes phagocytosis of all bone marrow derived cells. It can be a primary form as a autosomic recessive disease, or a secondary form associated with a variety of infections; EBV is the most common, the one with poorer prognosis. The incidence of lymphoproliferative disorders was increased in patients with inflammatory bowel disease (IBD) treated with thiopurines. Specific EBV-related clinical and virological management should be considered when treating a patient with IBD with immunosuppressive therapy. Moreover EBV infection in immunosuppressed patient can occur with more aggressive forms such as encephalitis and diffuse large B cell lymphoma. Our case confirms what is described in the literature; patients with IBD, particularly patients with CD receiving thiopurine therapy, who present 5 d of fever and cervical lymphadenopathy or previous evidence of lymphopenia should be screened for HLH.

  11. Seroprevalence of Epstein-Barr Virus, Cytomegalovirus, and Polyomaviruses in Children with Inflammatory Bowel Disease.

    PubMed

    Hradsky, Ondrej; Copova, Ivana; Zarubova, Kristyna; Durilova, Marianna; Nevoral, Jiri; Maminak, Miroslav; Hubacek, Petr; Bronsky, Jiri

    2015-11-01

    Young age and thiopurine therapy are risk factors for lymphoproliferative disease among patients with inflammatory bowel disease (IBD). The aims of this study were to evaluate the prevalence of seropositivity for the Epstein-Barr virus (EBV) and human cytomegalovirus (CMV) among children and adolescents with IBD, to assess the viral load of EBV, CMV, and BK and JC polyomaviruses (BKV, JCV) in these patients, and to assess the influence of different therapeutic regimens on seroprevalence and viral load. Children who had been followed in our center were tested for EBV, CMV, BKV, and JCV in a cross-sectional study. One hundred and six children were included who had Crohn's disease (68%), ulcerative colitis (29%), and unclassified IBD (3%). We found that 64% of patients were EBV seropositive. The proportion of EBV seropositive patients increased during childhood. Azathioprine therapy (p = 0.003) was associated with EBV seropositivity in a multiple logistic regression model, after adjusting for gender, age, and disease activity at determination. We found a significant association between the number of polymerase chain reaction copies and infliximab dose (p = 0.023). We did not find any significant association between CMV serology and CMV, BKV, or JCV viral load, or any other therapeutic regimen or clinical characteristics. Treatment with azathioprine appears to be a risk factor for early EBV seropositivity in children with IBD, and the infliximab dose was associated with a higher EBV viral load.

  12. Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation.

    PubMed

    Huang, Lu; Yang, Mengtian; Yuan, Yan; Li, Xiaojuan; Kuang, Ersheng

    2017-02-01

    Infection with the oncogenic γ-herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause several severe malignancies in humans. Inhibition of the lytic replication of EBV and KSHV eliminates the reservoir of persistent infection and transmission, consequently preventing the occurrence of diseases from the sources of infection. Antiviral drugs are limited in controlling these viral infectious diseases. Here, we demonstrate that niclosamide, an old anthelmintic drug, inhibits mTOR activation during EBV lytic replication. Consequently, niclosamide effectively suppresses EBV lytic gene expression, viral DNA lytic replication and virion production in EBV-infected lymphoma cells and epithelial cells. Niclosamide exhibits cytotoxicity toward lymphoma cells and induces irreversible cell cycle arrest in lytically EBV-infected cells. The ectopic overexpression of mTOR reverses the inhibition of niclosamide in EBV lytic replication. Similarly, niclosamide inhibits KSHV lytic replication. Thus, we conclude that niclosamide is a promising candidate for chemotherapy against the acute occurrence and transmission of infectious diseases of oncogenic γ-herpesviruses. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Enhanced aerobic glycolysis of nasopharyngeal carcinoma cells by Epstein-Barr virus latent membrane protein 1.

    PubMed

    Sung, Wei-Wen; Chen, Peir-Rong; Liao, Ming-Hui; Lee, Jeng-Woei

    2017-10-01

    Latent membrane protein 1 (LMP1) is a principal viral oncoprotein in Epstein-Barr virus (EBV)-associated malignancies, including nasopharyngeal carcinoma (NPC), which acts through regulating tumorigenesis and metabolic reprogramming of cancers. In the presence of oxygen, we demonstrated that glucose consumption, lactate production and lactate dehydrogenase (LDH) activity were significantly increased upon LMP1 expression in NPC cells and in a LMP1 variant derived from NPC patients-transformed BALB/c-3T3 cells. The amounts of the α subunit of hypoxia-inducible factor-1 (HIF-1α), a key regulator of aerobic glycolysis, and its targets, pyruvate dehydrogenase kinase 1 (PDK1) and the pyruvate kinase M2 (PKM2) isoform, were also consistently elevated by LMP1. Moreover, in parallel with reductions in the oxygen consumption rate and mitochondrial membrane potential in cells, an augmented extracellular lactate concentration was observed due to LMP1 induction. In conclusion, our results proved facilitation of the Warburg effect by LMP1 through alteration of mitochondrial function in NPC cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Epstein-Barr Virus oncoprotein super-enhancers control B cell growth

    PubMed Central

    Zhou, Hufeng; Schmidt, Stefanie CS; Jiang, Sizun; Willox, Bradford; Bernhardt, Katharina; Liang, Jun; Johannsen, Eric C; Kharchenko, Peter; Gewurz, Benjamin E; Kieff, Elliott; Zhao, Bo

    2015-01-01

    Summary Super-enhancers are clusters of gene-regulatory sites bound by multiple transcription factors that govern cell transcription, development, phenotype, and oncogenesis. By examining Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines (LCLs), we identified four EBV oncoproteins and five EBV-activated NF-κB subunits co-occupying ~1800 enhancer sites. Of these, 187 had markedly higher and broader histone H3K27ac signals characteristic of super-enhancers, and were designated “EBV super-enhancers”. EBV super-enhancer-associated genes included the MYC and BCL2 oncogenes, enabling LCL proliferation and survival. EBV super-enhancers were enriched for B cell transcription factor motifs and had a high co-occupancy of the transcription factors STAT5 and NFAT. EBV super-enhancer-associated genes were more highly expressed than other LCL genes. Disrupting EBV super-enhancers by the bromodomain inhibitor, JQ1 or conditionally inactivating an EBV oncoprotein or NF-κB decreased MYC or BCL2 expression and arrested LCL growth. These findings provide insight into mechanisms of EBV-induced lymphoproliferation and identify potential therapeutic interventions. PMID:25639793

  15. [A Case of Severe Chronic Active Epstein-Barr Virus Infection with Aplastic Anemia and Hepatitis].

    PubMed

    Lee, Ja In; Lee, Sung Won; Han, Nam Ik; Ro, Sang Mi; Noh, Yong-Sun; Jang, Jeong Won; Bae, Si Hyun; Choi, Jong Young; Yoon, Seung Kew

    2016-01-25

    Epstein-Barr virus (EBV) causes various acute and chronic diseases. Chronic active EBV infection (CAEBV) is characterized by infectious mononucleosis-like symptoms that persist for more than 6 months with high viral loads in peripheral blood and/or an unusual pattern of anti-EBV antibodies. Severe CAEBV is associated with poor prognosis with severe symptoms, an extremely high EBV-related antibody titer, and hematologic complications that often include hemophagocytic lymphohistiocytosis. However, CAEBV which led to the development of aplastic anemia (AA) has not been reported yet. A 73-year-old woman was admitted to our hospital with intermittent fever, general weakness and elevated liver enzymes. In the serologic test, EBV-related antibody titer was elevated, and real-time quantitative-PCR in peripheral blood showed viral loads exceeding 10(4) copies/μg DNA. Liver biopsy showed characteristic histopathological changes of EBV hepatitis and in situ hybridization with EBV-encoded RNA-1 was positive for EBV. Pancytopenia was detected in peripheral blood, and the bone marrow aspiration biopsy showed hypocellularity with replacement by adipocytes. AA progressed and the patient was treated with prednisolone but deceased 8 months after the diagnosis due to multiple organ failure and opportunistic infection. Herein, we report a rare case of severe CAEBV in an adult patient accompanied by AA and persistent hepatitis.

  16. [Cerebrospinal fluid findings in chronic active Epstein-Barr virus infection with central nervous system involvement].

    PubMed

    Yoshimori, Mayumi; Imadome, Ken-Ichi; Tomii, Shohei; Yamamoto, Kouhei; Miura, Osamu; Arai, Ayako

    2018-01-01

    As chronic active Epstein-Barr virus (EBV) infection (CAEBV) progresses, EBV-infected tumor cells invade the central nervous system (CNS). To establish a diagnostic procedure for CNS invasion, we retrospectively analyzed cerebrospinal fluid (CSF) obtained from eight patients. Two patients presented with consciousness disturbance and were diagnosed with CNS invasion based on scan and autopsy results, respectively. The remaining six patients were diagnosed without CNS invasion by clinical findings and scans. In the two patients with CNS invasion, the number of mononuclear cells and the protein concentration were increased, whereas the CSF to serum glucose ratio and the adenosine deaminase concentration were raised. In one of the two patients, however, bacterial meningitis could not be excluded. Cytological examination of CSF demonstrated class 1-3. Notably, the CSF EBV-DNA load was positive in all patients, independent of CNS invasion diagnosis, and the CSF load correlated with that of the peripheral blood. Taken together, this indicates that CSF may lack the specific markers of CNS invasion in CAEBV patients. The CSF EBV-DNA load and the cytological analysis did not reflect CNS invasion; therefore, new biomarkers need to be established.

  17. Interleukin-17A-producing T lymphocytes in chronic active Epstein-Barr virus infection.

    PubMed

    Ohta, Rieko; Imai, Masaki; Kawada, Jun-ichi; Kimura, Hiroshi; Ito, Yoshinori

    2013-02-01

    T helper (Th) 17 cells are reportedly effector T cells that produce interleukin (IL)-17A and play a significant role in the development of autoimmune diseases and immune responses for antimicrobial host defense. Production of IL-17A in chronic active Epstein-Barr virus infection (CAEBV) was studied to investigate its contribution to pathogenesis of this disease. Significantly more IL-17A-producing cells were detected in the peripheral blood of CAEBV patients than in that of healthy controls, although a significant difference in serum IL-17A production was not confirmed. Of the IL-17A-producing cells, 91.8% were cluster of differentiation (CD)4-positive Th17 cells. Moreover, there were significantly more IL-17A-producing cells among CD4(+) cells in peripheral blood of CAEBV patients than in that of controls (1.97 ± 0.69% vs. 1.09 ± 0.53%, P = 0.0073). These data suggest that IL-17A-producing cells may influence the pathophysiology of CAEBV. © 2012 The Societies and Wiley Publishing Asia Pty Ltd.

  18. Active myocarditis in a patient with chronic active Epstein-Barr virus infection.

    PubMed

    Takano, Hiroyuki; Nakagawa, Keiichi; Ishio, Naoki; Daimon, Michiko; Daimon, Masao; Kobayashi, Yoshio; Hiroshima, Kenzo; Komuro, Issei

    2008-10-30

    Chronic active Epstein-Barr virus (CAEBV) infection is characterized by chronic or recurrent infectious mononucleosis-like symptoms and the prognosis of CAEBV infection is quite poor. The incidence of myocarditis as a complication of EBV infection is not so high and it is unusual that heart failure appears as the initial symptom. However, it is very important to detect and treat chronic active myocarditis in the early phase of CAEBV infection because chronic active myocarditis disorganizes and decreases cardiomyocytes, resulting in the progression to heart failure. We report a case of a 45-year-old man with CAEBV infection for 5 years. Echocardiography revealed moderate left ventricular systolic dysfunction with mild pericardial effusion. Endomyocardial biopsies demonstrated massive lymphocytic infiltration with adjacent myocytolysis and necrosis of cardiomyocytes suggesting active myocarditis. Immunohistological analysis of biopsies revealed that the infiltrating cells were mainly T lymphocytes. And some of the infiltrating cells showed a positive signal for the EBV-encoded small nuclear RNA by in situ hybridization. Positron emission tomography using (18)F-fluoro-2-deoxyglucose ((18)F-FDG) performed revealed increased uptake of (18)F-FDG of whole left ventricular wall with mild heterogeneity.

  19. Cardiovascular complications associated with chronic active Epstein-Barr virus infection.

    PubMed

    Muneuchi, Jun; Ohga, Shouichi; Ishimura, Masataka; Ikeda, Kazuyuki; Yamaguchi, Kenichiro; Nomura, Akihiko; Takada, Hidetoshi; Abe, Yasunobu; Hara, Toshiro

    2009-04-01

    This study aimed to assess the outcome of cardiovascular diseases for patients with chronic active Epstein-Barr virus infection (CAEBV). The study enrolled 15 patients (7 boys and 8 girls) who fulfilled the diagnostic criteria for CAEBV, including 10 patients with T-cell type and 3 patients with natural killer (NK)-cell type. The median age at the CAEBV onset was 6.3 years (range, 1.2-17.8 years). Regular cardiologic studies were performed during the median follow-up period of 8 years (range, 2-20 years). Nine patients (60%) had cardiac diseases including coronary artery lesion (CAL) (n = 4, 44%), decreased left ventricular ejection fraction and pericardial effusion in (n = 3, 33%), complete atrioventricular block (n = 1), and sudden arrest (n = 1). The frequency of fever (78%, p = 0.04) or cytopenias (100%, p = 0.01), as the major symptom among patients with cardiac complications, was higher than among those without complications. The median time from disease onset to detection of CAL was 3.4 years (range, 1.8-8.6 years). The mean z-score increased to 3.98. Seven patients (78%) with cardiac complications died of disease progression, hematopoietic stem cell transplantation-related events, or both. In two patients, CAL regressed after allogeneic cord blood transplantation. Among CAEBV patients, CAL was the most common cardiac complication and could not be controlled without the eradication of EBV-infected T- and NK-cells.

  20. Chronic active Epstein-Barr virus infection mimicking Henoch-Schönlein purpura.

    PubMed

    Guissa, Vanessa R; Aragão, Paula A; Marques, Heloisa H; Jacob, Cristina M; Silva, Clovis A

    2010-01-01

    Chronic active Epstein-Barr virus (CAEBV) infection is characterized by chronic or recurrent symptoms for at least 3 months, such as fever, hepatosplenomegaly and lymphadenopathy. The diagnosis is established due to the presence of anti-EBV antibodies or isolation of this infectious agent in affected tissues. Three cases of CAEBV infection mimicking Henoch-Schönlein purpura (HSP) were described. CASE 1: Female 3-year old patient with cervical adenomegaly, anemia and fever developed palpable purpura, haematuria and arthritis. CAEBV infection was established by serology test. She received methylprednisolone and acyclovir. She had generalized lymphadenopathy, hepatomegaly, splenomegaly, disseminated intravascular coagulation and deceased. CASE 2: Male 12-year old patient with persistent anemia, lymphadenopathy, hepatomegaly and splenomegaly had CAEBV infection diagnosis by serology test. He developed purpura and arthritis and received methylprednisolone. CASE 3: Male 13-year old patient had purpura, abdominal pain, haematuria, hepatomegaly, splenomegaly, lymphadenopathy, anemia and elevated liver enzymes. The cervical lymph node biopsy was positive to EBV infection. He received methylprednisolone and acyclovir, developing acute fulminant hepatitis and death. CAEBV infection mimicking HSP was rarely observed in our population.

  1. Generalized myositis mimicking polymyositis associated with chronic active Epstein-Barr virus infection.

    PubMed

    Uchiyama, Tomoyuki; Arai, Kimito; Yamamoto-Tabata, Takako; Hirai, Kanji; Kishimoto, Kouji; Nakamura, Yoshiko; Hattori, Takamichi

    2005-05-01

    Chronic generalized myositis has not so far been reported as a complication of chronic active Epstein-Barr virus infection (CAEBV). We encountered three patients with chronic generalized myositis mimicking polymyositis associated with CAEBV. To clarify the pathological character of this myositis, we investigated the distribution, clonality, and the immunophenotype of EBV-infected cells and lymphocytes infiltrating in muscles. Clinically, two patients showed symmetrical proximal weakness and muscle atrophy as the initial and main symptom. Although the condition resembled polymyositis, they had also lingual and/or orbital myositis. The other patient showed generalized myositis at the late phase of CAEBV. In all of them, immunotherapy was ineffective and prognosis was poor. Intramuscular infiltrating lymphocytes in our patients were mainly CD45RO+, CD3+, CD4-, CD8-, TCR betaF1-, TCR deltaTCS1-, CD56-, CD79a-, CD21-, HLA-DR+, ZEBRA -, LMP1-, and EBER+ T cells. Oligoclonal expansion of EBV-infected T cells was shown in the muscles. However, there were no malignant lymphocytes. This new form of myositis must be distinguished from polymyositis and the other conventional forms of myositis. Careful investigation of hidden CAEBV is recommended when patients present with steroid non-responsive chronic progressive generalized myositis, in particular, with lingual or orbital involvement.

  2. Clinical features of adult-onset chronic active Epstein-Barr virus infection: a retrospective analysis.

    PubMed

    Arai, Ayako; Imadome, Ken-Ichi; Watanabe, Yuko; Yoshimori, Mayumi; Koyama, Takatoshi; Kawaguchi, Takeharu; Nakaseko, Chiaki; Fujiwara, Shigeyoshi; Miura, Osamu

    2011-05-01

    We performed a retrospective analysis of patients with adult-onset chronic active Epstein-Barr virus infection (CAEBV). First, we analyzed five patients (aged 28-72) diagnosed at our hospitals with EBV-infected clonally proliferating T cells. Four patients were administered cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy, but no remarkable decrease of viral load was observed in three of the patients. The other patient died 19 days after initiation of CHOP treatment due to disease progression. Addition of high-dose cytarabine to the regimens of two of the patients was discontinued shortly after administration, due to the development of grade 4 pericardial effusion. Together, these regimens may be insufficient for treating adult-onset CAEBV. We next reviewed 23 adult-onset CAEBV patients, adding 18 previously reported patients to the five patients described in the present study. T cells were frequently infected (87%), whereas NK- and T-cell types are known to be almost equally prevalent in childhood-onset cases. The time duration from the onset of disease to initiation of treatment averaged 20 months. Reports showed that 12 patients died; seven patients died at an average of 8 months after initiation of treatment. Patients' disease courses seemed to be rapidly progressive and more aggressive than those of childhood-onset cases. More cases must be studied to clarify clinical features and establish an optimal treatment strategy.

  3. Inflammatory cytokine production in chronic active Epstein-Barr virus infection.

    PubMed

    Onozawa, Erika; Shibayama, Haruna; Imadome, Ken-Ichi; Tsuzura, Akiho; Koyama, Takatoshi; Miura, Osamu; Arai, Ayako

    2017-01-01

    In order to clarify the mechanisms underlying the development of inflammation in chronic active Epstein-Barr virus infection (CABEV), we examined cytokine production using patient samples. Eleven patients were analyzed. The serum concentrations of IFN-γ, TNF-α, and IL-6 were significantly higher in patients than in healthy donors. The mRNAs of these cytokines in peripheral blood mononuclear cells were elevated in patients as compared with healthy donors. The mRNA of IFN-γ was significantly higher in patients than in healthy donors. We examined which fraction produced the cytokines in the CD4-, CD8-, and CD56-positive fractions of PBMCs. The mRNAs of IFN-γ, TNF-α, and IL-6 were highly expressed in EBV-infected cells, whereas expression was also observed in non-infected cells. We performed in vitro infection of EBV on a T-cell line, MOLT4. EBV infection enhanced the mRNA expressions of IFN-γ and TNF-α. These results suggest that the inflammatory cytokines in CAEBV are produced not only by EBV-infected but also non-infected cells. EBV itself may have roles in the cytokine production observed in infected cells.

  4. [Immunodeficiency and carcinogenesis in patients with chronic active Epstein-Barr virus infection].

    PubMed

    Nagafuchi, S; Fujisaki, T; Ohshima, K; Anzai, K; Otsuka, T; Kikuchi, H; Nasu, M; Kikuchi, M; Sawae, Y; Niho, Y

    1997-01-01

    Three adult patients with chronic active Epstein-Barr virus infection (CAEBV) had high anti-EBV-VCA antibody, positive anti-EA, low anti-EBNA and were associated with systemic lymphadenopathies and immunosuppression. The case 1 and 2 had elevated serum immunoglobulin levels, and recurrent infections, and case 3 showed pancytopenia. These 3 cases developed both EBV and latent membrane protein (LMP) positive malignant histiocytosis, EBV positive but LMP negative plasmacytoma, and EBV negative acute myelogeneous leukemia, respectively. It was suggested that CAEBV belonged to high risk groups for the development of malignant neoplasms. Since HLA of the case 1 and his father was identical, we conducted a in vitro cytotoxicity test using EBV transformed autologous B lymphocytes, K562 cells, and Raji cells to clarify the association of immunosuppression and HLA. The case 1 showed a low level of specific cytotoxicity to autologous EBV transformed B cells, while his parents were negative for the specific cytotoxicity. The patient and his parents developed inducible cytotoxicity to all targets after in vitro incubation of peripheral mononuclear cells with recombinant interleukin 2 (rIL-2) for 7 days. The patient and his mother showed lower enhancement of cytotoxicity, while HLA identical father could induce good cytotoxic activity to all targets as well as normal controls, indicating that a low IL-2 induced cytotoxic activity observed in CAEBV was independent of HLA associated immunoregulation at least in the case 1. Further studies are required to clarify the exact mechanisms responsible for the development of CAEBV.

  5. Chronic active Epstein-Barr virus infection associated with mutations in perforin that impair its maturation.

    PubMed

    Katano, Harutaka; Ali, Mir A; Patera, Andriani C; Catalfamo, Marta; Jaffe, Elaine S; Kimura, Hiroshi; Dale, Janet K; Straus, Stephen E; Cohen, Jeffrey I

    2004-02-15

    Chronic active Epstein-Barr virus infection (CAEBV) is a rare disease in which previously healthy persons develop severe, life-threatening illness. Mutations in the perforin gene have been found in familial hemophagocytic lymphohistiocytosis, which shares some features with CAEBV. We studied a patient who died at age 18, 10 years after the onset of CAEBV. The patient had high titers of antibodies to EBV, EBV RNA in lymph nodes, T-cell lymphoproliferative disease, and hemophagocytic lymphohistiocytosis. DNA sequencing showed novel mutations in both alleles of the perforin gene that resulted in amino acid changes in the protein. The quantity of the native form of perforin from the patient's stimulated peripheral blood mononuclear cells (PBMCs) was extremely low and immunoblotting showed accumulation of an uncleaved precursor form of perforin. Stimulated PBMCs from the patient were defective for Fas-independent cytotoxicity. These data imply that mutations in this patient resulted in reduced perforin-mediated cytotoxicity by his lymphocytes. This is the first case in which perforin mutations have been shown to result in accumulation of the uncleaved, immature form of perforin. Mutations in the perforin gene are associated with some cases of CAEBV with hemophagocytic lymphohistiocytosis.

  6. An atypical pattern of Epstein-Barr virus infection in a case with idiopathic tubulointerstitial nephritis.

    PubMed

    Okada, Hirokazu; Ikeda, Naofumi; Kobayashi, Tatsuya; Inoue, Tsutomu; Kanno, Yoshihiko; Sugahara, Souichi; Nakamoto, Hidetomo; Yamamoto, Takako; Suzuki, Hiromichi

    2002-10-01

    Recently, Epstein-Barr virus (EBV) received attention because a latent form of its infection in renal proximal tubular epithelial cells was found to cause idiopathic, chronic tubulointerstitial nephritis. In this report, we describe the case of a patient with a replicative form of EBV infection, chronic active EBV infection (CAEBV), who developed acute tubulointerstitial nephritis and minimal change nephrotic syndrome. A renal biopsy revealed papillary infoldings of atypical tubular epithelium and adjacent dense infiltration of lymphocytes. Using in situ polymerase chain reaction methods, we detected the EBV genome in some of the infiltrating lymphocytes, but not in the tubular epithelial cells. EBV-infected T cells are thought to activate other educated T cells, as well as secrete an unrestricted variety of cytokines, thus playing a pivotal role in CAEBV and its end organ disease. Therefore, in our case, the CAEBV activated, educated T cells may have followed the EBV-infected lymphocytes as they infiltrated into the peritubular interstitium, and promoted focal tubular epithelial atypia and minimal change nephrotic syndrome. The long-term observation of such patients is important because CAEBV may progress into lymphoproliferative diseases. Copyright 2002 S. Karger AG, Basel

  7. A case of a long-time survivor with chronic active Epstein-Barr virus infection.

    PubMed

    Takeoka, Yasunobu; Nakao, Yoshitaka; Ueda, Misako; Koh, Ki-Ryang; Aoyama, Yasutaka; Nakamae, Hirohisa; Yamamura, Ryousuke; Ohta, Kensuke; Takubo, Takayuki; Yamane, Takahisa; Hino, Masayuki; Tokura, Yoshiki; Ishihara, Shigehiko; Oshima, Koichi; Kimura, Hiroshi; Imashuku, Shinsaku

    2004-01-01

    Epstein-Barr virus (EBV) is associated with hypersensitivity to mosquito bites (HMB) and fatal EBV-associated hemophagocytic syndrome (HPS). The prognosis of patients with chronic active EBV infection (CAEBV) is very poor. We report a rare case of an adult woman patient with a 28-yr history of HMB, who developed EBV-HPS. EBV genome was detected in the serum and peripheral blood lymphocytes. Clonal proliferation of EBV was demonstrated by Southern blot analysis using an EBV genome terminal-repeat probe. This is a very rare case of a long-term survivor with CAEBV. The patient was initially treated with immunochemotherapy and achieved complete remission. However, the patient immediately relapsed and underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. Peripheral blood cell recovered well, and EBV genome disappeared from the peripheral blood. Allogeneic BMT may be effective in eradicating EBV-HPS. Unfortunately, the patient died of graft vs. host disease on the 92nd day after BMT.

  8. [Chronic active Epstein-Barr virus infection treated with reduced intensity stem cell transplantation].

    PubMed

    Sakata, Naoki; Sato, Emiko; Sawada, Akihisa; Yasui, Masahiro; Inoue, Masami; Kawa, Keisei

    2004-05-01

    A 31-year-old woman had been suffering from fever and a sore throat since January 1999, and had a left neck lymphadenopathy in December 1999. Pathological findings of the biopsied lymphnode suggested malignant lymphoma. She was finally diagnosed as having a chronic active Epstein-Barr virus(EBV) infection because of abnormal antibody titers against EBV antigens and an increased EBV load in her peripheral blood. After receiving chemotherapy consisting of CHOP and high dose cytarabine, the amount of the EBV genome decreased below the detection limit before BMT. Therefore, instead of a conventional myeloablative transplant, we performed BMT using reduced-intensity conditioning regimens consisting of fludarabine and melphalan from an HLA-identical sibling donor. After 14 months, the patient remained in complete remission. Menstruation occurred on day 83 following BMT, and the serum level of LH and FSH on day 316 were within normal range. Under these circumstances, RIST seems to be one of the curative treatments for the patients with CAEBV with minimal late side effects.

  9. Valacyclovir Pharmacokinetics and Exploratory Pharmacodynamics in Young Adults With Epstein-Barr Virus Infectious Mononucleosis

    PubMed Central

    Vezina, Heather E.; Balfour, Henry H.; Weller, Dennis R.; Anderson, Bruce J.; Brundage, Richard C.

    2017-01-01

    Primary Epstein-Barr virus (EBV) infection often results in infectious mononucleosis and is associated with serious sequelae. No treatment is approved for EBV infection, and an antiviral intervention would be significant. The objectives of this study are to characterize the pharmacokinetics and explore the pharmacodynamics of acyclovir in plasma and oral washings of 8 subjects receiving 7 days of valacyclovir 1500 mg twice daily for EBV infectious mononucleosis. Virologic and clinical responses are assessed over 12 days. Acyclovir is measured by liquid chromatography/ultraviolet detection. EBV DNA is quantitated by TaqMan polymerase chain reaction. NONMEM VI and linear regression are used for data analysis. Acyclovir profiles in plasma and oral washings are consistent with a 1-compartment model. Final model estimates of clearance, volume of distribution, and fraction of acyclovir in oral wash supernatant are 49.9 L/h, 74.1 L, and 1.14%, respectively. The quantity of EBV DNA in oral washings and blood, and the severity of illness, measured by a graded scale, decrease during treatment. After treatment, viral rebound occurs in oral washings but not in blood, and the severity of illness continues to decline. Acyclovir pharmacokinetic parameters do not correlate with response metrics. These results support further studies of valacyclovir for EBV infectious mononucleosis. PMID:19897764

  10. Splenic infarction associated with acute infectious mononucleosis due to Epstein-Barr virus infection.

    PubMed

    Heo, Dae-Hyuk; Baek, Dae-Youb; Oh, Sang-Min; Hwang, Joo-Hee; Lee, Chang-Seop; Hwang, Jeong-Hwan

    2017-02-01

    The purpose of this study was to report a case of a previously healthy 20-year-old woman diagnosed with splenic infarction following infectious mononucleosis (IM) by Epstein-Barr virus (EBV) infection and to perform the first systematic review of the clinical characteristics of splenic infarction associated with IM. A systematic review was conducted using English, French, and Japanese literatures of splenic infarction associated with IM due to EBV infection published between 1961 and 2015 in PubMed Medline. A total of 19 cases were extracted from the collected articles. Left upper quadrant (LUQ) pain was observed in 15 (79%) patients. Splenectomy was performed in five (26%) cases, among which four patients presented with stable vital signs. Splenic rupture was accompanied in two (10%) patients. The median time from the onset of IM symptoms to the diagnosis of splenic infarction was 5 days (range, 1-25 days). Fourteen (74%) of 19 patients experienced improvement through medical treatment, and there were no deaths. Splenic infarction associated with IM due to EBV infection can show a favorable clinical outcome after medical treatment. Clinicians should consider the possibility of splenic infarction when patients with IM experience LUQ pain. J. Med. Virol. 89:332-336, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  11. Epstein-Barr virus and cytomegalovirus infections and their clinical relevance in Egyptian leukemic pediatric patients.

    PubMed

    Loutfy, Samah Aly; Abo-Shadi, Maha A; Fawzy, Mohamed; El-Wakil, Mohamed; Metwally, Shimaa A; Moneer, Manar M; Fattah, Nasra F Abdel; Kassem, Sara; Elgebaly, Ahmed

    2017-03-06

    Epstein-Barr virus (EBV) and human cytomegalovirus (CMV) infections are environmental risk factors affecting the outcome of cancer due to an impairment in the cell-mediated immunity. Therefore, this study aimed to detect the frequency of EBV and CMV DNA and their association with clinical characteristics and outcome of pediatric leukemic patients. Samples of 50 immunocompromised pediatric leukemic patients and 30 apparently healthy children were subjected to the amplification of EBV DNA by one version of PCR targeting the Bam H1 W region of the genomic region of EBV, and the amplification of CMV DNA by targeting the CMV UL97 genomic region by a second round PCR. All investigations were performed on WBCs and sera. Results were correlated with the clinical and laboratory characteristics of the disease, and with overall survival. EBV and CMV DNA were detected in 20 and 54% of leukemic patients, respectively. Nine out of ten patients with EBV DNA (90%) were positive for CMV DNA in their sera. The presence of EBV DNA or CMV DNA was associated with neutropenia and a low total leukocyte count (TLC) (p = 0.02, 0.03, respectively). The presence of severe CMV disease, longer duration of febrile neutropenia, neutropenia, lymphopenia, thrombocytopenia and the presence of EBV DNA in patients' sera were significantly associated with worse overall survival. The detection of CMV disease and EBV DNA is relatively common in leukemic children and is significantly associated with a decline in the overall survival.

  12. Association between oral lichen planus and Epstein-Barr virus in Iranian patients.

    PubMed

    Shariati, Matin; Mokhtari, Mojgan; Masoudifar, Aria

    2018-01-01

    Oral lichen planus (OLP) is a common mucocutaneous disease with malignant transformation potential. Several etiologies such as humoral, autoimmunity, and viral infections might play a role, but still there is no definite etiology for this disease. The aim of this study was to investigate the presence of Epstein-Barr virus (EBV) genome in Iranian patients with OLP as compared to people with normal mucosa. The study was carried out on a case group including 38 tissue specimens of patients with histopathological confirmation of OLP and a control group including 38 samples of healthy mucosa. All samples were examined by nested polymerase chain reaction (PCR) method to determine the DNA of EBV. Twenty-two (57.9%) female samples and 16 (42.1%) male samples with OLP were randomly selected as the case group, and 20 (52.6%) female samples and 18 (47.4%) male samples with healthy mucosa as the control group. There was a statistically significant difference in the percentage of EBV positivity between the case (15.8%) and the control groups ( P < 0.05); in the case group, three female samples (13.6%) and three male samples (18.8%) were infected with EBV; the difference between the genders was not statistically significant ( P = 0.50). Results emphasized that EBV genome was significantly higher among Iranian patients with OLP so antiviral therapy might be helpful.

  13. Cancer stem-like cells in Epstein-Barr virus-associated nasopharyngeal carcinoma

    PubMed Central

    Wei-Man Lun, Samantha; Cheung, Siu-Tim; Lo, Kwok-Wai

    2014-01-01

    Although the Epstein-Barr virus (EBV) has spread to all populations in the world, EBV-associated nasopharyngeal carcinoma (NPC) is prevalent only in South China and Southeast Asia. The role of EBV in the malignant transformation of nasopharyngeal epithelium is the main focus of current researches. Radiotherapy and chemoradiotherapy have been successful in treating early stage NPC, but the recurrence rates remain high. Unfortunately, local relapse and metastasis are commonly unresponsive to conventional treatments. These recurrent and metastatic lesions are believed to arise from residual or surviving cells that have the properties of cancer stem cells. These cancer stem-like cells (CSCs) have the ability to self-renew, differentiate, and sustain propagation. They are also chemo-resistant and can form spheres in anchorage-independent environments. This review summarizes recent researches on the CSCs in EBV-associated NPC, including the findings regarding cell surface markers, stem cell-related transcription factors, and various signaling pathways. In particular, the review focuses on the roles of EBV latent genes [latent membrane protein 1 (LMP1) and latent membrane protein 2A (LMP2A)], cellular microRNAs, and adenosine triphosphate (ATP)-binding cassette chemodrug transporters in contributing to the properties of CSCs, including the epithelial-mesenchymal transition, stem-like transition, and chemo-resistance. Novel therapeutics that enhance the efficacy of radiotherapy and chemoradiotherapy and inhibitors that suppress the properties of CSCs are also discussed. PMID:25223912

  14. Seroepidemiology of Epstein-Barr virus and cytomegalovirus among Israeli male young adults.

    PubMed

    Levine, Hagai; Balicer, Ran D; Rozhavski, Vladi; Halperin, Tamar; Shreberk, Michal; Davidovitch, Nadav; Huerta-Hartal, Michael; Ankol, Omer E

    2012-11-01

    To assess the seroprevalence and seroconversion of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) Immunoglobulin G (IgG) antibodies and identify associated socioeconomic and smoking variables among male young adults in Israel, to explore health disparities and aid prevention efforts. A population-based seroprevalence study of EBV and CMV IgG antibodies in a systematic sample of Israeli males upon recruitment to mandatory military service during 1994-2004. Associations between socioeconomic and smoking variables and the seroprevalence of EBV/CMV were evaluated, controlling for possible confounders. A subset of seronegative subjects was assessed for seroconversion upon discharge from military service. Overall seroprevalence rates were 87% for EBV and 59% for CMV. An association between the seroprevalence of EBV and CMV was observed. Seroconversion was 56% for EBV as compared with 31% for CMV. Lower paternal education was found to be associated with both EBV and CMV seroprevalence. Lower socioeconomic status, North African origin, and urban residence were found to be associated with CMV seropositivity, as was smoking for EBV seropositivity. Socioeconomic disparities exist in the seroprevalence rates of CMV and EBV among Israeli male young adults. The results of the study could aid public health efforts and determine target populations when a vaccine becomes available. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Dynamics of Epstein-Barr virus DNA levels in serum during EBV-associated disease.

    PubMed

    Berger, C; Day, P; Meier, G; Zingg, W; Bossart, W; Nadal, D

    2001-08-01

    A real-time polymerase chain reaction assay for quantitation of Epstein-Barr virus (EBV) DNA in serum was developed. This assay detected EBV DNA in 24 (89%) of 27 sera from patients with infectious mononucleosis, but only in 9 (18%) of 51 sera from EBV carriers (P < 0.001) and in none of the sera from 32 EBV-seronegative individuals. EBV DNA levels were higher in sera from infectious mononucleosis (median 8,000, range 1833-150,069 copies/ml) than from carriers (median < 2, range < 2-2980; P < 0.001). In sera of 36 children with infectious mononucleosis followed prospectively, EBV DNA levels correlated inversely with the duration of symptoms. Among 18 children with tumors including Hodgkin's disease (n = 7), non-Hodgkin's lymphoma (n = 6), Burkitt's lymphoma (n = 1), lymphoproliferative disorder (n = 4), and osteosarcoma (n = 1), EBV DNA was detected in serum from those 9 (100%) expressing EBV in the tumor (Hodgkin's disease, 3; non-Hodgkin's lymphoma, 2; lymphoproliferative disorder, 4), the levels peaking at diagnosis and correlating with disease activity. Quantitation of EBV DNA in serum may offer a simple means of monitoring patients at risk of EBV-associated lymphoproliferation. Copyright 2001 Wiley-Liss, Inc.

  16. Coinfection by multiple strains of Epstein-Barr virus in infectious mononucleosis in immunocompetent patients.

    PubMed

    Plaza, Guillermo; Santón, Almundena; Bellas, Carment

    2003-05-01

    A molecular study of Epstein-Barr virus (EBV)-induced infectious mononucleosis (IM) was performed. The presence of a 30-bp deletion on the latent membrane protein-1 (LMP-1) oncogene from EBV in Caucasian IM patients was evaluated. Peripheral blood mononuclear cells were obtained from 27 IM patients and 18 adenoids, 28 tonsils and 16 EBV-related reactive lymphadenitis specimens were used as controls. DNA isolation, EBV polymerase chain reaction (PCR) and LMP-1 oncogene PCR analysis were performed. The 30-bp deletion on LMP-1 was identified in 29.6% of IM patients, but was always seen in conjunction with full-length LMP-1. Although the LMP-1-deleted strain seemed to be more prevalent in IM (29.6%) and EBV-related reactive lymphadenitis (37.5%,) than in adenoid (0%) or tonsil specimens (21.4%), these differences were not significant (p > 0.05; chi2). Thus, a 30-bp deletion on LMP-1 was present in almost a third of Caucasian IM patients. The finding of coinfections in IM patients confirms that primary infection by more than one EBV strain is possible.

  17. Strict lymphotropism of Epstein-Barr virus during acute infectious mononucleosis in nonimmunocompromised individuals.

    PubMed

    Karajannis, M A; Hummel, M; Anagnostopoulos, I; Stein, H

    1997-04-15

    Previous investigations of exfoliated oropharyngeal cells from individuals suffering from infectious mononucleosis (IM) suggested that the oropharyngeal epithelia are the primary target and also the site of life-long persistence of the Epstein-Barr virus (EBV). This concept was widely accepted. However, the investigation of histological sections with more sensitive EBV detection techniques has drawn this concept into doubt since EBV proved to be constantly absent in normal epithelial cells. To elucidate the discrepancy, throat washings and peripheral mononuclear blood cells from 16 patients suffering from IM were investigated for EBV-DNA and EBV gene products employing highly sensitive in situ hybridization, immunocytochemistry, and polymerase chain reaction. Although all patients exhibited latently infected B lymphocytes in peripheral blood, samples of exfoliated oropharyngeal cells were constantly EBV-negative with the exception of three cases. In these cases, the patients additionally suffered from purulent ulcerating tonsillitis, EBV-infected B cells, but no EBV-infected epithelial cells were detectable. These findings support the view that recirculating lymphocytes of B-cell origin, but not epithelial cells are the initial target of EBV during primary infection and that B cells also represent the site of life-long viral persistence.

  18. Impaired Cytokine Responses to Epstein-Barr Virus Antigens in Systemic Lupus Erythematosus Patients

    PubMed Central

    Draborg, Anette Holck; Sandhu, Noreen; Larsen, Nanna; Lisander Larsen, Janni; Jacobsen, Søren; Houen, Gunnar

    2016-01-01

    We analyzed cytokine responses against latent and lytic Epstein-Barr virus (EBV) antigens in systemic lupus erythematosus (SLE) patients and healthy controls (HCs) to obtain an overview of the distinctive immune regulatory response in SLE patients and to expand the previously determined impaired EBV-directed T-cell response. The concentrations of 14 cytokines (IL2, IL4, IL5, IL6, IL10, IL12, IL17, IL18, IL1β, IFNγ, TNFα, TNFβ, TGFβ, and GM-CSF) were quantified upon stimulation of whole blood with latent state antigen EBNA1, lytic cycle antigen EBV-EA/D, and the superantigen SEB. To avoid results affected by lack of lymphocytes, we focused on SLE patients with normal levels. Decreased induction of IL12, IFNγ, IL17, and IL6 upon EBNA1 stimulation and that of IFNγ, IL6, TNFβ, IL1β, and GM-CSF upon EBV-EA/D stimulation were detected in SLE patients compared to HCs. IFNγ responses, especially, were shown to be reduced. Induction of several cytokines was furthermore impaired in SLE patients upon SEB stimulation, but no difference was observed in basic levels. Results substantiate the previously proposed impaired regulation of the immune response against latent and lytic cycle EBV infection in SLE patients without lymphopenia. Furthermore, results indicate general dysfunction of leukocytes and their cytokine regulations in SLE patients. PMID:27110576

  19. The need and challenges for development of an Epstein-Barr virus vaccine

    PubMed Central

    Cohen, Jeffrey I.; Mocarski, Edward S.; Raab-Traub, Nancy; Corey, Lawrence; Nabel, Gary J.

    2012-01-01

    Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with several malignancies including nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and lymphoma after organ or stem cell transplant. A candidate vaccine containing soluble EBV glycoprotein gp350 protected cottontop tamarins from EBV lymphoma after challenge with EBV. In the only phase 2 trial of an EBV vaccine in humans, soluble gp350 in alum and monophosphoryl lipid A adjuvant reduced the rate of infectious mononucleosis in EBV seronegative adults, but did not affect the rate of EBV infection. A peptide vaccine corresponding to EBV latency proteins has been tested in a small number of adults to prevent infectious mononucleosis. Some of the barriers to development of an EBV vaccine include (a) whether additional viral proteins in addition to gp350 would be more effective for preventing mononucleosis or EBV malignancies, (b) the difficulty of performing clinical trials to prevent EBV associated malignancies in the absence of good surrogate markers for tumor development, and the long period of time between primary EBV infection and development of many EBV tumors, (c) the lack of knowledge of immune correlates for protection against EBV infection and disease, (d) the limitations in animal models to study protection against EBV infection and disease, and (e) the need for additional information on the economic and societal burden of infectious mononucleosis to assess the cost-benefit of a prophylactic vaccine. PMID:23598481

  20. Epstein-Barr virus and its association with rheumatoid arthritis and oral lichen planus.

    PubMed

    Adtani, Pooja; Malathi, Narasimhan

    2015-01-01

    Pathogenesis of autoimmune diseases (AD) is one of a multifactorial milieu. A genetic predisposition, an immune system failure, hormonal imbalance and environmental factors play important roles. Among the many environmental factors, the role of infection is gaining importance in the pathogenesis of various autoimmune disorders; among them, Epstein-Barr virus (EBV) plays a pivotal role. Literature states an association of various AD with EBV namely multiple sclerosis, autoimmune thyroiditis, systemic lupus erythematous, oral lichen planus (OLP), rheumatoid arthritis (RA), autoimmune hepatitis, Sjögren's syndrome and Kawasaki disease; among these, the most commonly occurring are OLP and RA. Considering the frequency of occurrences, our aim was to perform a qualitative analysis of EBV viral capsid antigen (EBV VCA) IgG in the sera of patients with RA, OLP and establish a comparison with normal. In-vitro experiment in a research laboratory. Five-milliliter blood sample was collected from 25 patients diagnosed with RA and OLP. Serum was separated and EBV VCA IgG antibody titer was detected using NovaTec EBV VCA IgG ELISA kit. Chi-square test. Six out of 25 subjects with RA and 4 out of 25 subjects with OLP tested positive for EBV VCA IgG. Both environmental and genetic factors are important contributory components for autoimmune conditions. Screening for viral etiology would improve the efficacy of conventional treatment and reduce the risk of relapses.

  1. The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis

    PubMed Central

    Pender, Michael P.

    2011-01-01

    There is increasing evidence that infection with the Epstein-Barr virus (EBV) plays a role in the development of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS. This article provides a four-tier hypothesis proposing (1) EBV infection is essential for the development of MS; (2) EBV causes MS in genetically susceptible individuals by infecting autoreactive B cells, which seed the CNS where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells that would otherwise die in the CNS by apoptosis; (3) the susceptibility to develop MS after EBV infection is dependent on a genetically determined quantitative deficiency of the cytotoxic CD8+ T cells that normally keep EBV infection under tight control; and (4) sunlight and vitamin D protect against MS by increasing the number of CD8+ T cells available to control EBV infection. The hypothesis makes predictions that can be tested, including the prevention and successful treatment of MS by controlling EBV infection. PMID:21075971

  2. Immune responses to Epstein-Barr virus in individuals with systemic and organ specific autoimmune disorders.

    PubMed

    Kannangai, R; Sachithanandham, J; Kandathil, A J; Ebenezer, D L; Danda, D; Vasuki, Z; Thomas, N; Vasan, S K; Sridharan, G

    2010-01-01

    Autoimmune diseases usually manifest in genetically predisposed individuals following an environmental trigger. There are several viral infections including Epstein-Barr virus (EBV) implicated in the pathogenesis of autoimmune disorders. The aim of this study was to look at the antibody pattern to EBV proteins in the plasma of both systemic and organ specific autoimmune disorders, estimate pro-inflammatory plasma cytokines (IL-8 and TNF-alpha) among these autoimmune patients and compare the observations with those in normal healthy controls. Samples from 44 rheumatoid arthritis patients, 25 Hashimoto's thyroiditis patients, appropriately age and sex matched healthy controls were tested for EBV IgM antibodies by an immunoblot assay and two cytokines (IL-8 and TNF-alpha) by commercial assays. Among the rheumatoid arthritis patients, 23 (52%) were positive for EBNA1 antibody, while 13 (52%) of the Hashimoto's thyroiditis patients and 12 (30%) of the healthy controls showed similar bands. The intensity of the bands was high in the autoimmune patients when compared to the bands seen in control samples. The difference in the EBNA1 reactivity between rheumatoid arthritis patients and controls were significant (P = 0.038). There was a significant difference in the IgM reactivity to VCAp19 protein between patients and controls (P = 0.011). Our study showed an increased EBV activation among the autoimmune patient groups compared to the normal healthy controls. Further studies are required to delineate the association between the aetiology of autoimmune disorders and EBV.

  3. Antibodies to a strain-specific citrullinated Epstein-Barr virus peptide diagnoses rheumatoid arthritis.

    PubMed

    Trier, Nicole Hartwig; Holm, Bettina Eide; Heiden, Julie; Slot, Ole; Locht, Henning; Lindegaard, Hanne; Svendsen, Anders; Nielsen, Christoffer Tandrup; Jacobsen, Søren; Theander, Elke; Houen, Gunnar

    2018-02-27

    Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Anti-citrullinated protein antibodies (ACPA) are crucial for the serological diagnosis of RA, where Epstein-Barr virus (EBV) has been suggested to be an environmental agent in triggering the onset of the disease. This study aimed to analyse antibody reactivity to citrullinated EBV nuclear antigen-2 (EBNA-2) peptides from three different EBV strains (B95-8, GD1 and AG876) using streptavidin capture enzyme-linked immunosorbent assay. One peptide, only found in a single strain (AG876), obtained a sensitivity and specificity of 77% and 95%, respectively and showed high sequence similarity to the filaggrin peptide originally used for ACPA detection. Comparison of antibody reactivity to commercial assays found that the citrullinated peptide was as effective in detecting ACPA as highly sensitive and specific commercial assays. The data presented demonstrate that the citrullinated EBNA-2 peptide indeed is recognised specifically by RA sera and that the single peptide is able to compete with assays containing multiple peptides. Furthermore, it could be hypothesized that RA may be caused by (a) specific strain(s) of EBV.

  4. Epstein-Barr Virus as a Trigger of Autoimmune Liver Diseases

    PubMed Central

    Rigopoulou, Eirini I.; Smyk, Daniel S.; Matthews, Claire E.; Billinis, Charalambos; Burroughs, Andrew K.; Lenzi, Marco; Bogdanos, Dimitrios P.

    2012-01-01

    The pathogenesis of autoimmune diseases includes a combination of genetic factors and environmental exposures including infectious agents. Infectious triggers are commonly indicated as being involved in the induction of autoimmune disease, with Epstein-Barr virus (EBV) being implicated in several autoimmune disorders. EBV is appealing in the pathogenesis of autoimmune disease, due to its high prevalence worldwide, its persistency throughout life in the host's B lymphocytes, and its ability to alter the host's immune response and to inhibit apoptosis. However, the evidence in support of EBV in the pathogenesis varies among diseases. Autoimmune liver diseases (AiLDs), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), have a potential causative link with EBV. The data surrounding EBV and AiLD are scarce. The lack of evidence surrounding EBV in AiLD may also be reflective of the rarity of these conditions. EBV infection has also been linked to other autoimmune conditions, which are often found to be concomitant with AiLD. This paper will critically examine the literature surrounding the link between EBV infection and AiLD development. The current evidence is far from being conclusive of the theory of a link between EBV and AiLD. PMID:22693505

  5. Autoimmune lymphoproliferative syndrome mimicking chronic active Epstein-Barr virus infection.

    PubMed

    Nomura, Keiko; Kanegane, Hirokazu; Otsubo, Keisuke; Wakiguchi, Hiroshi; Noda, Yukihiro; Kasahara, Yoshihito; Miyawaki, Toshio

    2011-06-01

    Chronic active Epstein-Barr virus infection (CAEBV) is defined as a systemic EBV-associated lymphoproliferative disease characterized by fever, lymphadenopathy, and splenomegaly in apparently immunocompetent persons. Recent studies have revealed that EBV infects T or natural killer cells in most patients with CAEBV; the etiology of CAEBV, however, remains unknown. Autoimmune lymphoproliferative disorder (ALPS) is an inherited disorder associated with defects in apoptosis, and clinically characterized by lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune disease. ALPS is most often associated with mutations in the FAS gene, which is an apoptosis-signaling receptor important for homeostasis of the immune system. Based on the clinical similarity between ALPS and CAEBV with respect to lymphoproliferation, we have examined the possibility of the co-occurrence of ALPS in patients with a diagnosis of CAEBV. In this study, we have identified FAS gene mutations in three Japanese patients with lymphadenopathy, hepatosplenomegaly, and unusual EBV infection, who were diagnosed with CAEBV. These observations, which indicate that the clinical development of ALPS may be associated with EBV infection, alert us to a potential diagnostic pitfall of CAEBV.

  6. Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications.

    PubMed

    Kleinschmidt-DeMasters, B K; Damek, Denise M; Lillehei, Kevin O; Dogan, Ahmed; Giannini, Caterina

    2008-11-01

    Unlike primary central nervous system lymphomas (PCNSLs) in patients with AIDS or organ transplants, PCNSLs in the elderly are usually not considered to be mediated by Epstein Barr virus (EBV); hence, diagnostic studies for EBV are not routinely performed. We encountered 4 patients, 65 years or older, who developed EBV-associated PCNSLs and who had been treated with a variety of immunosuppressive drugs for different autoimmune/collagen vascular disorders, including autoimmune polyneuropathy (mycophenolate mofetil for 5 years), polymyositis (prednisone for 16 years with intermittent methotrexate, azathioprine, and cyclophosphamide), myasthenia gravis (azathioprine >10 years), and rheumatoid arthritis (methotrexate >10 years). All patients had multifocal, necrotic brain lesions typical of EBV-positive PCNSLs on neuroimaging. Withdrawing immunosuppressives lead to PCNSL regression in some patients. The patient who had received mycophenolate mofetil was treated successfully for his EBV-associated PCNSL with rituximab and methotrexate, but later developed fatal systemic malignant melanoma, which was likely immunosuppression related. The striking feature of these cases is the variety of underlying diseases-and hence accompanying medications-that can be associated with EBV-associated PCNSLs. They serve as a diagnostic alert for neuropathologists and suggest that increased testing of PCNSLs for EBV by immunohistochemistry or in situ hybridization may be warranted in any patient on any immunosuppressive medication, but particularly the elderly.

  7. The Role of Epigenetic Regulation in Epstein-Barr Virus-Associated Gastric Cancer.

    PubMed

    Nishikawa, Jun; Iizasa, Hisashi; Yoshiyama, Hironori; Nakamura, Munetaka; Saito, Mari; Sasaki, Sho; Shimokuri, Kanami; Yanagihara, Masashi; Sakai, Kouhei; Suehiro, Yutaka; Yamasaki, Takahiro; Sakaida, Isao

    2017-07-25

    The Epstein-Barr virus (EBV) is detected in about 10% of gastric carcinoma cases throughout the world. In EBV-associated gastric carcinoma (EBVaGC), all tumor cells harbor the clonal EBV genome. The expression of latent EBV genes is strictly regulated through the methylation of EBV DNA. The methylation of viral DNA regulates the type of EBV latency, and methylation of the tumor suppressor genes is a key abnormality in EBVaGC. The methylation frequencies of several tumor suppressor genes and cell adhesion molecules are significantly higher in EBVaGC than in control cases. EBV-derived microRNAs repress translation from viral and host mRNAs. EBV regulates the expression of non-coding RNA in gastric carcinoma. With regard to the clinical application of demethylating agents against EBVaGC, we investigated the effects of decitabine against the EBVaGC cell lines. Decitabine inhibited the cell growth of EBVaGC cells. The promoter regions of p73 and Runt-related transcription factor 3(RUNX3) were demethylated, and their expression was upregulated by the treatment. We review the role of epigenetic regulation in the development and maintenance of EBVaGC and discuss the therapeutic application of DNA demethylating agents for EBVaGC.

  8. Epstein-Barr Virus Type 2 Infects T Cells in Healthy Kenyan Children.

    PubMed

    Coleman, Carrie B; Daud, Ibrahim I; Ogolla, Sidney O; Ritchie, Julie A; Smith, Nicholas A; Sumba, Peter O; Dent, Arlene E; Rochford, Rosemary

    2017-09-15

    The 2 strains of Epstein-Barr virus (EBV), EBV type 1 (EBV-1) and EBV-2, differ in latency genes, suggesting that they use distinct mechanisms to establish latency. We previously reported that EBV-2 infects T cells in vitro. In this study, we tested the possibility that EBV-2 infects T cells in vivo. Purified T-cell fractions isolated from children positive for EBV-1 or EBV-2 and their mothers were examined for the presence of EBV and for EBV type. We detected EBV-2 in all T-cell samples obtained from EBV-2-infected children at 12 months of age, with some children retaining EBV-2-positive T cells through 24 months of age, suggesting that EBV-2 persists in T cells. We were unable to detect EBV-2 in T-cell samples from mothers but could detect EBV-2 in samples of their breast milk and saliva. These data suggest that EBV-2 uses T cells as an additional latency reservoir but that, over time, the frequency of infected T cells may drop below detectable levels. Alternatively, EBV-2 may establish a prolonged transient infection in the T-cell compartment. Collectively, these novel findings demonstrate that EBV-2 infects T cells in vivo and suggest EBV-2 may use the T-cell compartment to establish latency. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  9. Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma

    PubMed Central

    Chang, Ellen T.; Ambinder, Richard F.; Lennette, Evelyne T.; Rubertone, Mark V.; Mann, Risa B.; Borowitz, Michael; Weir, Edward G.; Abbondanzo, Susan L.; Mueller, Nancy E.

    2012-01-01

    An altered anti–Epstein-Barr virus (EBV) serologic profile preceding diagnosis is associated with an increased risk of Hodgkin lymphoma. It is unknown whether this atypical pattern predicts Hodgkin lymphoma risk further subdivided by determination of EBV in tumor cells. A nested case-control study of 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty military personnel with archived serum in the US Department of Defense Serum Repository was conducted to determine whether a panel of anti-EBV antibody titers differed in EBV+ and EBV− Hodgkin lymphoma. Among 40 EBV+ Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti–EBNA-1/anti–EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8). In contrast, no significant associations were found among 88 EBV− Hodgkin lymphoma cases relative to their matched controls. In case-case analysis, EBV+ disease was significantly associated with a low anti–EBNA-1/anti–EBNA-2 antibody ratio. This distinc-tive serologic response to EBV latent antigens, indicative of immune dysfunction in other clinical settings, is associated with an increased risk of developing EBV+ but not EBV− Hodgkin lymphoma. PMID:22972983

  10. Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells.

    PubMed Central

    Herbst, H; Dallenbach, F; Hummel, M; Niedobitek, G; Pileri, S; Müller-Lantzsch, N; Stein, H

    1991-01-01

    Cryostat sections from lymph nodes of 47 Hodgkin disease patients were examined by immunohistology for the Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP), nuclear antigen 2, and late viral glycoprotein gp350/250. A distinct LMP-specific membrane and cytoplasmic staining was detected exclusively in Hodgkin and Reed-Sternberg cells in 18 patients (38%); EBV nuclear antigen 2 and gp350/250 immunoreactivity was absent in all instances. Thirty-two of 47 (68%) cases contained EBV-specific DNA sequences as detected by PCR, all LMP-positive cases being in this category. Our results confirm previous studies establishing the presence of EBV genomes in Hodgkin and Reed-Sternberg cells by demonstrating expression of an EBV-encoded protein in the tumor-cell population. The finding of LMP expression in the absence of EBV nuclear antigen 2 suggests a pattern of EBV gene expression different from that of B-lymphoblastoid cell lines and Burkitt lymphoma, whereas this finding shows similarities with that seen in undifferentiated nasopharyngeal carcinoma. Because the LMP gene has transforming potential, our findings support the concept of a pathoetiological role of EBV in many cases of Hodgkin disease. Images PMID:1647016

  11. Malaria, Epstein-Barr virus infection and the pathogenesis of Burkitt's lymphoma.

    PubMed

    Mawson, Anthony R; Majumdar, Suvankar

    2017-11-01

    A geographical and causal connection has long been recognized between malaria, Epstein-Barr virus (EBV) infection and Burkitt's lymphoma (BL), but the underlying mechanisms remain obscure. Potential clues are that the malaria parasite Plasmodium falciparum selectively absorbs vitamin A from the host and depends on it for its biological activities; secondly, alterations in vitamin A (retinoid) metabolism have been implicated in many forms of cancer, including BL. The first author has proposed that the merozoite-stage malaria parasite, emerging from the liver, uses its absorbed vitamin A as a cell membrane destabilizer to invade the red blood cells, causing anemia and other signs and symptoms of the disease as manifestations of an endogenous form of hypervitaminosis A (Mawson AR, Path Global Health 2013;107(3):122-9). Repeated episodes of malaria would therefore be expected to expose the tissues of affected individuals to potentially toxic doses of vitamin A. It is proposed that such episodes activate latent EBV infection, which in turn activates retinoid-responsive genes. Expression of these genes enhances viral replication and induces germinal center (GC) B cell expansion, activation-induced cytidine deaminase (AID) expression, and c-myc translocation, which in turn predisposes to BL. Thus, an endogenous form of retinoid toxicity related to malaria infection may be the common factor linking frequent malaria, EBV infection and BL, whereby prolonged exposure of lymphatic tissues to high concentrations of retinoids may combine to induce B-cell translocation and increase the risk of Burkitt's lymphoma. © 2017 UICC.

  12. Epstein-barr virus DNAemia monitoring for the management of post-transplant lymphoproliferative disorder.

    PubMed

    Kalra, Amit; Roessner, Cameron; Jupp, Jennifer; Williamson, Tyler; Tellier, Raymond; Chaudhry, Ahsan; Khan, Faisal; Taparia, Minakshi; Jimenez-Zepeda, Victor H; Stewart, Douglas A; Daly, Andrew; Storek, Jan

    2018-05-01

    Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation (HCT). Epstein-Barr virus (EBV) reactivation (detectable DNAemia) predisposes to the development of PTLD. We retrospectively studied 306 patients monitored for EBV DNAemia after Thymoglobulin-conditioned HCT to determine the utility of the monitoring in the management of PTLD. DNAemia was monitored weekly for ≥12 weeks post-transplantation. Reactivation was detected in 82% of patients. PTLD occurred in 14% of the total patients (17% of patients with reactivation). PTLD was treated with rituximab only when and if the diagnosis was established. This allowed us to evaluate potential DNAemia thresholds for pre-emptive therapy. We suggest 100,000-500,000 IU per mL whole blood as this would result in unnecessary rituximab administration to only 4-20% of patients and near zero mortality due to PTLD. After starting rituximab (for diagnosed PTLD), sustained regression of PTLD occurred in 25/25 (100%) patients in whom DNAemia became undetectable. PTLD progressed or relapsed in 12/17 (71%) patients in whom DNAemia was persistently detectable. In conclusion, for pre-emptive therapy of PTLD, we suggest threshold DNAemia of 100,000-500,000 IU/mL. Persistently detectable DNAemia after PTLD treatment with rituximab appears to have 71% positive predictive value and 100% negative predictive value for PTLD progression/relapse. Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  13. Transient immune deficiency in patients with acute Epstein-Barr virus infection.

    PubMed

    Junker, A K; Ochs, H D; Clark, E A; Puterman, M L; Wedgwood, R J

    1986-09-01

    To study the effect of primary Epstein-Barr virus (EBV) infection on antigen-specific antibody production, we immunized 17 college students who had developed acute infectious mononucleosis with the T-cell dependent neoantigen bacteriophage phi X174. During the early phase of infectious mononucleosis, the proportion of peripheral blood lymphocytes displaying Ia and T8 (CD8) phenotypes was increased and the T helper/suppressor (T4/T8) ratio was decreased (less than 1). These abnormalities disappeared during the convalescent phase. Correlating with EBV-induced changes in T lymphocytes, we demonstrated depressed humoral immune responses to bacteriophage phi X174 both in vivo and in vitro. In vitro coculture experiments indicated that the Ia+ suppressor T cells could inhibit antibody production and isotype switch. Removal of T8+ lymphocytes from patient T cells normalized in vitro antibody synthesis. In addition, impaired B-cell function was shown to be in part responsible for deficient antibody production. These studies demonstrate that infection with EBV affects both B and T lymphocytes and causes a broad-based transient immune deficiency in patients with uncomplicated infectious mononucleosis.

  14. Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients.

    PubMed

    Kim, Kelly Y; Le, Quynh-Thu; Yom, Sue S; Ng, Raymond H W; Chan, K C Allen; Bratman, Scott V; Welch, John J; Divi, Rao L; Petryshyn, Raymond A; Conley, Barbara A

    2017-08-01

    Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion. Published by Elsevier Inc.

  15. Diagnosis of infectious mononucleosis caused by Epstein-Barr virus in infants.

    PubMed

    Dohno, Sumitaka; Maeda, Akihiko; Ishiura, Yoshihito; Sato, Tetsuya; Fujieda, Mikiya; Wakiguchi, Hiroshi

    2010-08-01

    The diagnosis of infectious mononucleosis (IM) is usually on serologic tests. The responses of anti-Epstein-Barr virus (anti-EBV) antibodies are weak in infants. The authors encountered some IM infants in whom anti-EBV antibodies were undetectable during early stage, although EBV genome was found in their blood. The aim of the present study was therefore to clarify the frequency of anti-EBV-antibody negative IM cases. The EBV serostatus of 104 IM children diagnosed on Sumaya criteria was retrospectively studied. The EBV genome in peripheral blood mononuclear cells was measured. The anti-viral capsid antigen-IgM (anti-VCA-IgM)-positive rate in the acute phase was only 25% in infants but 80% in patients ≥ 4 years of age. Twenty percent of the infants were negative for all anti-EBV antibodies and required repeated serologic tests. For infants, the significant rise in anti-VCA-IgG was the most sensitive marker. Three seronegative infants with IM symptoms, with circulating EBV genome during acute phase, were eventually considered as having IM on anti-VCA-IgG seroconversion thereafter. To diagnose IM in infants the serologic test alone in the acute phase is not sensitive enough. It is proposed that the EBV genome be evaluated in peripheral blood mononuclear cells when infants presenting with IM symptoms are negative for anti-EBV antibodies during the acute phase. © 2010 Japan Pediatric Society.

  16. Valacyclovir pharmacokinetics and exploratory pharmacodynamics in young adults with Epstein-Barr virus infectious mononucleosis.

    PubMed

    Vezina, Heather E; Balfour, Henry H; Weller, Dennis R; Anderson, Bruce J; Brundage, Richard C

    2010-07-01

    Primary Epstein-Barr virus (EBV) infection often results in infectious mononucleosis and is associated with serious sequelae. No treatment is approved for EBV infection, and an antiviral intervention would be significant. The objectives of this study are to characterize the pharmacokinetics and explore the pharmacodynamics of acyclovir in plasma and oral washings of 8 subjects receiving 7 days of valacyclovir 1500 mg twice daily for EBV infectious mononucleosis. Virologic and clinical responses are assessed over 12 days. Acyclovir is measured by liquid chromatography/ultraviolet detection. EBV DNA is quantitated by TaqMan polymerase chain reaction. NONMEM VI and linear regression are used for data analysis. Acyclovir profiles in plasma and oral washings are consistent with a 1-compartment model. Final model estimates of clearance, volume of distribution, and fraction of acyclovir in oral wash supernatant are 49.9 L/h, 74.1 L, and 1.14%, respectively. The quantity of EBV DNA in oral washings and blood, and the severity of illness, measured by a graded scale, decrease during treatment. After treatment, viral rebound occurs in oral washings but not in blood, and the severity of illness continues to decline. Acyclovir pharmacokinetic parameters do not correlate with response metrics. These results support further studies of valacyclovir for EBV infectious mononucleosis.

  17. [Potential role of the Epstein-Barr virus in the pathogenesis of systemic lupus erythematosus and kidney diseases].

    PubMed

    Roszkowiak, Bogna; Niemir, Zofia I

    2004-01-01

    Epstein-Barr virus (EBV) is mainly regarded as a tumorigenic agent widely distributed in the adult population. Recent results also indicate its potential role in systemic autoimmune diseases as well as in renal disorders. This is thought to be due to the virus's capacity to invade B cells and change from the lytic linear form to the circular latent one, which allows restriction in its gene expression array. In this way the virus avoids recognition by CD4+ and CD8+ cells and escapes immunological control. Defective control of lytic and/or latent EBV infection may contribute to the development of systemic or renal pathology.

  18. Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes

    SciTech Connect

    Klein, George, E-mail: Georg.Klein@ki.se; Klein, Eva; Kashuba, Elena

    Epstein-Barr virus, EBV, and humans have a common history that reaches back to our primate ancestors. The virus co-evolved with man and has established a largely harmless and highly complex co-existence. It is carried as silent infection by almost all human adults. A serendipitous discovery established that it is the causative agent of infectious mononucleosis. Still, EBV became known first in 1964, in a rare, geographically prevalent malignant lymphoma of B-cell origin, Burkitt lymphoma BL. Its association with a malignancy prompted intensive studies and its capacity to immortalize B-lymphocytes in vitro was soon demonstrated. Consequently EBV was classified therefore asmore » a potentially tumorigenic virus. Despite of this property however, the virus carrier state itself does not lead to malignancies because the transformed cells are recognized by the immune response. Consequently the EBV induced proliferation of EBV carrying B-lymphocytes is manifested only under immunosuppressive conditions. The expression of EBV encoded genes is regulated by the cell phenotype. The virus genome can be found in malignancies originating from cell types other than the B-lymphocyte. Even in the EBV infected B-cell, the direct transforming capacity is restricted to a defined window of differentiation. A complex interaction between virally encoded proteins and B-cell specific cellular proteins constitute the proliferation inducing program. In this short review we touch upon aspects which are the subject of our present work. We describe the mechanisms of some of the functional interactions between EBV encoded and cellular proteins that determine the phenotype of latently infected B-cells. The growth promoting EBV encoded genes are not expressed in the virus carrying BL cells. Still, EBV seems to contribute to the etiology of this tumor by modifying events that influence cell survival and proliferation. We describe a possible growth promoting mechanism in the genesis of Burkitt

  19. No association between Epstein-Barr Virus and Mouse Mammary Tumor Virus with Breast Cancer in Mexican Women

    NASA Astrophysics Data System (ADS)

    Morales-Sánchez, Abigail; Molina-Muñoz, Tzindilú; Martínez-López, Juan L. E.; Hernández-Sancén, Paulina; Mantilla, Alejandra; Leal, Yelda A.; Torres, Javier; Fuentes-Pananá, Ezequiel M.

    2013-10-01

    Breast cancer is the most frequent malignancy affecting women worldwide. It has been suggested that infection by Epstein Barr Virus (EBV), Mouse Mammary Tumor Virus or a similar virus, MMTV-like virus (MMTV-LV), play a role in the etiology of the disease. However, studies looking at the presence of these viruses in breast cancer have produced conflicting results, and this possible association remains controversial. Here, we used polymerase chain reaction assay to screen specific sequences of EBV and MMTV-LV in 86 tumor and 65 adjacent tissues from Mexican women with breast cancer. Neither tumor samples nor adjacent tissue were positive for either virus in a first round PCR and only 4 tumor samples were EBV positive by a more sensitive nested PCR. Considering the study's statistical power, these results do not support the involvement of EBV and MMTV-LV in the etiology of breast cancer.

  20. CRISPR/Cas9-mediated genome editing of Epstein-Barr virus in human cells.

    PubMed

    Yuen, Kit-San; Chan, Chi-Ping; Wong, Nok-Hei Mickey; Ho, Chau-Ha; Ho, Ting-Hin; Lei, Ting; Deng, Wen; Tsao, Sai Wah; Chen, Honglin; Kok, Kin-Hang; Jin, Dong-Yan

    2015-03-01

    The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) system is a highly efficient and powerful tool for RNA-guided editing of the cellular genome. Whether CRISPR/Cas9 can also cleave the genome of DNA viruses such as Epstein-Barr virus (EBV), which undergo episomal replication in human cells, remains to be established. Here, we reported on CRISPR/Cas9-mediated editing of the EBV genome in human cells. Two guide RNAs (gRNAs) were used to direct a targeted deletion of 558 bp in the promoter region of BART (BamHI A rightward transcript) which encodes viral microRNAs (miRNAs). Targeted editing was achieved in several human epithelial cell lines latently infected with EBV, including nasopharyngeal carcinoma C666-1 cells. CRISPR/Cas9-mediated editing of the EBV genome was efficient. A recombinant virus with the desired deletion was obtained after puromycin selection of cells expressing Cas9 and gRNAs. No off-target cleavage was found by deep sequencing. The loss of BART miRNA expression and activity was verified, supporting the BART promoter as the major promoter of BART RNA. Although CRISPR/Cas9-mediated editing of the multicopy episome of EBV in infected HEK293 cells was mostly incomplete, viruses could be recovered and introduced into other cells at low m.o.i. Recombinant viruses with an edited genome could be further isolated through single-cell sorting. Finally, a DsRed selectable marker was successfully introduced into the EBV genome during the course of CRISPR/Cas9-mediated editing. Taken together, our work provided not only the first genetic evidence that the BART promoter drives the expression of the BART transcript, but also a new and efficient method for targeted editing of EBV genome in human cells. © 2015 The Authors.

  1. Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation

    PubMed Central

    Lossius, Andreas; Johansen, Jorunn N.; Torkildsen, Øivind; Vartdal, Frode; Holmøy, Trygve

    2012-01-01

    Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if so, by which mechanisms the virus may contribute. In this review, we discuss possible viral and immunological mechanisms that might explain associations between EBV and autoimmune diseases and whether these associations represent causes or effects of inflammation and autoimmunity. PMID:23342374

  2. Humoral markers of active Epstein-Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus.

    PubMed

    Rasmussen, N S; Nielsen, C T; Houen, G; Jacobsen, S

    2016-12-01

    We investigated if signs of active Epstein-Barr virus and cytomegalovirus infections associate with certain autoantibodies and a marker of type I interferon activity in patients with systemic lupus erythematosus. IgM and IgG plasma levels against Epstein-Barr virus early antigen diffuse and cytomegalovirus pp52 were applied as humoral markers of ongoing/recently active Epstein-Barr virus and cytomegalovirus infections, respectively. Plasma galectin-3 binding protein served as a surrogate marker of type I interferon activity. The measurements were conducted in 57 systemic lupus erythematosus patients and 29 healthy controls using ELISAs. Regression analyses and univariate comparisons were performed for associative evaluation between virus serology, plasma galectin-3 binding protein and autoantibodies, along with other clinical and demographic parameters. Plasma galectin-3 binding protein concentrations were significantly higher in systemic lupus erythematosus patients (P = 0.009) and associated positively with Epstein-Barr virus early antigen diffuse-directed antibodies and the presence of autoantibodies against extractable nuclear antigens in adjusted linear regressions (B = 2.02 and 2.02, P = 0.02 and P = 0.002, respectively). Furthermore, systemic lupus erythematosus patients with anti-extractable nuclear antigens had significantly higher antibody levels against Epstein-Barr virus early antigen diffuse (P = 0.02). Our study supports a link between active Epstein-Barr virus infections, positivity for anti-extractable nuclear antigens and increased plasma galectin-3 binding protein concentrations/type I interferon activity in systemic lupus erythematosus patients. © The Author(s) 2016.

  3. Compartmentalization and Transmission of Multiple Epstein-Barr Virus Strains in Asymptomatic Carriers

    PubMed Central

    Sitki-Green, Diane; Covington, Mary; Raab-Traub, Nancy

    2003-01-01

    Infection with the Epstein-Barr virus (EBV) is often subclinical in the presence of a healthy immune response; thus, asymptomatic infection is largely uncharacterized. This study analyzed the nature of EBV infection in 20 asymptomatic immunocompetent hosts over time through the identification of EBV strain variants in the peripheral blood and oral cavity. A heteroduplex tracking assay specific for the EBV gene LMP1 precisely identified the presence of multiple EBV strains in each subject. The strains present in the peripheral blood and oral cavity were often completely discordant, indicating the existence of distinct infections, and the strains present and their relative abundance changed considerably between time points. The possible transmission of strains between the oral cavity and peripheral blood compartments could be tracked within subjects, suggesting that reactivation in the oral cavity and subsequent reinfection of B lymphocytes that reenter the periphery contribute to the maintenance of persistence. In addition, distinct virus strains persisted in the oral cavity over many time points, suggesting an important role for epithelial cells in the maintenance of persistence. Asymptomatic individuals without tonsillar tissue, which is believed to be an important source of virus for the oral cavity, also exhibited multiple strains and a cyclic pattern of transmission between compartments. This study revealed that the majority of patients with infectious mononucleosis were infected with multiple strains of EBV that were also compartmentalized, suggesting that primary infection involves the transmission of multiple strains. Both the primary and carrier states of infection with EBV are more complex than previously thought. PMID:12525618

  4. Persistence of Epstein-Barr virus in self-reactive memory B cells.

    PubMed

    Tracy, Sean I; Kakalacheva, Kristina; Lünemann, Jan D; Luzuriaga, Katherine; Middeldorp, Jaap; Thorley-Lawson, David A

    2012-11-01

    Epstein-Barr virus infection has been epidemiologically associated with the development of multiple autoimmune diseases, particularly systemic lupus erythematosus and multiple sclerosis. Currently, there is no known mechanism that can account for these associations. The germinal-center (GC) model of EBV infection and persistence proposes that EBV gains access to the memory B cell compartment via GC reactions by driving infected cells to differentiate using the virus-encoded LMP1 and LMP2a proteins, which act as functional homologues of CD40 and the B cell receptor, respectively. The ability of LMP2a, when expressed in mice, to allow escape of autoreactive B cells suggests that it could perform a similar role in infected GC B cells, permitting the survival of potentially pathogenic autoreactive B cells. To test this hypothesis, we cloned and expressed antibodies from EBV(+) and EBV(-) memory B cells present during acute infection and profiled their self- and polyreactivity. We find that EBV does persist within self- and polyreactive B cells but find no evidence that it favors the survival of pathogenic autoreactive B cells. On the contrary, EBV(+) memory B cells express lower levels of self-reactive and especially polyreactive antibodies than their uninfected counterparts do. Our work suggests that EBV has only a modest effect on the GC process, which allows it to access and persist within a subtly unique niche of the memory compartment characterized by relatively low levels of self- and polyreactivity. We suggest that this might reflect an active process where EBV and its human host have coevolved so as to minimize the virus's potential to contribute to autoimmune disease.

  5. Epstein-Barr virus negative primary hepatic leiomyoma: Case report and literature review

    PubMed Central

    Luo, Xian-Zhang; Ming, Chang-Sheng; Chen, Xiao-Ping; Gong, Nian-Qiao

    2013-01-01

    Primary hepatic leiomyoma is a neoplasm of mesenchymal origin and occurs only rarely. Secondary to benign smooth muscle proliferation, it is usually found in adult women and is associated with Epstein-Barr virus (EBV) infection. Here, we report the 29th case of primary hepatic leiomyoma with its unique features related to diagnosis, treatment and developmental biology. A 48-year-old man, with an immunocompromised status, complained of pain in the upper quadrant of the abdomen. Serological analysis indicated no presence of hepatitis virus, no human immunodeficiency virus, and no EBV infection. The levels of α-fetoprotein and carcinoembryonic antigen were normal. A mass was detected in segment III of the hepatic lobe by ultrasonography and an abdominal computed tomography scan. Endoscopy had negative findings. Exploratory laparotomy found no existing extrahepatic tumor and left lateral lobectomy was performed. Pathological examination showed the mass to be a typical leiomyoma. The cells were positive for α-smooth muscle actin and desmin, and negative for the makers of gastrointestinal stromal tumor (GIST), including CD117, CD34 and DOG1 (discovered on GIST1). In situ hybridization revealed negative status for EBV-encoded small RNA. After left lateral lobectomy, the patient was not given chemotherapy or radiotherapy. During a 2-year follow-up, no sign of local recurrence or distant metastasis was observed. In conclusion, we report a rare case of primary hepatic leiomyoma in a male patient without EBV infection. Hepatic resection was curative. This case presents data to expand our knowledge concerning the complex and heterogeneous nature of primary liver leiomyoma, indicating that EBV infection is important but neither necessary nor sufficient for the development of primary liver leiomyoma. PMID:23840159

  6. Asymptomatic Primary Infection with Epstein-Barr Virus: Observations on Young Adult Cases.

    PubMed

    Abbott, Rachel J; Pachnio, Annette; Pedroza-Pacheco, Isabela; Leese, Alison M; Begum, Jusnara; Long, Heather M; Croom-Carter, Debbie; Stacey, Andrea; Moss, Paul A H; Hislop, Andrew D; Borrow, Persephone; Rickinson, Alan B; Bell, Andrew I

    2017-11-01

    Epstein-Barr virus (EBV) is typically acquired asymptomatically in childhood. In contrast, infection later in life often leads to infectious mononucleosis (IM), a febrile illness characterized by anti-EBV IgM antibody positivity, high loads of circulating latently infected B cells, and a marked lymphocytosis caused by hyperexpansion of EBV-specific CD8 + T cells plus a milder expansion of CD56 dim NKG2A + KIR - natural killer (NK) cells. How the two situations compare is unclear due to the paucity of studies on clinically silent infection. Here we describe five prospectively studied patients with asymptomatic infections identified in a seroepidemiologic survey of university entrants. In each case, the key blood sample had high cell-associated viral loads without a marked CD8 lymphocytosis or NK cell disturbance like those seen in patients during the acute phase of IM. Two of the cases with the highest viral loads showed a coincident expansion of activated EBV-specific CD8 + T cells, but overall CD8 + T cell numbers were either unaffected or only mildly increased. Two cases with slightly lower loads, in whom serology suggests the infection may have been caught earlier in the course of infection, also showed no T or NK cell expansion at the time. Interestingly, in another case with a higher viral load, in which T and NK cell responses were undetectable in the primary blood sample in which infection was detected, EBV-specific T cell responses did not appear until several months later, by which time the viral loads in the blood had already fallen. Thus, some patients with asymptomatic primary infections have very high circulating viral loads similar to those in patients during the acute phase of IM and a cell-mediated immune response that is qualitatively similar to that in IM patients but of a lower magnitude. However, other patients may have quite different immune responses that ultimately could reveal novel mechanisms of host control. IMPORTANCE Epstein-Barr virus

  7. Two rare cases of Epstein-Barr virus-associated lymphoproliferative disorders in inflammatory bowel disease patients on thiopurines and other immunosuppressive medications.

    PubMed

    Subramaniam, K; Cherian, M; Jain, S; Latimer, M; Corbett, M; D'Rozario, J; Pavli, P

    2013-12-01

    The setting of chronic immunosuppression in inflammatory bowel disease (IBD) may promote the proliferation of Epstein-Barr virus-positive neoplastic clones. We report two rare cases of Epstein-Barr virus-associated lymphoproliferative disorder in IBD patients: one resembled lymphomatoid granulomatosis, and the other was a lymphoma resembling Hodgkin lymphoma. There are currently no guidelines for the prevention of lymphoproliferative disorder in IBD patients on immunosuppressive therapy. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  8. Lymphomas in Ile-Ife, Nigeria: Immunohistochemical Characterization and Detection of Epstein-Barr virus Encoded RNA

    PubMed Central

    Onwubuya, Ifeyinwa M.; Adelusola, Kayode A.; Durosinmi, Muheez A.; Ezike, Kevin N.

    2015-01-01

    Background The proper histopathological characterization of malignant lymphomas requires the use of immunohistochemistry along with other molecular pathology techniques. Materials and Methods Malignant lymphomas histologically diagnosed in our hospital were reclassified according to the WHO scheme using immunohistochemistry while in-situ hybridization was performed for the detection of Epstein-Barr virus encoded RNA. Results There were 83 cases of lymphoma. The male to female ratio was 1.9:1 while the overall mean age was 41.7 years. Non-Hodgkin lymphomas (NHL) constituted about 79.5% of cases. The majority of cases (98.8%) were B-cell lymphomas. Nine subtypes of lymphomas were identified with diffuse large B-cell lymphomas (56.4% of which were of the germinal centre type) constituting the largest group (47.0%). Intermediate and high grade subtypes were more common. The majority of cases (72.3%) were nodal lymphomas with cervical lymph node being the commonest site (48.2%). Only classical Hodgkin lymphoma (HL) (20.5%) was seen of which the mixed cellularity subtype was the most common. Epstein Barr virus (EBV) encoded ribonucleic acid was detected in 7 cases (8.4%) including 4 cases of HL, 2 cases of Burkitt lymphoma and the only case of plasmablastic lymphoma. About five cases were reclassified as non-lymphoid malignant lesions. Conclusion Immunohistochemistry is vital to the proper classification of lymphomas even in a resource poor environment. Although nine subtypes of lymphomas were identified, diffuse large B-cell lymphomas formed the largest single group. Epstein-Barr virus probably plays an important role in lymphomatogenesis in this environment. A larger multicentre study is required to prove this. PMID:26266128

  9. Lymphomas in Ile-Ife, Nigeria: Immunohistochemical Characterization and Detection of Epstein-Barr virus Encoded RNA.

    PubMed

    Onwubuya, Ifeyinwa M; Adelusola, Kayode A; Durosinmi, Muheez A; Sabageh, Donatus; Ezike, Kevin N

    2015-06-01

    The proper histopathological characterization of malignant lymphomas requires the use of immunohistochemistry along with other molecular pathology techniques. Malignant lymphomas histologically diagnosed in our hospital were reclassified according to the WHO scheme using immunohistochemistry while in-situ hybridization was performed for the detection of Epstein-Barr virus encoded RNA. There were 83 cases of lymphoma. The male to female ratio was 1.9:1 while the overall mean age was 41.7 years. Non-Hodgkin lymphomas (NHL) constituted about 79.5% of cases. The majority of cases (98.8%) were B-cell lymphomas. Nine subtypes of lymphomas were identified with diffuse large B-cell lymphomas (56.4% of which were of the germinal centre type) constituting the largest group (47.0%). Intermediate and high grade subtypes were more common. The majority of cases (72.3%) were nodal lymphomas with cervical lymph node being the commonest site (48.2%). Only classical Hodgkin lymphoma (HL) (20.5%) was seen of which the mixed cellularity subtype was the most common. Epstein Barr virus (EBV) encoded ribonucleic acid was detected in 7 cases (8.4%) including 4 cases of HL, 2 cases of Burkitt lymphoma and the only case of plasmablastic lymphoma. About five cases were reclassified as non-lymphoid malignant lesions. Immunohistochemistry is vital to the proper classification of lymphomas even in a resource poor environment. Although nine subtypes of lymphomas were identified, diffuse large B-cell lymphomas formed the largest single group. Epstein-Barr virus probably plays an important role in lymphomatogenesis in this environment. A larger multicentre study is required to prove this.

  10. The role of Epstein-Barr virus infection in the development of autoimmune thyroid diseases.

    PubMed

    Janegova, Andrea; Janega, Pavol; Rychly, Boris; Kuracinova, Kristina; Babal, Pavel

    2015-01-01

    Autoimmune thyroid diseases, including Graves' and Hashimoto's thyroiditis, are the most frequent autoimmune disorders. Viral infection, including Epstein-Barr virus (EBV), is one of the most frequently considered environmental factors involved in autoimmunity. Its role in the development of AITD has not been confirmed so far. Surgical specimens of Graves' and Hashimoto's diseases and nodular goitres were included in the study. The expression of EBV latent membrane protein 1 (LMP1) was analysed by immunohistochemistry, with the parallel detection of virus-encoded small nuclear non-polyadenylated RNAs (EBER) by in situ hybridisation. In none of the Graves' disease specimens but in 34.5% of Hashimoto's thyroiditis cases the cytoplasmic expression of LMP1 was detected in follicular epithelial cells and in infiltrating lymphocytes. EBER nuclear expression was detected in 80.7% of Hashimoto's thyroiditis cases and 62.5% of Graves' disease cases, with positive correlation between LMP1 and EBER positivity in all Hashimoto's thyroiditis LMP1-positive cases. We assume that high prevalence of EBV infection in cases of Hashimoto's and Graves' diseases imply a potential aetiological role of EBV in autoimmune thyroiditis. The initiation of autoimmune thyroiditis could start with EBV latency type III infection of follicular epithelium characterised by LMP1 expression involving the production of inflammatory mediators leading to recruitment of lymphocytes. The EBV positivity of the infiltrating lymphocytes could be only the presentation of a carrier state, but in cases with EBER+/ LMP1+ lymphocytes (transforming latent infection) it could represent a negative prognostic marker pointing to a higher risk of primary thyroid lymphoma development.

  11. Epstein-Barr virus in inflammatory bowel disease: the spectrum of intestinal lymphoproliferative disorders.

    PubMed

    Nissen, Loes H C; Nagtegaal, Iris D; de Jong, Dirk J; Kievit, Wietske; Derikx, Lauranne A A P; Groenen, Patricia J T A; van Krieken, J Han J M; Hoentjen, Frank

    2015-05-01

    Inflammatory bowel disease (IBD) patients on thiopurine therapy are at increased risk of Epstein-Barr virus (EBV)-associated lymphomas. This virus is frequently detected in the intestinal mucosa of IBD patients and may cause a wide spectrum of lymphoproliferations similar to post-transplantation lymphoproliferative disorders (PTLDs). We aimed to assess whether histological aberrations aid in predicting EBV presence and to correlate histological assessment and EBV load with disease outcome in IBD. We included all IBD patients from our centre who underwent EBV testing of intestinal biopsies between January 2004 and October 2013. All biopsies were classified according to the WHO PTLD classification and the EBV load was scored per high-power field (HPF). Clinical data were collected from patient charts. Reported clinical outcomes included colectomy, need for chemotherapy and mortality. Our cohort included 58 patients: 28 were EBV-positive and 30 EBV-negative. An atypical infiltrate was seen more frequently in EBV-positive than in EBV-negative patients (57.1 versus 3.3%; p < 0.001). A high EBV load occurred more frequently in EBV-positive patients undergoing colectomy than in EBV-positive patients without colectomy (50.0 versus 10.0%; p = 0.048). Monomorphic lymphoproliferative disorders, including two overt lymphomas, were present in 10 patients. Reduction of immunosuppression resulted in histological normalization and loss of EBV expression in seven of eight non-lymphoma patients. The presence of atypical infiltrate in the intestinal mucosa of IBD patients warrants EBV testing. Reduction of immunosuppression is an effective strategy to achieve morphological normalization and loss of EBV. Lymphoproliferation related to IBD appears to have less aggressive clinical behaviour than PTLDs. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  12. Epstein-Barr Virus Promotes Interferon-α Production by Plasmacytoid Dendritic Cells

    PubMed Central

    Quan, Timothy E.; Roman, Robert M.; Rudenga, Benjamin J.; Holers, V. Michael; Craft, Joe

    2010-01-01

    Objective Epstein-Barr virus (EBV) infection has been linked to systemic lupus erythematosus (SLE) as demonstrated by the presence of increased seroprevalence and elevated viral loads, but the mechanism of this linkage has not been elucidated. Increased IFN-α levels and signatures, associated with innate immune responses, have been found in patients with SLE. Plasmacytoid dendritic cells (pDC) are innate immune cells that mediate viral immunity by producing large quantities of interferon alpha (IFN-α), but the role they play during infection with EBV remains unclear. To address this issue, we investigated the ability of EBV to promote IFN-α production by pDC in healthy subjects. Methods Human pDC were sorted and cultured in the presence of EBV, EBV small RNA (EBER), and EBV double-stranded DNA (dsDNA). IFN-α production by pDC was measured by enzyme-linked immunosorbent assay (ELISA), with activation of these cells measured by flow cytometry. Results We demonstrate that EBV DNA and RNA promote IFN-α production by human pDC through engagement of Toll-like receptor (TLR) 9 and TLR7, respectively, with initial viral recognition by pDC mediated by binding to major histocompatibility (MHC) class II molecules. Conclusion These data demonstrate that MHC class II-specific engagement by virus and subsequent viral nucleic acid recognition mediates IFN-α production by pDC. Our results suggest that elevated levels of IFN-α found in lupus patients may be a result of aberrantly controlled chronic viral infection. PMID:20178121

  13. N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.

    PubMed

    Gao, Xiao; Lampraki, Eirini-Maria; Al-Khalidi, Sarwah; Qureshi, Muhammad Asif; Desai, Rhea; Wilson, Joanna Beatrice

    2017-01-01

    Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure

  14. Sensitive, microliter PCR with consensus degenerate primers for Epstein Barr virus amplification

    PubMed Central

    Oh, Kyudam; Pak, Nikita; Saunders, D. Curtis; Conrardy, Christina; Landers, James P.; Tong, Suxiang; Forest, Craig R.

    2016-01-01

    Sensitive identification of the etiology of viral diseases is key to implementing appropriate prevention and treatment. The gold standard for virus identification is the polymerase chain reaction (PCR), a technique that allows for highly specific and sensitive detection of pathogens by exponentially amplifying a specific region of DNA from as little as a single copy through thermocycling a biochemical cocktail. Today, molecular biology laboratories use commercial instruments that operate in 0.5–2 h/analysis using reaction volumes of 5–50 μL contained within polymer tubes or chambers. Towards reducing this volume and maintaining performance, we present a semi-quantitative, systematic experimental study of how PCR yield is affected by tube/chamber substrate, surface-area-to-volume ratio (SA:V), and passivation methods. We perform PCR experiments using traditional PCR tubes as well as using disposable polymer microchips with 1 μL reaction volumes thermocycled using water baths. We report the first oil encapsulation microfluidic PCR method without fluid flow and its application to the first microfluidic amplification of Epstein Barr virus using consensus degenerate primers, a powerful and broad PCR method to screen for both known and novel members of a viral family. The limit of detection is measured as 140 starting copies of DNA from a starting concentration of 3×105 copies/mL, regarded as an accepted sensitivity threshold for diagnostic purposes, and reaction specificity was improved as compared to conventional methods. Also notable, these experiments were conducted with conventional reagent concentrations, rather than commonly spiked enzyme and/or template mixtures. This experimental study of the effects of substrate, SA:V, and passivation, together with sensitive and specific microfluidic PCR with consensus degenerate primers represent advances towards lower cost and higher throughput pathogen screening. PMID:23080522

  15. Exhausted cytotoxic control of Epstein-Barr virus in human lupus.

    PubMed

    Larsen, Martin; Sauce, Delphine; Deback, Claire; Arnaud, Laurent; Mathian, Alexis; Miyara, Makoto; Boutolleau, David; Parizot, Christophe; Dorgham, Karim; Papagno, Laura; Appay, Victor; Amoura, Zahir; Gorochov, Guy

    2011-10-01

    Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.

  16. Telomerase Activity Impacts on Epstein-Barr Virus Infection of AGS Cells

    PubMed Central

    Rac, Jürgen; Haas, Florian; Schumacher, Andrina; Middeldorp, Jaap M.; Delecluse, Henri-Jacques; Speck, Roberto F.

    2015-01-01

    The Epstein-Barr virus (EBV) is transmitted from host-to-host via saliva and is associated with epithelial malignancies including nasopharyngeal carcinoma (NPC) and some forms of gastric carcinoma (GC). Nevertheless, EBV does not transform epithelial cells in vitro where it is rapidly lost from infected primary epithelial cells or epithelial tumor cells. Long-term infection by EBV, however, can be established in hTERT-immortalized nasopharyngeal epithelial cells. Here, we hypothesized that increased telomerase activity in epithelial cells enhances their susceptibility to infection by EBV. Using HONE-1, AGS and HEK293 cells we generated epithelial model cell lines with increased or suppressed telomerase activity by stable ectopic expression of hTERT or of a catalytically inactive, dominant negative hTERT mutant. Infection experiments with recombinant prototypic EBV (rB95.8), recombinant NPC EBV (rM81) with increased epithelial cell tropism compared to B95.8, or recombinant B95.8 EBV with BZLF1-knockout that is not able to undergo lytic replication, revealed that infection frequencies positively correlate with telomerase activity in AGS cells but also partly depend on the cellular background. AGS cells with increased telomerase activity showed increased expression mainly of latent EBV genes, suggesting that increased telomerase activity directly acts on the EBV infection of epithelial cells by facilitating latent EBV gene expression early upon virus inoculation. Thus, our results indicate that infection of epithelial cells by EBV is a very selective process involving, among others, telomerase activity and cellular background to allow for optimized host-to-host transmission via saliva. PMID:25856387

  17. Exhausted Cytotoxic Control of Epstein-Barr Virus in Human Lupus

    PubMed Central

    Larsen, Martin; Sauce, Delphine; Deback, Claire; Arnaud, Laurent; Mathian, Alexis; Miyara, Makoto; Boutolleau, David; Parizot, Christophe; Dorgham, Karim; Papagno, Laura; Appay, Victor; Amoura, Zahir; Gorochov, Guy

    2011-01-01

    Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients. PMID:22028659

  18. Seroepidemiological Study of Epstein-Barr Virus in Different Population Groups in Croatia.

    PubMed

    Beader, Nataša; Kolarić, Branko; Slačanac, Domagoj; Tabain, Irena; Vilibić-Čavlek, Tatjana

    2018-02-01

    The Epstein-Barr virus (EBV) is one of the most common viruses found in humans, causing lifelong infection in up to 95% of the world population. To analyze the seroprevalence of EBV infection in different population groups in Croatia. During a 2 year period (2015-2016), a total of 2022 consecutive serum samples collected from Croatian residents were tested for the presence of EBV-specific viral capsid antigen (VCA) immunoglobulin M (IgM) and IgG antibodies using an enzyme-linked immunoassay. IgM/IgG-positive samples were further tested for IgG avidity. The overall prevalence of EBV IgG antibodies was 91.4%. Females had significantly higher IgG seroprevalence than males (93.1% vs. 89.9%, P = 0.008). According to age, IgG seropositivity increased progressively from 59.6% in children age < 9 years to 98.3% in 30-39 year olds, and remained stable thereafter (P < 0.001). The IgG seroprevalence differed significantly among groups: 68.1% in children/adolescents and 95.9% in adults; multiple sclerosis (100%), hemodialysis patients (97.7%), heart transplant recipients (93.8%), hematological malignancies (91.2%), and Crohn's disease (88.5%), P < 0.001. IgM antibodies were detected in 9% of participants. Using IgG avidity, recent primary EBV infection was documented in 83.8% of IgM-positive subjects < 9 years old, 69.2% age 10-19, 33.3% age 20-29, and 3.6-4.2% > 40. All IgM positive participants > 40 years showed high IgG avidity. Logistic regression showed that age is associated with EBV IgG seropositivity. EBV is widespread in the Croatian population. Older age appears to be the main risk factor for EBV seropositivity.

  19. Epstein-Barr Virus Nuclear Antigen Leader Protein Coactivates EP300.

    PubMed

    Wang, Chong; Zhou, Hufeng; Xue, Yong; Liang, Jun; Narita, Yohei; Gerdt, Catherine; Zheng, Amy Y; Jiang, Runsheng; Trudeau, Stephen; Peng, Chih-Wen; Gewurz, Benjamin E; Zhao, Bo

    2018-05-01

    Epstein-Barr virus nuclear antigen (EBNA) leader protein (EBNALP) is one of the first viral genes expressed upon B-cell infection. EBNALP is essential for EBV-mediated B-cell immortalization. EBNALP is thought to function primarily by coactivating EBNA2-mediated transcription. Chromatin immune precipitation followed by deep sequencing (ChIP-seq) studies highlight that EBNALP frequently cooccupies DNA sites with host cell transcription factors (TFs), in particular, EP300, implicating a broader role in transcription regulation. In this study, we investigated the mechanisms of EBNALP transcription coactivation through EP300. EBNALP greatly enhanced EP300 transcription activation when EP300 was tethered to a promoter. EBNALP coimmunoprecipitated endogenous EP300 from lymphoblastoid cell lines (LCLs). EBNALP W repeat serine residues 34, 36, and 63 were required for EP300 association and coactivation. Deletion of the EP300 histone acetyltransferase (HAT) domain greatly reduced EBNALP coactivation and abolished the EBNALP association. An EP300 bromodomain inhibitor also abolished EBNALP coactivation and blocked the EP300 association with EBNALP. EBNALP sites cooccupied by EP300 had significantly higher ChIP-seq signals for sequence-specific TFs, including SPI1, RelA, EBF1, IRF4, BATF, and PAX5. EBNALP- and EP300-cooccurring sites also had much higher H3K4me1 and H3K27ac signals, indicative of activated enhancers. EBNALP-only sites had much higher signals for DNA looping factors, including CTCF and RAD21. EBNALP coactivated reporters under the control of NF-κB or SPI1. EP300 inhibition abolished EBNALP coactivation of these reporters. Clustered regularly interspaced short palindromic repeat interference targeting of EBNALP enhancer sites significantly reduced target gene expression, including that of EP300 itself. These data suggest a previously unrecognized mechanism by which EBNALP coactivates transcription through subverting of EP300 and thus affects the expression of

  20. An elderly patient with chronic active Epstein-Barr virus infection with mixed cryoglobulinemia and review of the literature.

    PubMed

    Ichinose, Kunihiro; Origuchi, Tomoki; Tashiro, Naoki; Kawashiri, Shin-Ya; Iwamoto, Naoki; Fujikawa, Keita; Aramaki, Toshiyuki; Arima, Kazuhiko; Tamai, Mami; Yamasaki, Satoshi; Nakamura, Hideki; Moriuchi, Hiroyuki; Kawakami, Atsushi

    2013-09-01

    A 76-year-old woman was diagnosed with chronic active Epstein-Barr virus (EBV) infection (CAEBV) with sustained fever, anemia, numbness of the lower limbs, and liver dysfunction. The patient had an unusual anti-EBV antibody profile and high viral load, positive rheumatoid factor, and cryoglobulinemia. She suffered from recurrent hemosputum with pleural effusion and thrombocytopenia caused by CAEBV infection, and she died in July 2008. Here, we present a rare case of CAEBV infection with cryoglobulinemia in an elderly patient.

  1. Epstein-Barr virus-associated enteropathy as a complication of infectious mononucleosis mimicking peripheral T-cell lymphoma.

    PubMed

    Tamura, Shinobu; Maruyama, Dai; Miyagi Maeshima, Akiko; Taniguchi, Hirokazu; Kakugawa, Yasuo; Mori, Masakazu; Azuma, Teruhisa; Kim, Sung-Won; Watanabe, Takashi; Kobayashi, Yukio; Tobinai, Kensei

    2013-01-01

    A 32-year-old man presented with a fever. A laboratory examination detected atypical lymphocytes and liver enzyme elevation. The serological tests for Epstein-Barr virus (EBV) were consistent with an acute infection pattern. Computed tomograpy showed bowel wall thickening, and colonoscopy revealed numerous ulcerations. The histological findings from the biopsy specimens from the colon were consistent with peripheral T-cell lymphoma (PTCL), and in situ hybridization detected EBER-1 in the atypical lymphocytes. Because his clinical and endoscopic abnormalities improved without medication, we diagnosed the patient with EBV-associated enteropathy. We herein report a rare case of EBV-associated enteropathy that required careful differentiation from PTCL.

  2. Corticosteroid therapy in Epstein-Barr virus infection. Effect on lymphocyte class, subset, and response to early antigen.

    PubMed

    Brandfonbrener, A; Epstein, A; Wu, S; Phair, J

    1986-02-01

    Corticosteroid treatment of impending upper airway obstruction due to Epstein-Barr virus (EBV) infectious mononucleosis did not alter the pattern of lymphocyte changes induced by this viral infection during the first two weeks following administration of prednisone. By 12 weeks, 11 treated students had significantly fewer lymphocytes, including B, total T, helper, and T-suppressor cell numbers, than 11 untreated EBV-infected students, and values were closer to those noted in uninfected controls. Corticosteroid therapy did not alter the serologic response to early antigens of EBV. Fever and lymphadenopathy resolved somewhat more quickly in treated students.

  3. Prevalence of human papillomavirus and Epstein-Barr virus DNA in penile cancer cases from Brazil.

    PubMed

    Afonso, Larissa Alves; Moyses, Natalia; Alves, Gilda; Ornellas, Antônio Augusto; Passos, Mauro Romero Leal; Oliveira, Ledy do Horto dos Santos; Cavalcanti, Silvia Maria Baeta

    2012-02-01

    Penile cancer is a potentially mutilating disease. Although its occurrence is relatively rare worldwide, penile cancer rates can be high in developing countries. A few studies have been conducted on the involvement of human papillomavirus (HPV) in penile carcinoma, which have found HPV present in 30-70% of penile malignant lesions, with a higher prevalence of HPV 16 and 18. It has been assumed that cofactors, such as Epstein-Barr virus (EBV) infections, may play a role in the progression of penile neoplasia. The aim of this study was to determine HPV and EBV prevalence in 135 penile malignant lesions from Brazilian men through the use of MY09/11 polymerase chain reaction (PCR), type-specific PCR and restriction fragment length polymorphism analysis. HPV prevalence among the men tested was 60.7%. Of the men who tested positive, 27 presented with HPV 16 (29.7%), five with HPV 18 (5.5%), 21 with HPV 45 (23.1%) and nine with HPV 6 (9.9%). Seven mixed infections were detected (9.2%), while 11 cases remained untyped (13.4%). Regarding EBV positivity, 46.7% of the samples contained EBV DNA with EBV-1 as the most prevalent type (74.6%). More than 23% of the men were co-infected with both HPV and EBV, while 35% presented exclusively with HPV DNA and 20% presented only with EBV DNA. Penile carcinoma aetiology has not been fully elucidated and the role of HPV and EBV infections individually or synergistically is still controversial. Hence, more studies are needed to determine their possible role in carcinogenesis.

  4. Epstein-Barr virus-positive gastric cancer: a distinct molecular subtype of the disease?

    PubMed

    Jácome, Alexandre Andrade Dos Anjos; Lima, Enaldo Melo de; Kazzi, Ana Izabela; Chaves, Gabriela Freitas; Mendonça, Diego Cavalheiro de; Maciel, Marina Mara; Santos, José Sebastião Dos

    2016-04-01

    Approximately 90% of the world population is infected by Epstein-Barr virus (EBV). Usually, it infects B lymphocytes, predisposing them to malignant transformation. Infection of epithelial cells occurs rarely, and it is estimated that about to 10% of gastric cancer patients harbor EBV in their malignant cells. Given that gastric cancer is the third leading cause of cancer-related mortality worldwide, with a global annual incidence of over 950,000 cases, EBV-positive gastric cancer is the largest group of EBV-associated malignancies. Based on gene expression profile studies, gastric cancer was recently categorized into four subtypes; EBV-positive, microsatellite unstable, genomically stable and chromosomal instability. Together with previous studies, this report provided a more detailed molecular characterization of gastric cancer, demonstrating that EBV-positive gastric cancer is a distinct molecular subtype of the disease, with unique genetic and epigenetic abnormalities, reflected in a specific phenotype. The recognition of characteristic molecular alterations in gastric cancer allows the identification of molecular pathways involved in cell proliferation and survival, with the potential to identify therapeutic targets. These findings highlight the enormous heterogeneity of gastric cancer, and the complex interplay between genetic and epigenetic alterations in the disease, and provide a roadmap to implementation of genome-guided personalized therapy in gastric cancer. The present review discusses the initial studies describing EBV-positive gastric cancer as a distinct clinical entity, presents recently described genetic and epigenetic alterations, and considers potential therapeutic insights derived from the recognition of this new molecular subtype of gastric adenocarcinoma.

  5. Dynamic Epstein-Barr Virus Gene Expression on the Path to B-Cell Transformation

    PubMed Central

    Price, Alexander M.; Luftig, Micah A.

    2016-01-01

    Epstein-Barr Virus is an oncogenic human herpesvirus in the γ-herpesvirinae sub-family that contains a 170–180 kb double stranded DNA genome. In vivo, EBV commonly infects B and epithelial cells and persists for the life of the host in a latent state in the memory B cell compartment of the peripheral blood. EBV can be reactivated from its latent state leading to increased expression of lytic genes that primarily encode for enzymes necessary to replicate the viral genome as well as structural components of the virion. Lytic cycle proteins also aid in immune evasion, inhibition of apoptosis, and the modulation of other host responses to infection. In vitro, EBV has the potential to infect primary human B cells and induce cellular proliferation to yield effectively immortalized lymphoblastoid cell lines, or LCLs. EBV immortalization of B cells in vitro serves as a model system for studying EBV-mediated lymphomagenesis. While much is known about the steady state viral gene expression within EBV immortalized LCLs and other EBV-positive cell lines, relatively little is known about the early events after primary B-cell infection. It was previously thought that upon latent infection EBV only expressed the well-characterized latency associated transcripts found in LCLs. However, recent work has characterized the early, but transient, expression of lytic genes necessary for efficient transformation as well as delayed responses in the known latency genes. This review summarizes these recent findings that show how dynamic and controlled expression of multiple EBV genes can control the activation of B cells, entry into the cell cycle, inhibition of apoptosis, and control of innate and adaptive immune responses. PMID:24373315

  6. Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders.

    PubMed

    Park, Sanghui; Ko, Young H

    2014-01-01

    Primary infection with Epstein-Barr virus (EBV) is usually asymptomatic and, in a normal host, EBV remains latent in B cells after primary infection for the remainder of life. Uncommonly, EBV can infect T or natural killer (NK) cells in a person with a defect in innate immunity, and EBV infection can cause unique systemic lymphoproliferative diseases (LPD) of childhood. Primary infection in young children can be complicated by hemophagocytic lymphohistiocytosis or fulminant systemic T-cell LPD of childhood. Uncommonly, patients can develop chronic active EBV (CAEBV) disease-type T/NK LPD, which includes CAEBV infection of the systemic form, hydroa vacciniforme-like T-cell LPD, and mosquito-bite hypersensitivity. The clinical course of CAEBV disease-type T/NK LPD can be smoldering, persistent or progressive, depending on the balance between viral factors and host immunity. Aggressive NK-cell leukemia, hydroa vacciniforme-like T-cell lymphoma, or uncommonly extranodal NK/T-cell lymphoma can develop in children and young adults with CAEBV disease-type T/NK-cell LPD. Extranodal T/NK-cell lymphoma is a disease of adults, and its incidence begins to increase in the third decade and comprises the major subtype of T/NK LPD throughout life. Aggressive NK-cell leukemia and nodal T/NK-cell lymphoma of the elderly are fulminant diseases, and immune senescence may be an important pathogenetic factor. This review describes the current progress in identifying different types of EBV-associated T/NK-cell LPD and includes a brief presentation of data from Korea. © 2014 Japanese Dermatological Association.

  7. Atypical hydroa vacciniforme-like epstein-barr virus associated T/NK-cell lymphoproliferative disorder.

    PubMed

    Lee, Hye Young; Baek, Jin Ok; Lee, Jong Rok; Park, Sang Hui; Jeon, In Sang; Roh, Joo Young

    2012-12-01

    Epstein-Barr virus (EBV)-associated T-cell/natural killer (NK)-cell lymphoproliferative disorders (EBV-T/NK-LPDs) accompany severe chronic active EBV infection (CAEBV) or comprise the CAEBV disease entity. The CAEBV disease entity has the common feature of lymphoproliferation of T or NK cells (primarily), and B cells (rarely), with chronic activation of EBV infection. The disease is rare and seems to be more prevalent in East Asian countries. The CAEBV disease entity encompasses heterogenous disorders, including hydroa vacciniforme (HV), hypersensitivity to mosquito bites, EBV-associated hemophagocytic syndrome, NK/T-cell lymphoma, and NK-cell leukemia. Atypical HV-like eruptions are present on sun-exposed and nonexposed areas with facial edema, fever, and hepatosplenomegaly, unlike classic HV. Recently, it has been suggested that classic HV and atypical HV-like eruptions are variants within the same disease spectrum of EBV-T/NK-LPD. We report a Korean boy with an atypical HV-like eruption and various systemic manifestations, including fever, sore throat, abdominal pain, headaches, seizures, and hematologic abnormalities for 2 years. After the initial mild eruption, which resembled a viral exanthem, ulceronecrotic skin lesions gradually developed and were associated with a high-grade fever and constitutional symptoms. He had a CAEBV infection, which showed a predominant proliferation of NK cells with high EBV DNA levels in the peripheral blood. However, in the skin lesions, there were nonneoplastic CD4 T-cell infiltrations predominantly showing a monoclonal T-cell receptor-γ gene rearrangement and positive EBV in situ hybridization.

  8. [Clinical and laboratory characteristics of chronic active Epstein-Barr virus infection in children].

    PubMed

    Mao, Jun-Qing; Yang, Shi-Long; Song, Hua; Zhao, Fen-Ying; Xu, Xiao-Jun; Gu, Min-Er; Tang, Yong-Min

    2014-11-01

    To study the clinical and laboratory characteristics of chronic active Epstein-Barr virus (EBV) infection (CAEBV) in children and to provide a basis for the diagnosis and treatment of CAEBV. The clinical data of 13 children with CAEBV, as well as 15 cases of acute EBV infection (AEBV) as controls, were analyzed, including clinical manifestations, EBV antibodies, EBV DNA, and peripheral blood lymphocyte subsets. Both groups of patients had infectious mononucleosis-like symptoms such as fever, hepatomegaly, splenomegaly, and lymphadenectasis, but CAEBV patients had a longer course of disease and continuous and recurrent symptoms. Compared with the AEBV group, the CAEBV group had a significantly higher EBV DNA load in peripheral blood (P<0.05), a significantly higher VCA-IgG titer (P<0.05), and significantly lower numbers of white blood cells, lymphocytes, B cells, total T cells, CD4+ T cells, and CD8+ T cells in peripheral blood (P<0.05). Among 13 CAEBV patients followed up, 8 cases died, 2 cases showed an improvement, 2 cases had a recurrence, and 1 case was lost to follow-up after being transferred to another hospital. All the AEBV patients were cured and had no recurrence during the one-year follow-up. The clinical manifestations of CAEBV vary in children. It is difficult to distinguish CAEBV from AEBV early. More attention should be paid to CAEBV because of its severe complications, poor prognosis, and high mortality. Measurement of EBV DNA load, VCA-IgG titer, and lymphocyte subsets in peripheral blood may be helpful in the diagnosis and differential diagnosis of CAEBV.

  9. Differential chemokine, chemokine receptor and cytokine expression in Epstein-Barr virus-associated lymphoproliferative diseases.

    PubMed

    Ohshima, Koichi; Karube, Kennosuke; Hamasaki, Makoto; Tutiya, Takeshi; Yamaguchi, Takahiro; Suefuji, Hiroaki; Suzuki, Keiko; Suzumiya, Junji; Ohga, Shouichi; Kikuchi, Masahiro

    2003-08-01

    T cell immunity plays an important role in the clinicopathology of Epstein-Barr virus (EBV)-associated diseases. Acute EBV-induced infectious mononucleosis (IM) is a common self-limiting disease, however, other EBV-associated diseases, including chronic active EBV infection (CAEBV), NK cell lymphoma (NKL), and Hodgkin's lymphoma (HL), exhibit distinct clinical features. Chemokines are members of a family of small-secreted proteins. The relationships between chemokines and the chemokine receptor (R) are thought to be important for selectivity of local immunity. Some chemokines, chemokine R and cytokines closely associate with the T cell subtypes, Th1 and Th2 T cells and cytotoxic cells. To clarify the role of T cell immunity in EBV-associated diseases, we conducted gene expression profiling, using chemokine, chemokine R and cytokine DNA chips. Compared to EBV negative non-specific lymphadenitis, CAEBV and NKL exhibited diffuse down- and up-regulation, respectively, of these gene profiles. IM had a predominantly Th1-type profile, whereas HL had a mixed Th1/Th2-type profile. Reduction of the Th1-type cytokine interferon gamma (IFN-gamma) in CAEBV was confirmed by Reverse transcriptase-polymerase chain reaction, whereas IFN-gamma expression was markedly enhanced in NKL, and moderately enhanced in IM. Compared to IM, CAEBV showed slight elevation of "regulated upon activation, normal T expressed and secreted" (RANTES), but almost all other genes assayed were down-regulated. NKL exhibited elevated expression of numerous genes, particularly IFN-gamma-inducible-10 (IP-10) and monokine induced by IFN-gamma (MIG). HL showed variable elevated and reduced expression of various genes, with increased expression of IL-13 receptor and MIG. Our study demonstrated the enormous potential of gene expression profiling for clarifying the pathogenesis of EBV-associated diseases.

  10. Integration sites of Epstein-Barr virus genome on chromosomes of human lymphoblastoid cell lines

    SciTech Connect

    Wuu, K.D.; Chen, Y.J.; Wang-Wuu, S.

    1994-09-01

    Epstein-Barr virus (EBV) is the pathogen of infectious mononucleosis. The viral genome is present in more than 95% of the African cases of Burkitt lymphoma and it is usually maintained in episomal form in the tumor cells. Viral integration has been described only for Nanalwa which is a Burkitt lymphoma cell line lacking episomes. In order to examine the role of EBV in the immortalization of human Blymphocytes, we investigated whether the EBV integration into the human genome is essential. If the integration does occur, we would like to know whether the integration is randomly distributed or whether the viralmore » DNA integrates preferentially at certain sites. Fourteen in vitro immortalized human lymphoblastoid cell lines (LCLs) were examined by fluorescence in situ hybridization (FISH) with a biotinylated EBV BamHI w DNA fragment as probe. The episomal form of EBV DNA was found in all cells of these cell lines, while only about 65% of the cells have the integrated viral DNA. This might suggest that integration is not a pre-requisite for cell immortalization. Although all chromosomes, except Y, have been found with integrated viral genome, chromsomes 1 and 5 are the most frequent EBV DNA carrier (p<0.05). Nine chromosome bands, namely, 1p31, 1q31, 2q32, 3q13, 3q26, 5q14, 6q24, 7q31 and 12q21, are preferential targets for EBV integration (p<0.001). Eighty percent of the total 938 EBV hybridization signals were found to be at G-band-positive area. This suggests that the mechanism of EBV integration might be different from that of the retroviruses, which specifically integrate to G-band-negative areas. Thus, we conclude that the integration of EBV to host genome is non-random and it may have something to do with the structure of chromosome and DNA sequences.« less

  11. Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation.

    PubMed

    Kosowicz, John G; Lee, Jaeyeun; Peiffer, Brandon; Guo, Zufeng; Chen, Jianmeng; Liao, Gangling; Hayward, S Diane; Liu, Jun O; Ambinder, Richard F

    2017-08-15

    Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib. IMPORTANCE EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors. Copyright © 2017 American Society for Microbiology.

  12. Human cytomegalovirus and Epstein-Barr virus in etiopathogenesis of apical periodontitis: a systematic review.

    PubMed

    Jakovljevic, Aleksandar; Andric, Miroslav

    2014-01-01

    During the last decade, a hypothesis has been established that human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) may be implicated in the pathogenesis of apical periodontitis. The aim of this review was to analyze the available evidence that indicates that HCMV and EBV can actually contribute to the pathogenesis of periapical lesions and to answer the following focused question: is there a relationship between HCMV and EBV DNA and/or RNA detection and the clinical features of human periapical lesions? The literature search covered MEDLINE, Science Citation Index Expanded (SCIexpanded), Scopus, and The Cochrane Library database. Quantitative statistical analysis was performed on the pooled data of HCMV and EBV messenger RNA transcripts in tissues of symptomatic and asymptomatic periapical lesions. The electronic database search yielded 48 hits from PubMed, 197 hits from Scopus, 40 hits from Web of Science, and 1 from the Cochrane Library. Seventeen cross-sectional studies have been included in the final review. The pooled results from quantitative systematic method analysis showed no statistically significant relationship between the presence of HCMV and EBV messenger RNA transcripts (P = .083 and P = .306, respectively) and the clinical features of apical periodontitis. The findings of HCMV and EBV transcripts in apical periodontitis were controversial among the included studies. Herpesviruses were common in symptomatic and large-size periapical lesions, but such results failed to reach statistical significance. Further studies, including those based on an experimental animal model, should provide more data on herpesviruses as a factor in the pathogenesis of periapical inflammation. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  13. Development of Drugs for Epstein - Barr virus using High-Throughput in silico Virtual Screening

    PubMed Central

    Li, Ning; Thompson, Scott; Jiang, Hualiang; Lieberman, Paul M.; Luo, Cheng

    2010-01-01

    Importance of the field Epstein-Barr virus (EBV) is a ubiquitious human herpesvirus that is causally associated with endemic forms of Burkitt’s lymphoma (BL), nasopharyngeal carcinoma, and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects over 90% of the adult population and is responsible for ~1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases. Areas covered in this review In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes, as well as proteins that are expressed exclusively during latent infection, like EBNA1 and LMP1. Since the atomic structure of the EBNA1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, like EBNA1, to treat EBV infection and disease. What the reader will gain The reader will be familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process. Take home message Despite the impressive efficacy of nucleoside analogues for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. Since EBV-latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease. PMID:22822721

  14. Photodynamic therapy induced production of cytokines by latent Epstein Barr virus infected epithelial tumor cells

    NASA Astrophysics Data System (ADS)

    Koon, H. K.; Lo, K. W.; Lung, M. L.; Chang, C. K. C.; Wong, R. N. S.; Mak, N. K.

    2007-02-01

    Photodynamic therapy (PDT) is a method to treat cancer or non-cancer diseases by activation of the light-sensitive photosensitizers. Epstein Barr virus (EBV) has been implicated in the development of certain cancers such as nasopharyngeal carcinoma and B cell lymphoma. This study aims to examine the effects of EBV infection on the production of pro-inflammatory cytokines and chemokines in cells after the photosensitizer Zn-BC-AM PDT treatment. Epithelial tumor cell lines HONE-1 and latent EBV-infected HONE-1 (EBV-HONE-1) cells were used in this study. Cells were treated with the photosensitizer Zn-BC-AM for 24 hours before light irradiation. RT-PCR and quantitative ELISA methods were used for the evaluation of mRNA expression and production of cytokines, respectively. Results show that Zn-BC-AM PDT increases the production of IL-1a and IL-1b in EBV-HONE-1. Over a 10-fold increase in the production of IL-6 was observed in the culture supernatant of Zn-BC-AM PDT-treated HONE-1 cells. PDT-induced IL-6 production was observed in HONE-1 cells. EBV-HONE-1 has a higher background level of IL-8 production than the HONE-1. The production of IL-8 was suppressed in EBV-HONE-1cells after Zn-BC-AM PDT. Our results indicate that the response of HONE-1 cells to Zn-BC-AM PDT depends on the presence of latent EBV infection. Since IL-8 is a cytokine with angiogenic activity, Zn-BC-AM PDT may exert an anti-angiogenic effect through the suppression of IL-8 production by the EBV-infected cells.

  15. Methylation of Epstein-Barr virus Rta promoter in EBV primary infection, reactivation and lymphoproliferation.

    PubMed

    Germi, Raphaële; Guigue, Nicolas; Lupo, Julien; Semenova, Touyana; Grossi, Laurence; Vermeulen, Odile; Epaulard, Olivier; de Fraipont, Florence; Morand, Patrice

    2016-10-01

    During Epstein-Barr virus (EBV) latency, the EBV genome is largely silenced by methylation. This silencing is overturned during the switch to the lytic cycle. A key event is the production of the viral protein Zta which binds to three Zta-response elements (ZRE) from the Rta promoter (Rp), two of which (ZRE2 and ZRE3) include three CpG motifs methylated in the latent genome. The bisulphite pyrosequencing reaction was used to quantify the methylation of ZRE2, ZRE3a, and ZRE3b in EBV-positive cell lines and in ex vivo samples of EBV-related diseases, in order to assess whether the level of methylation in these ZREs could provide additional information to viral DNA load and serology in the characterization of EBV-associated diseases. In PBMC from two patients with infectious mononucleosis, over time Rp became increasingly methylated whereas EBV load decreased. In tonsil from patients with chronic tonsillitis, the methylation was less than in EBV-associated tumors, regardless of the viral load. This was even more striking when only the ZRE3a and ZRE3b were considered since some samples presented unbalanced profiles on ZRE2. EBV reactivation in cell culture showed that the reduction in the overall level of methylation was closely related to the production of unmethylated virions. Thus, an assessment of the level of methylation may help to better characterize EBV replication in PBMC and in biopsies with high EBV load, during infectious mononucleosis and EBV-associated cancers. J. Med. Virol. 88:1814-1820, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Current and past Epstein-Barr virus infection in risk of initial CNS demyelination.

    PubMed

    Lucas, R M; Ponsonby, A-L; Dear, K; Valery, P; Pender, M P; Burrows, J M; Burrows, S R; Chapman, C; Coulthard, A; Dwyer, D E; Dwyer, T; Kilpatrick, T; Lay, M-L J; McMichael, A J; Taylor, B V; van der Mei, I A F; Williams, D

    2011-07-26

    To assess risk of a first clinical diagnosis of CNS demyelination (FCD) in relation to measures of Epstein-Barr virus (EBV) infection within the context of other known risk factors. This was a multicenter incident case-control study. FCD cases (n = 282) aged 18-59 years and controls (n = 558, matched on age, sex, and region) were recruited from 4 Australian centers between November 1, 2003, and December 31, 2006. A nested study (n = 215 cases, n = 216 controls) included measurement of whole blood quantitative EBV DNA load and serum EBV-specific antibodies. Conditional logistic regression was used to analyze case-control differences. There were no significant case-control differences in the proportion with detectable EBV DNA (55.8% vs 50.5%, respectively, p = 0.28), or in quantitative EBV DNA load (p = 0.33). Consistent with previous work, higher anti-EBV-specific immunoglobulin G (IgG) titers and a history of infectious mononucleosis were associated with increased FCD risk and there was an additive interaction with HLA-DRB1*1501 status. We found additional interactions between high anti-EBNA IgG titer and SNPs in HLA-A (adjusted odds ratios [AOR] = 19.84 [95% confidence interval (CI) 5.95 to 66.21] for both factors compared to neither) and CTLA-4 genes (AOR = 0.31 [95% CI 0.13 to 0.76] for neither factor compared to both). EBV DNA load was lower at higher serum 25-hydroxyvitamin D concentrations in controls (r = -0.17, p = 0.01). An adverse effect of higher EBV DNA load on FCD risk was increased with higher 25-hydroxyvitamin D concentration (p[interaction] = 0.02). Past infection with EBV, but not current EBV DNA load in whole blood, is significantly associated with increased FCD risk. These associations appear to be modified by immune-related gene variants.

  17. Epstein-Barr virus exploits intrinsic B-lymphocyte transcription programs to achieve immortal cell growth.

    PubMed

    Zhao, Bo; Zou, James; Wang, Hongfang; Johannsen, Eric; Peng, Chih-wen; Quackenbush, John; Mar, Jessica C; Morton, Cynthia Casson; Freedman, Matthew L; Blacklow, Stephen C; Aster, Jon C; Bernstein, Bradley E; Kieff, Elliott

    2011-09-06

    Epstein-Barr virus nuclear antigen 2 (EBNA2) regulation of transcription through the cell transcription factor RBPJ is essential for resting B-lymphocyte (RBL) conversion to immortal lymphoblast cell lines (LCLs). ChIP-seq of EBNA2 and RBPJ sites in LCL DNA found EBNA2 at 5,151 and RBPJ at 10,529 sites. EBNA2 sites were enriched for RBPJ (78%), early B-cell factor (EBF, 39%), RUNX (43%), ETS (39%), NFκB (22%), and PU.1 (22%) motifs. These motif associations were confirmed by LCL RBPJ ChIP-seq finding 72% RBPJ occupancy and Encyclopedia Of DNA Elements LCL ChIP-seq finding EBF, NFκB RELA, and PU.1 at 54%, 31%, and 17% of EBNA2 sites. EBNA2 and RBPJ were predominantly at intergene and intron sites and only 14% at promoter sites. K-means clustering of EBNA2 site transcription factors identified RELA-ETS, EBF-RUNX, EBF, ETS, RBPJ, and repressive RUNX clusters, which ranked from highest to lowest in H3K4me1 signals and nucleosome depletion, indicative of active chromatin. Surprisingly, although quantitatively less, the same genome sites in RBLs exhibited similar high-level H3K4me1 signals and nucleosome depletion. The EBV genome also had an LMP1 promoter EBF site, which proved critical for EBNA2 activation. LCL HiC data mapped intergenic EBNA2 sites to EBNA2 up-regulated genes. FISH and chromatin conformation capture linked EBNA2/RBPJ enhancers 428 kb 5' of MYC to MYC. These data indicate that EBNA2 evolved to target RBL H3K4me1 modified, nucleosome-depleted, nonpromoter sites to drive B-lymphocyte proliferation in primary human infection. The primed RBL program likely supports antigen-induced proliferation.

  18. Detection of autoimmunity in early primary Epstein-Barr virus infection by Western blot analysis.

    PubMed

    Mascia, M T; Sandri, G; Guerzoni, C; Roncaglia, R; Mantovani, G; Ferri, C

    2008-01-01

    The Epstein-Barr virus (EBV) represents a potentially important factor in the pathogenesis of certain autoimmune disorders such as systemic lupus erythematosus (SLE), and Sjögren's syndrome, probably through a molecular mimicry mechanism. Several studies have focused on the relationship between previous EBV infection and clinically overt connective tissue diseases (CTDs), while the aim of this study was to investigate the immunological alterations during the early phase of primary acute EBV infection by means of ENA Western blotting (WB) analysis. This technique is able to detect a wide spectrum of anti-ENA autoantibodies, potentially directed against diverse epitopes of the same antigen. Sera from 54 subjects (F/M=24/30, mean age 17+/-6 SD years) with primary acute EBV infection were analysed using indirect immunofluorescence (IF) on Hep-2 cells for ANA, and both ELISA and WB for ENA. Only 8 ANA+ and no ENA+ were found by means of IF and ELISA techniques, respectively; however, one or more ENA autoantibodies were detected in 24/54 (44%) sera using WB. The autoantibodies were no longer present at the second evaluation. Subjects with immunological alterations had not developed any significant clinical manifestations at a 5-year follow-up. This study demonstrated the appearance of autoantibody production in a high proportion of individuals with primary acute EBV infection; interestingly, the observed serological subsets are quite similar to clinical SLE clusters. Moreover, the absence of immunological disorders during the follow-up reinforces the role of multiple genetic and/or environmental co-factors in the pathogenesis of CTDs.

  19. Elevated antinuclear antibodies and altered anti-Epstein-Barr virus immune responses.

    PubMed

    Cuomo, Laura; Cirone, Mara; Di Gregorio, Ana Oliva; Vitillo, Marina; Cattivelli, Marina; Magliocca, Vittoria; Maiorano, Silvana; Meledandri, Marcello; Scagnolari, Carolina; La Rocca, Sebastiano; Trivedi, Pankaj

    2015-01-02

    It has been shown that Epstein-Barr virus (EBV) is able to alter the immune response towards self-antigens and may enhance risk of autoimmune diseases such as systemic lupus erythematosus (SLE) in genetically predisposed individuals. In this study, we evaluated the specific antibody immune response against EBV in patients with anti-nuclear autoantibodies (ANA) in comparison with ANA-negative healthy controls. For this purpose, 92 patients with an high anti-ANA reactivity with or without concomitant extractable nuclear antigen (ENA) or double stranded DNA (dsDNA) positivity were selected and compared with 146 healthy donors. We found that anti-EBV-VCA and EA IgG concentrations were significantly higher in ANA-positive patients in comparison to the controls (VCA P<0.0001 and EA P<0,03) as well as in those ANA-positive patients that showed a concomitant ENA positivity (P=0.0002). Interestingly, elevated anti-EBNA-1 IgG was found in a group of patients who had anti SSA/Ro antibodies. Anti-VCA IgM Abs were more frequently found in those patients with a very high titer of ANA (P=0.06); moreover detection of anti-VCA IgM/IgG in absence of anti-EBNA-1 IgG was more frequent in the patient than in the control group. Both these conditions correlate with a recent EBV infection or reactivation. The data suggest that EBV, particularly during acute infection or in its reactivation phase, could be involved in the ANA and ENA autoantibody formation. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Correlation of nasopharyngeal carcinoma with rare earth elements and the Epstein-Barr virus

    PubMed Central

    Zhang, Xiangmin; Zeng, Xiangfu; Liu, Lianbin; Lan, Xiaolin; Huang, Jing; Zeng, Hongxue; Li, Rong; Luo, Keqing; Wu, Wei; Zhou, Maohua; Li, Shaojin

    2018-01-01

    The concentration and distribution of rare earth elements (REE) in nasopharyngeal carcinoma (NPC) were measured to investigate connections with tumor size, lymph node metastasis, clinical stages, and Epstein-Barr virus (EBV) infection. There were 30 patients with NPC who met the criteria for inclusion in the present study. The EBV copy number, as well as the concentration and distribution of REE, was analyzed. EBV was detected using reverse transcription-polymerase chain reaction, with the concentrations of REE in NPC tissues measured using inductively coupled plasma-tandem mass spectrometry. The mean values were used when comparing concentrations of REE in NPC tissues as the standard deviation of this parameter was the lowest. Light REE had the highest concentrations, followed by medium, and then heavy REE. The concentrations of REE decreased with increasing tumor size and with the presence of lymph node metastasis. The concentrations of REE gradually increased between stage II and IVa, but markedly decreased thereafter. The elements that exhibited the greatest decreases were terbium, holmium and ytterbium. Furthermore, the concentrations of REE in NPC were not associated with sex (r=0.301, P=0.106) or age (r=−0.011, P=0.955), and were negatively associated with EBV (r=−0.744, P<0.001). By contrast, the EBV copy number increased alongside advancements in clinical stage. Changes in the concentrations of REE in NPC were more prominent for medium and heavy elements. Additionally, alterations in the concentrations of heavy REE may affect the occurrence and development of NPC. PMID:29541176

  1. Correlation of nasopharyngeal carcinoma with rare earth elements and the Epstein-Barr virus.

    PubMed

    Zhang, Xiangmin; Zeng, Xiangfu; Liu, Lianbin; Lan, Xiaolin; Huang, Jing; Zeng, Hongxue; Li, Rong; Luo, Keqing; Wu, Wei; Zhou, Maohua; Li, Shaojin

    2018-04-01

    The concentration and distribution of rare earth elements (REE) in nasopharyngeal carcinoma (NPC) were measured to investigate connections with tumor size, lymph node metastasis, clinical stages, and Epstein-Barr virus (EBV) infection. There were 30 patients with NPC who met the criteria for inclusion in the present study. The EBV copy number, as well as the concentration and distribution of REE, was analyzed. EBV was detected using reverse transcription-polymerase chain reaction, with the concentrations of REE in NPC tissues measured using inductively coupled plasma-tandem mass spectrometry. The mean values were used when comparing concentrations of REE in NPC tissues as the standard deviation of this parameter was the lowest. Light REE had the highest concentrations, followed by medium, and then heavy REE. The concentrations of REE decreased with increasing tumor size and with the presence of lymph node metastasis. The concentrations of REE gradually increased between stage II and IVa, but markedly decreased thereafter. The elements that exhibited the greatest decreases were terbium, holmium and ytterbium. Furthermore, the concentrations of REE in NPC were not associated with sex (r=0.301, P=0.106) or age (r=-0.011, P=0.955), and were negatively associated with EBV (r=-0.744, P<0.001). By contrast, the EBV copy number increased alongside advancements in clinical stage. Changes in the concentrations of REE in NPC were more prominent for medium and heavy elements. Additionally, alterations in the concentrations of heavy REE may affect the occurrence and development of NPC.

  2. Associations of Epstein-Barr Virus DNA in PBMCs and the Subtypes with Breast Cancer Risk

    PubMed Central

    Zhang, Wei; Wang, Min-Yi; Wei, Xue-Ling; Lin, Ying; Su, Feng-Xi; Xie, Xiao-Ming; Tang, Lu-Ying; Ren, Ze-Fang

    2017-01-01

    Objective: Epstein-Barr virus (EBV) has been found to be implicated in the development of breast cancer. The purpose of the present study was to identify the associations of EBV DNA and the subtypes in peripheral blood mononuclear cells (PBMCs) with the risk of breast cancer. Material and Methods: A case-control study with 671 breast cancer cases and 859 age-matched controls was conducted in Guangzhou, China. Face-to-face interviews were performed and blood samples were collected immediately after admission to the hospital for patients or after the interview for controls. EBV DNA in PBMCs and the subtypes were detected using Polymerase Chain Reaction (PCR) and restricted fragment length polymorphisms (RFLP). IgA antibodies against EBV VCA-p18 and EBNA-1 were examined using commercial enzyme-linked immunosorbent assay kits. Unconditional logistic regression analysis was applied to evaluate the associations of the DNA positivity and subtypes of EBV with the risk of breast cancer. Results: Among the 1530 subjects, 164 cases (24.4 %) and 206 controls (24.0 %) were positive for EBV DNA in PBMCs and no significant difference occurred between cases and controls. The presence of EBV DNA was related to the positivity of EBV IgA antibodies. Of the DNA positive samples, 71 cases and 109 controls for F/f subtype and 58 cases and 112 controls for C/D subtype were successfully obtained. The D subtype was associated with an increased breast cancer risk compared with the C subtype [OR (95% CI): 2.86 (1.25~6.53)]. We did not find an association of the F/f polymorphism with breast cancer risk. Conclusions: The present study suggested that the presence of EBV DNA in PBMCs may not be an appropriate biomarker for breast cancer risk. The subtype D of EBV was likely to be related to breast tumorigenesis. PMID:28928885

  3. Epstein-Barr virus in oral shedding of children with multiple sclerosis

    PubMed Central

    Yea, Carmen; Tellier, Raymond; Chong, Patrick; Westmacott, Garrett; Marrie, Ruth Ann; Bar-Or, Amit

    2013-01-01

    Objective: To investigate Epstein-Barr virus (EBV) oral shedding frequency and EBV genetic diversity in pediatric patients with multiple sclerosis (MS). Methods: This was a prospective case-control study. We used PCR-based assays to detect viral DNA in the monthly mouth swabs of 22 pediatric patients with MS and 77 age- and sex-matched healthy controls. EBV-positive samples were further analyzed for sequence variation in the EBV BCRF1 (ebvIL-10) gene using direct DNA sequencing methods, and in the EBV LMP1 gene by mass spectrometry. Results: Nineteen of the 22 (86.4%) children with MS were seropositive for remote EBV infection compared to 35 out of 77 (45.5%) healthy controls (p = 0.008). Baseline analysis of mouth swabs revealed a higher proportion of EBV-positive samples from EBV-seropositive patients with MS compared to EBV-seropositive healthy controls (52.6% vs 20%, p = 0.007). Longitudinal analysis of monthly swabs revealed average EBV detection rates of 50.6% in patients with MS and 20.4% in controls (p = 0.01). The oral shedding frequencies of Herpesviruses herpes simplex virus–1, cytomegalovirus, human herpesvirus (HHV)-6, and HHV-7 did not differ between groups. Changes in the predominant EBV genetic variants were detected more frequently in patients with MS; however, no specific EBV genetic variant was preferentially associated with MS. Conclusion: Children with MS demonstrate abnormally increased rates of EBV viral reactivation and a broader range of genetic variants, suggesting a selective impairment in their immunologic control of EBV. PMID:24014504

  4. [Polyradiculomeningoencephalitis caused by Epstein-Barr virus infection--description of a case with fatal outcome].

    PubMed

    Ringelstein, E B; Sobczak, H; Pfeifer, B; Hacke, W

    1984-03-01

    A 21 years old high school student, who, since early childhood, suffered from complete spinal paraplegia of unknown cause at D 10, suddenly, after a three week period with influenca -like prodromal symptoms, presented with acute polyradiculomeningoencephalitis . Positive reactions following Paul-Bunnell- Davidsohn -test and tests for specific antivirus IgG as well as specific IgM revealed acute Epstein-Barr-Virus infection, although no glandular signs could be found. The clinical findings consisted of peripheral sensory-motor tetraparesis, ataxia, nystagmus and disturbances of the caudal cranial nerves. Initially, the diagnosis of Fisher's syndrome was made. The orbicularis oculi reflex, however, indicated a circumscribed brainstem lesion in the medial reticular formation. This finding lead to the additional clinical diagnosis of encephalitis. Shortly after admission, a heart-arrest occurred, and, after successful reanimation, the patient presented with a "locked-in syndrome". On the 12th day after admission, he succumbed during a sudden drop of blood-pressure. Necropsy revealed septic shock as the cause of death, due to perforation of a duodenal ulcer. In the lower thoracic spinal cord a neurocytoma was found, which once lead to the paraplegia. Additionally, moderate inflammatory infiltrations were found in the basal leptomeninges, in the walls of several subcortical vessels and in the hypoglossal nerve. The infiltrations, at some sites, contained a large number of atypical lymphoid cells in the inflammatory meningeal exsudate . Microglial proliferation with satellitosis was found in the inferior olives, thus confirming the clinical diagnosis of polyradiculomeningoencephalitis . This case report should emphasize special features of EBV-infection with neurological complications: (1) in inflammatory diseases of the peripheral and central nervous system, infectious mononucleosis should always be drawn into the diagnostic considerations, even if heterophil antibodies

  5. Epstein-Barr virus-associated gastric carcinoma among patients with pernicious anemia.

    PubMed

    Boysen, Trine; Friborg, Jeppe; Stribolt, Katrine; Hamilton-Dutoit, Stephen; Goertz, Sanne; Wohlfahrt, Jan; Melbye, Mads

    2011-12-01

    Approximately 9% of gastric carcinomas worldwide are associated with Epstein-Barr virus (EBV), making it the most frequent EBV-associated malignancy. Pernicious anemia, a condition with chronic gastritis and achlorhydria, is strongly associated with gastric carcinoma. Both chronic inflammation and the lack of stomach acid may influence the likelihood of EBV infection of the neoplastic gastric epithelium, but the prevalence of EBV-associated gastric carcinoma among patients with pernicious anemia is unknown. Therefore, we conducted a Danish nationwide case-control study comparing gastric carcinoma patients with pernicious anemia (PA-GC) with those without pernicious anemia (nonPA-GC), frequency matched 1:2. Tumor tissues were reclassified by expert histopathologists blinded to pernicious anemia and EBV status. In total, 186 samples (55 PA-GC and 131 nonPA-GC) were identified. EBV-associated gastric carcinoma (EBV-GC) was more common among PA-GC compared with nonPA-GC, adjusted odds ratio (OR) = 2.53 (CI: 0.88; 7.14), p = 0.08, with further adjustment for lymphocytic infiltrate OR = 2.94 (0.99-8.67), p = 0.05. Gastric carcinomas with signet-ring cell morphology were significantly less common in patients with PA-GC compared with nonPA-GC (OR = 0.05, CI 0.01; 0.24). Although these conditions are rare, we found suggestive evidence that EBV-associated gastric carcinomas are more common among gastric carcinoma patients with pernicious anemia compared with those without. Copyright © 2011 UICC.

  6. Changing patterns in the Epstein-Barr virus (EBV)and Hodgkin lymphoma association in Tunisia.

    PubMed

    Dhiab, Myriam Ben; Ziadi, Sonia; Saad, Hanene; Louhichi, Teheni; Trimeche, Mounir

    2016-09-01

    We compared the features of the Epstein-Barr virus (EBV) and Hodgkin lymphoma (HL) association in Tunisia in two periods of time, 1991-2001 (111 cases) and 2002-2012 (122 cases). The investigation of the EBV status by EBER in situ hybridization showed a significant decrease in the prevalence of EBV-positive HL from 69.3 % for the period 1991-2001 to 40.1 % for the 2002-2012 period (p = 0.00001). EBV positivity has decreased in all age groups but was more pronounced among young patients, in the 15-24-year age group (46.1 vs 10.3 %, p = 0.003), in the 25-34-year age group (56.2 vs 25 %, p = 0.04), and among children (88.4 vs 59.2 %, p = 0.01). This decrease in EBV-positive HL over time contrasted with a remarkable increase in EBV-negative HL in young adults aged 15-34 years (51.2 vs 83 %; p = 0.001), especially among women (59.1 vs 91.2 %; p = 0.01). The decrease in EBV-positive HL over time concerns particularly the nodular sclerosis histological subtype (69.2 vs 31.6 %, p = 0.000001). These results indicate that the epidemiology of HL and its association with EBV are changing over time, with a trend toward a Western profile, and point toward the emergence of other environmental causative factors, especially among young women, which remain to be identified.

  7. Evidence of Epstein-Barr Virus Association with Gastric Cancer and Non-Atrophic Gastritis

    PubMed Central

    Martínez-López, Juan L.E.; Torres, Javier; Camorlinga-Ponce, Margarita; Mantilla, Alejandra; Leal, Yelda A.; Fuentes-Pananá, Ezequiel M.

    2014-01-01

    Different lines of evidence support an association between Epstein-Barr virus (EBV) and gastric cancer (GC). The main understood risk factor to develop GC is infection by Helicobacter pylori (H. pylori), which triggers a local inflammatory response critical for progression from gastritis to GC. The role of EBV in early inflammatory gastric lesions has been poorly studied. A recent study proposed a cutoff value of 2000 EBV particles to identify patients with increased chances of infection of the gastric epithelium, which may favor the inflammatory process. To better understand the role of EBV in cancer progression, we analyzed 75 samples of GC, 147 control samples of non-tumor gastric tissue derived from GC patients and 75 biopsies from patients with non-atrophic gastritis (NAG). A first-round PCR was used for EBV detection in tumor and non-tumor controls and a more sensitive nested PCR for gastritis samples; both PCRs had lower detection limits above the proposed cutoff value. With this strategy 10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples. Our results support a role for EBV in GC and early precursor lesions, either as directly oncogenic infecting epithelial cells or indirectly as an inflammatory trigger. PMID:24448220

  8. Clinical features of Epstein-Barr virus-associated infectious mononucleosis in hospitalized Korean children

    PubMed Central

    Son, Keun Hyung

    2011-01-01

    Purpose Few studies have been conducted on the recent status of infectious mononucleosis (IM) in Korean children. The aim of this study was to evaluate the recent trend in the clinical manifestations of Epstein-Barr virus (EBV)-associated IM as well as the clinical differences according to age. Methods A retrospective study was performed on 81 children hospitalized with EBV-associated IM who fulfilled the serological criteria for the diagnosis of EBV infection (viral capsid antigen immunoglobulin M positive). The patients were divided into 3 age groups: <5 years, 5 to 9 years, and ≥10 years. We evaluated the recent trend in clinical manifestations and the differences in clinical and laboratory findings among the 3 age groups. Results Thirty (37%) children were under 5 years of age, 38 (46.9%) were 5 to 9 years of age, and 13 (16%) were 10 years of age or older. The differences in the symptoms and signs among the 3 age groups were not statistically significant, except for headache. The mean duration of fever was 7.7 days (range, 0 to 18 days). A comparison of liver enzyme elevation among the age groups showed an association with advancing age (26.6%, 63.1%, and 76.9%, respectively, P=0.04) Conclusion This study showed that EBV-associated IM in Korean children continues to occur mostly in children under 10 years of age. In children with EBV-associated IM, the incidence of headache and liver enzyme elevation, the duration of fever, and the proportion of females to males were all positively associated with advancing age. PMID:22232623

  9. Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection

    PubMed Central

    Funata, Sayaka; Matsusaka, Keisuke; Yamanaka, Ryota; Yamamoto, Shogo; Okabe, Atsushi; Fukuyo, Masaki; Aburatani, Hiroyuki; Fukayama, Masashi; Kaneda, Atsushi

    2017-01-01

    Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer. Epstein-Barr virus positive gastric cancer is the most frequently hypermethylated tumor among human malignancies. Herein, we performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP-sequencing for histone modification alteration during EBV infection into gastric cancer cell line MKN7. Among 7,775 genes with increased DNA methylation in promoter regions, roughly half were “DNA methylation-sensitive” genes, which acquired DNA methylation in the whole promoter regions and thus were repressed. These included anti-oncogenic genes, e.g. CDKN2A. The other half were “DNA methylation-resistant” genes, where DNA methylation is acquired in the surrounding of promoter regions, but unmethylated status is protected in the vicinity of transcription start site. These genes thereby retained gene expression, and included DNA repair genes. Histone modification was altered dynamically and coordinately with DNA methylation alteration. DNA methylation-sensitive genes significantly correlated with loss of H3K27me3 pre-marks or decrease of active histone marks, H3K4me3 and H3K27ac. Apoptosis-related genes were significantly enriched in these epigenetically repressed genes. Gain of active histone marks significantly correlated with DNA methylation-resistant genes. Genes related to mitotic cell cycle and DNA repair were significantly enriched in these epigenetically activated genes. Our data show that orchestrated epigenetic alterations are important in gene regulation during EBV infection, and histone modification status in promoter regions significantly associated with acquisition of de novo DNA methylation or protection of unmethylated status at transcription start site. PMID:28903418

  10. Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection.

    PubMed

    Funata, Sayaka; Matsusaka, Keisuke; Yamanaka, Ryota; Yamamoto, Shogo; Okabe, Atsushi; Fukuyo, Masaki; Aburatani, Hiroyuki; Fukayama, Masashi; Kaneda, Atsushi

    2017-08-15

    Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer. Epstein-Barr virus positive gastric cancer is the most frequently hypermethylated tumor among human malignancies. Herein, we performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP-sequencing for histone modification alteration during EBV infection into gastric cancer cell line MKN7. Among 7,775 genes with increased DNA methylation in promoter regions, roughly half were "DNA methylation-sensitive" genes, which acquired DNA methylation in the whole promoter regions and thus were repressed. These included anti-oncogenic genes, e.g. CDKN2A . The other half were "DNA methylation-resistant" genes, where DNA methylation is acquired in the surrounding of promoter regions, but unmethylated status is protected in the vicinity of transcription start site. These genes thereby retained gene expression, and included DNA repair genes. Histone modification was altered dynamically and coordinately with DNA methylation alteration. DNA methylation-sensitive genes significantly correlated with loss of H3K27me3 pre-marks or decrease of active histone marks, H3K4me3 and H3K27ac. Apoptosis-related genes were significantly enriched in these epigenetically repressed genes. Gain of active histone marks significantly correlated with DNA methylation-resistant genes. Genes related to mitotic cell cycle and DNA repair were significantly enriched in these epigenetically activated genes. Our data show that orchestrated epigenetic alterations are important in gene regulation during EBV infection, and histone modification status in promoter regions significantly associated with acquisition of de novo DNA methylation or protection of unmethylated status at transcription start site.

  11. Biopsy-proven case of Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system.

    PubMed

    Kano, Kohei; Katayama, Takayuki; Takeguchi, Shiori; Asanome, Asuka; Takahashi, Kae; Saito, Tsukasa; Sawada, Jun; Saito, Masato; Anei, Ryogo; Kamada, Kyousuke; Miyokawa, Naoyuki; Nishihara, Hiroshi; Hasebe, Naoyuki

    2017-06-01

    A 75-year-old woman was admitted to our hospital with rapidly deteriorating consciousness disturbance. She had a 7-year history of rheumatoid arthritis (RA), which had been treated with methotrexate (MTX) and prednisolone. Brain T2-weighted MRI showed diffuse high-intensity lesions in the cerebral subcortical and deep white matter, bilateral basal ganglia and thalamus. A cerebrospinal fluid examination revealed elevated protein levels and positive Epstein-Barr virus (EBV) DNA. Human immunodeficiency virus was negative. Brain biopsy showed perivascular lymphocytic infiltration in the parenchyma and meninx with EBV-encoded small RNA (EBER). Since this case did not fulfill the criteria for chronic active EBV infection (CAEBV), she was diagnosed with Epstein-Barr virus (EBV)-associated vasculitis of the central nervous system. High-dose methylprednisolone, acyclovir, ganciclovir and foscarnet were not effective. Although EBV is a causative agent of infectious mononucleosis (IM), lymphomas and nasopharyngeal carcinomas, vasculitic pathology of the central nervous system with EBV reactivation in the elderly is rare. Immunosuppressive drugs such as steroids and MTX are widely used to treat autoimmune disorders, but may exacerbate the reactivation of EBV. This is the first case of biopsy-proven EBV-positive/HIV-negative vasculitis during the treatment of RA with MTX and steroids. This case indicates that EBV-associated vasculitis needs to be considered as a differential diagnosis of CNS vasculitis. © 2016 Japanese Society of Neuropathology.

  12. Favorable outcome of Epstein-Barr virus-associated B-cell lymphoproliferative disorder complicated by immunoglobulin G4-related disease treated with rituximab-based therapy: a case report.

    PubMed

    Ueda, Koki; Ikeda, Kazuhiko; Ogawa, Kazuei; Sukegawa, Masumi; Sano, Takahiro; Kimura, Satoshi; Suzuki, Osamu; Hashimoto, Yuko; Takeishi, Yasuchika

    2016-08-24

    After acute infection of Epstein-Barr virus, Epstein-Barr virus-infected B cells survive but usually do not show clonal proliferation. However, Epstein-Barr virus-infected B cells occasionally acquire a proliferative capacity that provokes clonal lymphoproliferative disorders. We herein present a case with Epstein-Barr virus-infected CD30+ B cell and immunoglobulin G4+ plasmacytoid cell proliferation in the lymph nodes, suggesting a pathological and clinical interaction between Epstein-Barr virus-associated B-cell lymphoproliferative disorders and immunoglobulin G4-related disease. Immunoglobulin G4-related disease has been recognized as a benign disease with proliferation of IgG4-related disease+ plasmacytoid cells. Several studies have recently reported the coexistence of immunoglobulin G4-related disease+ plasmacytoid cells with Epstein-Barr virus-infected B cells in lymph nodes in some immunoglobulin G4-related disease cases. However, the pathogenic role of the clonal proliferation of Epstein-Barr virus-infected B cells in immunoglobulin G4-related disease, as well as the treatments for patients with both Epstein-Barr virus-infected B cells and immunoglobulin G4-related disease, have never been discussed. A 50-year-old Japanese man was referred to us for persistent fatigue and lymphadenopathy. His blood examination showed elevated IgG4, and detected high levels of Epstein-Barr virus DNA. A lymph node biopsy revealed IgG4+ plasmacytoid cells and infiltration of large lymphoid cells, which were positive for CD20, CD30, Epstein-Barr virus-related late membrane protein 1, and Epstein-Barr virus-encoded RNA, and were negative for IgG4. Based on the diagnosis of both Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease, the patient received eight cycles of rituximab combined with cyclophosphamide and prednisolone, which resulted in the complete disappearance of lymphadenopathy. Moreover, his serum IgG4 level was significantly

  13. Kinetics of Epstein-Barr Virus (EBV) Neutralizing and Virus-Specific Antibodies after Primary Infection with EBV

    PubMed Central

    Bu, Wei; Hayes, Gregory M.; Liu, Hui; Gemmell, Lorraine; Schmeling, David O.; Radecki, Pierce; Aguilar, Fiona; Burbelo, Peter D.; Woo, Jennifer; Balfour, Henry H.

    2016-01-01

    Prospective studies of antibodies to multiple Epstein-Barr virus (EBV) proteins and EBV neutralizing antibodies in the same individuals before, during, and after primary EBV infection have not been reported. We studied antibody responses to EBV in college students who acquired primary EBV infection during prospective surveillance and correlated the kinetics of antibody response with the severity of disease. Neutralizing antibodies and enzyme-linked immunosorbent assay (ELISA) antibodies to gp350, the major target of neutralizing antibody, reached peak levels at medians of 179 and 333 days after the onset of symptoms of infectious mononucleosis, respectively. No clear correlation was found between the severity of the symptoms of infectious mononucleosis and the peak levels of antibody to individual viral proteins or to neutralizing antibody. In summary, we found that titers of neutralizing antibody and antibodies to multiple EBV proteins increase over many months after primary infection with EBV. PMID:26888186

  14. Kinetics of Epstein-Barr Virus (EBV) Neutralizing and Virus-Specific Antibodies after Primary Infection with EBV.

    PubMed

    Bu, Wei; Hayes, Gregory M; Liu, Hui; Gemmell, Lorraine; Schmeling, David O; Radecki, Pierce; Aguilar, Fiona; Burbelo, Peter D; Woo, Jennifer; Balfour, Henry H; Cohen, Jeffrey I

    2016-04-01

    Prospective studies of antibodies to multiple Epstein-Barr virus (EBV) proteins and EBV neutralizing antibodies in the same individuals before, during, and after primary EBV infection have not been reported. We studied antibody responses to EBV in college students who acquired primary EBV infection during prospective surveillance and correlated the kinetics of antibody response with the severity of disease. Neutralizing antibodies and enzyme-linked immunosorbent assay (ELISA) antibodies to gp350, the major target of neutralizing antibody, reached peak levels at medians of 179 and 333 days after the onset of symptoms of infectious mononucleosis, respectively. No clear correlation was found between the severity of the symptoms of infectious mononucleosis and the peak levels of antibody to individual viral proteins or to neutralizing antibody. In summary, we found that titers of neutralizing antibody and antibodies to multiple EBV proteins increase over many months after primary infection with EBV. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  15. The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events.

    PubMed

    Dunmire, Samantha K; Grimm, Jennifer M; Schmeling, David O; Balfour, Henry H; Hogquist, Kristin A

    2015-12-01

    Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is associated with cancer and autoimmune disease. While many studies have been performed examining acute disease in adults following primary infection, little is known about the virological and immunological events during EBV's lengthy 6 week incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 weeks prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy numbers, suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 weeks before symptoms. However, high levels of EBV in the blood were only observed close to symptom onset-coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the number of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We observed no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral

  16. The Incubation Period of Primary Epstein-Barr Virus Infection: Viral Dynamics and Immunologic Events

    PubMed Central

    Dunmire, Samantha K.; Grimm, Jennifer M.; Schmeling, David O.; Balfour, Henry H.; Hogquist, Kristin A.

    2015-01-01

    Epstein-Barr virus (EBV) is a human herpesvirus that causes acute infectious mononucleosis and is associated with cancer and autoimmune disease. While many studies have been performed examining acute disease in adults following primary infection, little is known about the virological and immunological events during EBV’s lengthy 6 week incubation period owing to the challenge of collecting samples from this stage of infection. We conducted a prospective study in college students with special emphasis on frequent screening to capture blood and oral wash samples during the incubation period. Here we describe the viral dissemination and immune response in the 6 weeks prior to onset of acute infectious mononucleosis symptoms. While virus is presumed to be present in the oral cavity from time of transmission, we did not detect viral genomes in the oral wash until one week before symptom onset, at which time viral genomes were present in high copy numbers, suggesting loss of initial viral replication control. In contrast, using a sensitive nested PCR method, we detected viral genomes at low levels in blood about 3 weeks before symptoms. However, high levels of EBV in the blood were only observed close to symptom onset–coincident with or just after increased viral detection in the oral cavity. These data imply that B cells are the major reservoir of virus in the oral cavity prior to infectious mononucleosis. The early presence of viral genomes in the blood, even at low levels, correlated with a striking decrease in the number of circulating plasmacytoid dendritic cells well before symptom onset, which remained depressed throughout convalescence. On the other hand, natural killer cells expanded only after symptom onset. Likewise, CD4+ Foxp3+ regulatory T cells decreased two fold, but only after symptom onset. We observed no substantial virus specific CD8 T cell expansion during the incubation period, although polyclonal CD8 activation was detected in concert with viral

  17. Epstein-Barr Virus BKRF4 Gene Product Is Required for Efficient Progeny Production.

    PubMed

    Masud, H M Abdullah Al; Watanabe, Takahiro; Yoshida, Masahiro; Sato, Yoshitaka; Goshima, Fumi; Kimura, Hiroshi; Murata, Takayuki

    2017-12-01

    Epstein-Barr virus (EBV), a member of human gammaherpesvirus, infects mainly B cells. EBV has two alternative life cycles, latent and lytic, and is reactivated occasionally from the latent stage to the lytic cycle. To combat EBV-associated disorders, understanding the molecular mechanisms of the EBV lytic replication cycle is also important. Here, we focused on an EBV lytic gene, BKRF4. Using our anti-BKRF4 antibody, we revealed that the BKRF4 gene product is expressed during the lytic cycle with late kinetics. To characterize the role of BKRF4, we constructed BKRF4-knockout mutants using the bacterial artificial chromosome (BAC) and CRISPR/Cas9 systems. Although disruption of the BKRF4 gene had almost no effect on viral protein expression and DNA synthesis, it significantly decreased progeny virion levels in HEK293 and Akata cells. Furthermore, we show that BKRF4 is involved not only in production of progeny virions but also in increasing the infectivity of the virus particles. Immunoprecipitation assays revealed that BKRF4 interacted with a virion protein, BGLF2. We showed that the C-terminal region of BKRF4 was critical for this interaction and for efficient progeny production. Immunofluorescence analysis revealed that BKRF4 partially colocalized with BGLF2 in the nucleus and perinuclear region. Finally, we showed that BKRF4 is a phosphorylated, possible tegument protein and that the EBV protein kinase BGLF4 may be important for this phosphorylation. Taken together, our data suggest that BKRF4 is involved in the production of infectious virions. IMPORTANCE Although the latent genes of EBV have been studied extensively, the lytic genes are less well characterized. This study focused on one such lytic gene, BKRF4, which is conserved only among gammaherpesviruses (ORF45 of Kaposi's sarcoma-associated herpesvirus or murine herpesvirus 68). After preparing the BKRF4 knockout virus using B95-8 EBV-BAC, we demonstrated that the BKRF4 gene was involved in infectious

  18. Detection of human papillomavirus and Epstein-Barr virus DNA sequences in oral mucosa of HIV-infected patients by the polymerase chain reaction.

    PubMed Central

    Snijders, P. J.; Schulten, E. A.; Mullink, H.; ten Kate, R. W.; Jiwa, M.; van der Waal, I.; Meijer, C. J.; Walboomers, J. M.

    1990-01-01

    The presence of human papillomavirus (HPV) and Epstein-Barr virus (EBV) was analyzed in 21 oral biopsy specimens of HIV-infected patients using the polymerase chain reaction (PCR) method. Biopsies were categorized as hairy leukoplakia (HL) (n = 12), candidiasis (n = 3), oral warts (n = 2), and clinically normal epithelium (n = 4). For HPV detection a modified general primer-mediated PCR method (GP-PCR), which detects a broad spectrum of HPV genotypes at sub-picogram levels, was used. Human papillomavirus DNA was only found in two oral warts and was identified as HPV type 32. Epstein-Barr virus DNA was detected in 16 biopsy specimens, including the 12 HLs, 2 cases of candidiasis, and 2 samples of normal epithelium. Epstein-Barr virus positivity in HL could be confirmed by Southern blot analysis and DNA in situ hybridization using biotinylated DNA probes (bio-DISH). Epstein-Barr virus bio-DISH was also positive in one sample of normal epithelium from a patient with HL. The results indicate that HL is strongly associated with EBV and not with any of the common HPV types that react with general HPV primers in the PCR. However the detection of EBV in normal oral epithelium by PCR and bio-DISH suggests that the presence of this virus is not exclusively related to HL. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:2169191

  19. Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population: 11-year follow-up study.

    PubMed

    Torniainen-Holm, Minna; Suvisaari, Jaana; Lindgren, Maija; Härkänen, Tommi; Dickerson, Faith; Yolken, Robert H

    2018-03-01

    Earlier studies have documented an association between cytomegalovirus and cognitive impairment, but results have been inconsistent. Few studies have investigated the association of cytomegalovirus and Epstein-Barr virus with cognitive decline longitudinally. Our aim was to examine whether cytomegalovirus and Epstein-Barr virus are associated with cognitive decline in adults. The study sample is from the Finnish Health 2000 Survey (BRIF8901, n = 7112), which is representative of the Finnish adult population. The sample was followed up after 11 years in the Health 2011 Survey. In addition, persons with dementia were identified from healthcare registers. In the Finnish population aged 30 and over, the seroprevalence of cytomegalovirus was estimated to be 84% and the seroprevalence of Epstein-Barr virus 98%. Seropositivity of the viruses and antibody levels were mostly not associated with cognitive performance. In the middle-aged adult group, cytomegalovirus serointensity was associated with impaired performance in verbal learning. However, the association disappeared when corrected for multiple testing. No interactions between infection and time or between the two infections were significant when corrected for multiple testing. Seropositivity did not predict dementia diagnosis. The results suggest that adult levels of antibodies to cytomegalovirus and Epstein-Barr virus may not be associated with a significant decline in cognitive function or with dementia at population level. Copyright © 2018. Published by Elsevier Inc.

  20. Epstein-Barr virus-positive mucocutaneous ulcer in Crohn's disease. A condition to consider in immunosuppressed IBD patients.

    PubMed

    Juan, Alba; Lobatón, Triana; Tapia, Gustavo; Mañosa, Míriam; Cabré, Eduard; Domènech, Eugeni

    2017-08-01

    Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a little known entity that can affect the oropharyngeal mucosa, the gastrointestinal tract and the skin. The main risk factor for the development of this lesion is immunosuppression. Because its features are similar to other Epstein-Barr virus-associated lymphoproliferative disorders, a differential diagnosis can sometimes prove challenging. Here, we report the case of a man diagnosed with Crohn's disease and treated with azathioprine and infliximab who developed ulceration at the rectum that was refractory to conventional medical treatment. Although the histological characteristics were suggestive of an EBVMCU, lymphoproliferative disease could not be ruled out. The patient did not improve after discontinuation of the treatment, a proctectomy was performed and the diagnosis of this disease was confirmed. Although very few cases of EBVMCU affecting the colon have been reported, its diagnosis should be always considered in refractory cases of inflammatory bowel disease with patients undergoing immunosuppressive treatment. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  1. Quantitative analysis of Epstein-Barr virus (EBV)-related gene expression in patients with chronic active EBV infection.

    PubMed

    Iwata, Seiko; Wada, Kaoru; Tobita, Satomi; Gotoh, Kensei; Ito, Yoshinori; Demachi-Okamura, Ayako; Shimizu, Norio; Nishiyama, Yukihiro; Kimura, Hiroshi

    2010-01-01

    Chronic active Epstein-Barr virus (CAEBV) infection is a systemic Epstein-Barr virus (EBV)-positive lymphoproliferative disorder characterized by persistent or recurrent infectious mononucleosis-like symptoms in patients with no known immunodeficiency. The detailed pathogenesis of the disease is unknown and no standard treatment regimen has been developed. EBV gene expression was analysed in peripheral blood samples collected from 24 patients with CAEBV infection. The expression levels of six latent and two lytic EBV genes were quantified by real-time RT-PCR. EBV-encoded small RNA 1 and BamHI-A rightward transcripts were abundantly detected in all patients, and latent membrane protein (LMP) 2 was observed in most patients. EBV nuclear antigen (EBNA) 1 and LMP1 were detected less frequently and were expressed at lower levels. EBNA2 and the two lytic genes were not detected in any of the patients. The pattern of latent gene expression was determined to be latency type II. EBNA1 was detected more frequently and at higher levels in the clinically active patients. Quantifying EBV gene expression is useful in clarifying the pathogenesis of CAEBV infection and may provide information regarding a patient's disease prognosis, as well as possible therapeutic interventions.

  2. Presence of natural killer-cell clones with variable proliferative capacity in chronic active Epstein-Barr virus infection.

    PubMed

    Nagata, H; Numata, T; Konno, A; Mikata, I; Kurasawa, K; Hara, S; Nishimura, M; Yamamoto, K; Shimizu, N

    2001-10-01

    Chronic active Epstein-Barr virus infection (CAEBV) is a syndrome that takes diverse clinical courses and is often associated with lymphoproliferative disorders of T/natural killer (NK)-cell lineage. We describe a patient with CAEBV associated with persistent pharyngeal ulcer, and with subsequent nasal T/NK-cell lymphoma in her neck lymph nodes and nasopharynx. Immunophenotyping of lymphoid cells showed that the lineage of Epstein-Barr virus (EBV)-positive cells in the patient was of NK-cell origin. By means of high-dose recombinant interleukin-2, we established an EBV-positive cell line of NK-cell lineage from her peripheral blood. Southern blot analysis for the number of terminal repeat sequences of EBV detected three NK-cell clones in the patient's lymph node. One of these clones was identical to the established cell line but was not observed in the pharyngeal ulcer, while the other two clones were present in the pharyngeal ulcer. These results suggest that the patient had expansion of the three NK-cell clones, one of which had proliferative capacity in vitro and was involved in the formation of the lymphoma. Moreover, the results suggest that the proliferative capacity of EBV-positive cells can be variable even in a single patient, and this variability may explain the clinical diversity in CAEBV.

  3. Diagnostic dilemma: Epstein-Barr virus (EBV) infectious mononucleosis with lung involvement or co-infection with Legionnaire's disease?

    PubMed

    Cunha, Burke A; Gian, John

    Hospitalized adults with fever and "pneumonia" can be a difficult diagnostic challenge particularly when the clinical findings may be due to different infectious diseases. We recently had an elderly female who presented with fever, fatigue and dry cough with elevated serum transaminases and lung infiltrates. The diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis (IM) was made based on a positive Monospot test, elevated EBV VCA IgM titer, and highly elevated EBV viral load. Her chest infiltrates were not accompanied by hilar adenopathy which may occur with EBV IM. Her dry cough persisted and she developed abdominal pain. Legionnaire's disease was considered because she had extra-pulmonary findings characteristic of Legionnaire's disease, e.g., relative bradycardia, abdominal pain, hyponatremia, hypophosphatemia, elevated ferritin levels, microscopic hematuria. Legionella titers were negative, but Legionella (serogroup 1) urinary antigen was positive. We present a diagnostic dilemma in an elderly female with both Legionnaire's disease and Epstein-Barr virus infectious mononucleosis with pulmonary involvement. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Transcriptome-wide analysis of alternative RNA splicing events in Epstein-Barr virus-associated gastric carcinomas

    PubMed Central

    Armero, Victoria E. S.; Tremblay, Marie-Pier; Allaire, Andréa; Boudreault, Simon; Martenon-Brodeur, Camille; Duval, Cyntia; Durand, Mathieu; Lapointe, Elvy; Thibault, Philippe; Tremblay-Létourneau, Maude; Perreault, Jean-Pierre; Scott, Michelle S.

    2017-01-01

    Multiple human diseases including cancer have been associated with a dysregulation in RNA splicing patterns. In the current study, modifications to the global RNA splicing landscape of cellular genes were investigated in the context of Epstein-Barr virus-associated gastric cancer. Global alterations to the RNA splicing landscape of cellular genes was examined in a large-scale screen from 295 primary gastric adenocarcinomas using high-throughput RNA sequencing data. RT-PCR analysis, mass spectrometry, and co-immunoprecipitation studies were also used to experimentally validate and investigate the differential alternative splicing (AS) events that were observed through RNA-seq studies. Our study identifies alterations in the AS patterns of approximately 900 genes such as tumor suppressor genes, transcription factors, splicing factors, and kinases. These findings allowed the identification of unique gene signatures for which AS is misregulated in both Epstein-Barr virus-associated gastric cancer and EBV-negative gastric cancer. Moreover, we show that the expression of Epstein–Barr nuclear antigen 1 (EBNA1) leads to modifications in the AS profile of cellular genes and that the EBNA1 protein interacts with cellular splicing factors. These findings provide insights into the molecular differences between various types of gastric cancer and suggest a role for the EBNA1 protein in the dysregulation of cellular AS. PMID:28493890

  5. Structural analyses of EBER1 and EBER2 ribonucleoprotein particles present in Epstein-Barr virus-infected cells.

    PubMed Central

    Glickman, J N; Howe, J G; Steitz, J A

    1988-01-01

    The ribonucleoprotein (RNP) particles containing the Epstein-Barr virus-associated small RNAs EBER1 and EBER2 were analyzed to determine their RNA secondary structures and sites of RNA-protein interaction. The secondary structures were probed with nucleases and by chemical modification with single-strand-specific reagents, and the sites of modification or cleavage were mapped by primer extension. These data were used to develop secondary structures for the two RNAs, and likely sites of close RNA-protein contact were identified by comparing modification patterns for naked RNA and RNA in RNP particles. In addition, sites of interaction between each Epstein-Barr virus-encoded RNA (EBER) and the La antigen were identified by analyzing RNA fragments resistant to digestion by RNase A or T1 after immunoprecipitation by an anti-La serum sample from a lupus patient. Our results confirm earlier findings that the La protein binds to the 3' terminus of each molecule. Possible functions for the EBER RNPs are discussed. Images PMID:2828685

  6. Disseminated hyperkeratotic and granulomatous nodules in a child with fatal Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis.

    PubMed

    Brinkmeier, Thomas; Reuter, Thomas; Metze, Dieter; Frosch, Peter J; Herbst, Rudolf A

    2006-01-01

    Hemophagocytic lymphohistiocytosis is a rare and potentially fatal syndrome associated with a variety of genetic, malignant, autoimmune, or infectious conditions. The importance of cutaneous presentations of this syndrome has only recently been brought forward. We report the first case of Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis presenting with papulonodular and granulomatous skin lesions. A girl of African origin developed several umbilicated papules on her extremities and face at the age of 18 months. She was born in Germany, had never visited Africa, and was otherwise healthy. Over the next 5 months the lesions progressed in size and number and became hyperkeratotic. Histopathologic analysis of early lesions revealed a superficial lympho- and plasmacellular dermatitis with some features of panniculitis. Later biopsy specimens from nodular lesions showed the formation of tuberculoid granulomas in the deep dermis. At the age of 23 months she became severely ill, rapidly developing high fever, hepatosplenomegaly, icterus, pancytopenia, and ascites. On the basis of bone marrow and lymph node biopsies, the diagnosis of hemophagocytic lymphohistiocytosis was established. However, this phenomenon could not be detected in any of the skin specimens. An active Epstein-Barr virus infection was diagnosed by polymerase chain reaction in blood, lymphoid tissue, and skin. Despite chemotherapy with etoposide and cortisone, the girl expired 14 days after clinical onset of her systemic disease.

  7. Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis and Guillain-Barre Syndrome in a 16-Month-Old Child

    PubMed Central

    Shimizu, Mariko; Ioi, Aya; Mayumi, Azusa; Higuchi, Kohei; Sawada, Akihisa; Sato, Maho; Yasui, Masahiro; Yanagihara, Keiko; Inoue, Masami

    2016-01-01

    A 16-month-old girl was diagnosed with Epstein-Barr virus hemophagocytic lymphohistiocytosis and transferred to our hospital on the 58th day of the hemophagocytic lymphohistiocytosis after treatment failure according to the Hemophagocytic Lymphohistiocytosis-2004 protocol. On admission to our hospital, she had a flaccid paralysis of her lower limbs. Nerve conduction studies showed a acute motor axonal neuropathy, and a diagnosis of Guillain-Barre syndrome was established. Intravenous immunoglobulin G was started on the 57th day of the Guillain-Barre syndrome. To date, her neurological recovery is incomplete. For hemophagocytic lymphohistiocytosis, after treatment failure of THP-COP regimen (pirarubicin, cyclophosphamide, vincristine, and prednisone) and 2 courses of ESCAP regimen (etoposide, prednisone, cytarabine, L-asparaginase), we are now in the process of coordinating unrelated umbilical cord blood transplantation. To the best of our knowledge, we report the youngest case of Guillain-Barre syndrome accompanied by Epstein-Barr virus hemophagocytic lymphohistiocytosis. Rapid progression of Guillain-Barre syndrome, the electrophysiological subtype of Guillain-Barre syndrome, and treatment delay possibly led to poor neurological outcome. PMID:28503601

  8. Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis and Guillain-Barre Syndrome in a 16-Month-Old Child.

    PubMed

    Matsui, Motohiro; Shimizu, Mariko; Ioi, Aya; Mayumi, Azusa; Higuchi, Kohei; Sawada, Akihisa; Sato, Maho; Yasui, Masahiro; Yanagihara, Keiko; Inoue, Masami

    2016-01-01

    A 16-month-old girl was diagnosed with Epstein-Barr virus hemophagocytic lymphohistiocytosis and transferred to our hospital on the 58th day of the hemophagocytic lymphohistiocytosis after treatment failure according to the Hemophagocytic Lymphohistiocytosis-2004 protocol. On admission to our hospital, she had a flaccid paralysis of her lower limbs. Nerve conduction studies showed a acute motor axonal neuropathy, and a diagnosis of Guillain-Barre syndrome was established. Intravenous immunoglobulin G was started on the 57th day of the Guillain-Barre syndrome. To date, her neurological recovery is incomplete. For hemophagocytic lymphohistiocytosis, after treatment failure of THP-COP regimen (pirarubicin, cyclophosphamide, vincristine, and prednisone) and 2 courses of ESCAP regimen (etoposide, prednisone, cytarabine, L-asparaginase), we are now in the process of coordinating unrelated umbilical cord blood transplantation. To the best of our knowledge, we report the youngest case of Guillain-Barre syndrome accompanied by Epstein-Barr virus hemophagocytic lymphohistiocytosis. Rapid progression of Guillain-Barre syndrome, the electrophysiological subtype of Guillain-Barre syndrome, and treatment delay possibly led to poor neurological outcome.

  9. Regulation and dysregulation of Epstein-Barr virus latency: implications for the development of autoimmune diseases.

    PubMed

    Niller, Hans Helmut; Wolf, Hans; Minarovits, Janos

    2008-05-01

    Epstein-Barr virus (EBV) is a human herpesvirus hiding in a latent form in memory B cells in the majority of the world population. Although, primary EBV infection is asymptomatic or causes a self-limiting disease, infectious mononucleosis, the virus is associated with a wide variety of neoplasms developing in immunosuppressed or immunodeficient individuals, but also in patients with an apparently intact immune system. In memory B cells, tumor cells, and lymphoblastoid cell lines (LCLs, transformed by EBV in vitro) the expression of the viral genes is highly restricted. There is no virus production (lytic viral replication associated with the expression of all viral genes) in tight latency. The expression of latent viral oncogenes and RNAs is under a strict epigenetic control via DNA methylation and histone modifications that results either in a complete silencing of the EBV genome in memory B cells, or in a cell-type dependent usage of latent promoters in tumor cells, germinal center B cells, and LCLs. Both the latent and lytic EBV proteins are potent immunogens and elicit vigorous B- and T-cell responses. In immunosuppressed and immunodeficient patients, or in individuals with a functional defect of EBV-specific T cells, lytic EBV replication is regularly activated and an increased viral load can be detected in the blood. Enhanced lytic replication results in new infection events and EBV-associated transformation events, and seems to be a risk factor both for malignant transformation and the development of autoimmune diseases. One may speculate that an increased load or altered presentation of a limited set of lytic or latent EBV proteins that cross-react with cellular antigens triggers and perpetuates the pathogenic processes that result in multiple sclerosis, systemic lupus erythematosus (SLE), and rheumatoid arthritis. In addition, in SLE patients EBV may cause defects of B-cell tolerance checkpoints because latent membrane protein 1, an EBV-encoded viral

  10. Tumor Suppressor p53 Stimulates the Expression of Epstein-Barr Virus Latent Membrane Protein 1.

    PubMed

    Wang, Qianli; Lingel, Amy; Geiser, Vicki; Kwapnoski, Zachary; Zhang, Luwen

    2017-10-15

    Epstein-Barr virus (EBV) is associated with multiple human malignancies. EBV latent membrane protein 1 (LMP1) is required for the efficient transformation of primary B lymphocytes in vitro and possibly in vivo The tumor suppressor p53 plays a seminal role in cancer development. In some EBV-associated cancers, p53 tends to be wild type and overly expressed; however, the effects of p53 on LMP1 expression is not clear. We find LMP1 expression to be associated with p53 expression in EBV-transformed cells under physiological and DNA damaging conditions. DNA damage stimulates LMP1 expression, and p53 is required for the stimulation. Ectopic p53 stimulates endogenous LMP1 expression. Moreover, endogenous LMP1 blocks DNA damage-mediated apoptosis. Regarding the mechanism of p53-mediated LMP1 expression, we find that interferon regulatory factor 5 (IRF5), a direct target of p53, is associated with both p53 and LMP1. IRF5 binds to and activates a LMP1 promoter reporter construct. Ectopic IRF5 increases the expression of LMP1, while knockdown of IRF5 leads to reduction of LMP1. Furthermore, LMP1 blocks IRF5-mediated apoptosis in EBV-infected cells. All of the data suggest that cellular p53 stimulates viral LMP1 expression, and IRF5 may be one of the factors for p53-mediated LMP1 stimulation. LMP1 may subsequently block DNA damage- and IRF5-mediated apoptosis for the benefits of EBV. The mutual regulation between p53 and LMP1 may play an important role in EBV infection and latency and its related cancers. IMPORTANCE The tumor suppressor p53 is a critical cellular protein in response to various stresses and dictates cells for various responses, including apoptosis. This work suggests that an Epstein-Bar virus (EBV) principal viral oncogene is activated by cellular p53. The viral oncogene blocks p53-mediated adverse effects during viral infection and transformation. Therefore, the induction of the viral oncogene by p53 provides a means for the virus to cope with infection and

  11. A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord.

    PubMed

    Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

    2015-06-29

    The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. 2015 BMJ Publishing Group Ltd.

  12. A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord

    PubMed Central

    Wilaisakditipakorn, Tanaporn; Vilaisaktipakorn, Pitchamol; Bunupuradah, Torsak; Puthanakit, Thanyawee

    2015-01-01

    The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. PMID:26123466

  13. Mycoplasma pneumoniae preceding Lemierre's syndrome due to Fusobacterium nucleatum complicated by acute Epstein-Barr virus (EBV) infectious mononucleosis in an immunocompetent host.

    PubMed

    Klein, Natalie C; Petelin, Andrew; Cunha, Burke A

    2013-01-01

    We report an unusual case of Lemierre's syndrome due to a rare species of Fusobacterium, that is, Fusobacterium nucleatum preceded by Mycoplasma pneumoniae pharyngitis and followed later by Epstein-Barr virus infectious mononucleosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Unique variations of Epstein-Barr virus-encoded BARF1 gene in nasopharyngeal carcinoma biopsies.

    PubMed

    Wang, Yun; Wang, Xiao-Feng; Sun, Zhi-Fu; Luo, Bing

    2012-06-01

    The Epstein-Barr virus (EBV) BamHI-A rightward frame 1 (BARF1) gene is frequently expressed in EBV-associated epithelial malignancies and involves in oncogenicity and immunomodulation. To characterize the variations of BARF1 gene in different populations, the sequences of BARF1 gene in Northern Chinese nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC) and healthy donors were analyzed. The correlation of BARF1 variation with polymorphisms of BamHI F fragment (type F and f variants) and EBV-coded viral interleukin-10 (vIL-10) gene (B95-8 and SPM patterns) was also explored. Two major subtypes of BARF1 gene, designated as B95-8 and V29A, were identified. B95-8 subtype had identical amino acid sequence to B95-8 and was the dominant subtype among the EBV isolates from Northern China. V29A subtype, with one consistent amino acid change at residue 29 (V→A) and several nucleotide changes, showed higher frequency in NPC cases (25.3%, 20/79) than in EBVaGC cases (0/45) or healthy donors (4.3%, 2/46) (NPC vs. EBVaGC: P=0.0001; NPC vs. healthy donor: P=0.004). A preferential linkage between BamHI F and BARF1/vIL-10 polymorphisms was found. Type f isolates was specially correlated with the V29A/SPM genotype in NPC isolates and type f/V29A/SPM was preferentially found in NPC. BARF1/c-fms homology domain, transforming domain and cytotoxic T lymphocyte (CTL) epitopes of BARF1 were highly conserved in most isolates, suggesting the important role of BARF1 in virus infection and the potential usefulness in EBV-targeting immunotherapy of EBV-associated tumors. The relatively higher prevalence of type f/V29A/SPM strains in NPC may also suggest the association between these variations in multiple viral genes and NPC. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. P32/TAP, a cellular protein that interacts with EBNA-1 of Epstein-Barr virus.

    PubMed

    Wang, Y; Finan, J E; Middeldorp, J M; Hayward, S D

    1997-09-15

    The Epstein-Barr virus (EBV) EBNA-1 protein has a central role in the maintenance of a latent EBV infection and is the only virus-encoded protein expressed in all EBV-associated tumors. EBNA-1 is required for replication of the episomal form of the latent viral genome and transactivates the latency C and LMP-1 promoters. The mechanisms by which EBNA-1 performs these functions are not known. Here we describe the cloning, expression, and characterization of a cellular protein, P32/TAP, which strongly interacts with EBNA-1. We show that P32/TAP is expressed at high levels in Raji cells and is synthesized as a proprotein of 282 amino acids (aa) that is posttranslationally processed by a two-step cleavage process to yield a mature protein of 209 aa. It has been previously reported that P32/TAP is expressed on the cell surface. Our transient expression assays detected full-length P32/TAP (1-282 aa) in the cytoplasm while mature P32/TAP protein localized to the nucleus. Three lines of evidence support P32/TAP interaction with EBNA-1. First, in the yeast two-hybrid system we mapped two interactive N-terminal regions of EBNA-1, aa 40-60 and aa 325-376, each of which contains arginine-glycine repeats. These regions interact with the C-terminal half of P32/TAP. Second, the full-length cytoplasmic P32/TAP protein can translocate nuclear EBNA-1 into the cytoplasm. Third, P32/TAP co-immunoprecipitated with EBNA-1. We have confirmed that a Gal4 fusion protein containing the C-terminal region of P32/TAP (aa 244-282) transactivates expression from a reporter containing upstream Gal4-binding sites. Deletion of the P32/TAP interactive regions of EBNA-1 severely diminished EBNA-1 transactivation of FRTKCAT in transient expression assays. Our data suggest that interaction with P32/TAP may contribute to EBNA-1-mediated transactivation. Copyright 1997 Academic Press.

  16. Epstein-Barr virus infection and breast invasive ductal carcinoma in Egyptian women: A single center experience.

    PubMed

    El-Naby, Noha Ed Hassab; Hassan Mohamed, Hameda; Mohamed Goda, Asmaa; El Sayed Mohamed, Ahmed

    2017-06-01

    A controversy of the role of Epstein-Barr virus (EBV) infection in breast carcinomas has been reported in the literature. We carried on this research to explore possible association between EBV infection and breast invasive ductal carcinoma (IDC) in Egyptian women attending our center. This study carried out at Sohag university hospital on 84 paraffin embedded samples of breast tissue, of them 42 breast IDC as the case group and 42 breast fibroadenomas as the control group. Nested PCRand immunohistochemistry (IHC) done separately for all samples to identify the Epstein-Barr nuclear antigen-1 (EBNA-1) gene and EBV latent membrane protein-1 (LMP-1) respectively, in breast cancer cells and controls. Specimen considered positive when both (EBNA-1) gene and LMP-1 were detected using PCR and IHC separately for the same sample, this was achieved by 10/42 (23.81%) of breast IDC (case group) and 6/42 (14.29%) of breast fibro-adenomas (control group) (P-value=0.4). Nodal involvement was the only parameter that demonstrated a significant statistical relationship with EBV presence in cancerous tissue with p-value=0.003. Our research could not find a significant statistical association between EBV infection and breast IDC in Egyptian women attending our center, but, there might be an association between the existence of EBV and tumor aggressiveness. Copyright © 2017 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. All rights reserved.

  17. Expression of Epstein-Barr virus among oral potentially malignant disorders and oral squamous cell carcinomas in the South Indian tobacco-chewing population.

    PubMed

    Reddy, Sujatha S; Sharma, Shivani; Mysorekar, Vijaya

    2017-07-01

    Oral cancer is the sixth most common malignancy in the world. Viruses are the causative agents of approximately 10-15% of all cancers worldwide (Cancers, 6, 2014 and 2155). The tumorigenic roles of Epstein-Barr virus in oral cancer are unclear. Literature search results are conflicting and dependent on various factors such as geographical/regional variations, sociocultural lifestyles, dietary habits, chewing/smoking tobacco habit. This study is the first original observation about frequency of Epstein-Barr virus among South Indian tobacco-chewing patients to elucidate its involvement in oral carcinogenesis and to know whether this can be a valuable diagnostic and prognostic indicator. A total number of 75 tobacco chewer subjects aged between 23 and 76 years with histopathologically confirmed oral potentially malignant disorders (25), oral squamous cell carcinoma (25), and age-matched healthy controls (25) formed the study group. Immunohistochemical expression of Epstein-Barr virus latent membrane protein 1 was assessed among cases and healthy controls. Out of the total 75 subjects, six subjects (8%) were positive for Epstein-Barr virus antigen and 69 subjects (92%) negative. The antigen positivity was observed among two cases of moderately differentiated oral squamous cell carcinoma, two cases of leukoplakia, and two healthy controls. No significant association between Epstein-Barr virus positivity was observed among oral potentially malignant disorders and oral squamous cell carcinoma among South Indian tobacco-chewing patients. This can be partially explained by the methodology employed, by the patient population analyzed and different habits in various geographical regions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Persistently high Epstein-Barr virus (EBV) loads in peripheral blood lymphocytes from patients with chronic active EBV infection.

    PubMed

    Maeda, A; Wakiguchi, H; Yokoyama, W; Hisakawa, H; Tomoda, T; Kurashige, T

    1999-04-01

    Chronic active Epstein-Barr virus infection (CAEBV) is a severe illness with unusual EBV activation that persists for years, and its pathogenesis is largely unknown. After the creation of an accurate and reproducible polymerase chain reaction system to quantify EBV DNA, virus loads in peripheral blood lymphocytes (PBL) were determined in 54 children: 15 with CAEBV, 16 with infectious mononucleosis (IM), and 23 healthy children. Children with CAEBV and those with IM had high virus loads. Lower loads were detected in 47% of seropositive healthy donors. There were two distinct differences between children with CAEBV and those with IM: The former had greater viral replication (10(3)-10(7) copies/2.5x10(5) PBL) than those with IM, and viral replication declined in children with IM whereas active replication persisted for years in subjects with CAEBV. Persisting high virus loads are a possible diagnostic criterion for CAEBV. EBV loads may enable classification and prognosis of EBV infections.

  19. Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA.

    PubMed

    Correia, Samantha; Palser, Anne; Elgueta Karstegl, Claudio; Middeldorp, Jaap M; Ramayanti, Octavia; Cohen, Jeffrey I; Hildesheim, Allan; Fellner, Maria Dolores; Wiels, Joelle; White, Robert E; Kellam, Paul; Farrell, Paul J

    2017-08-01

    Viral gene sequences from an enlarged set of about 200 Epstein-Barr virus (EBV) strains, including many primary isolates, have been used to investigate variation in key viral genetic regions, particularly LMP1, Zp, gp350, EBNA1, and the BART microRNA (miRNA) cluster 2. Determination of type 1 and type 2 EBV in saliva samples from people from a wide range of geographic and ethnic backgrounds demonstrates a small percentage of healthy white Caucasian British people carrying predominantly type 2 EBV. Linkage of Zp and gp350 variants to type 2 EBV is likely to be due to their genes being adjacent to the EBNA3 locus, which is one of the major determinants of the type 1/type 2 distinction. A novel classification of EBNA1 DNA binding domains, named QCIGP, results from phylogeny analysis of their protein sequences but is not linked to the type 1/type 2 classification. The BART cluster 2 miRNA region is classified into three major variants through single-nucleotide polymorphisms (SNPs) in the primary miRNA outside the mature miRNA sequences. These SNPs can result in altered levels of expression of some miRNAs from the BART variant frequently present in Chinese and Indonesian nasopharyngeal carcinoma (NPC) samples. The EBV genetic variants identified here provide a basis for future, more directed analysis of association of specific EBV variations with EBV biology and EBV-associated diseases. IMPORTANCE Incidence of diseases associated with EBV varies greatly in different parts of the world. Thus, relationships between EBV genome sequence variation and health, disease, geography, and ethnicity of the host may be important for understanding the role of EBV in diseases and for development of an effective EBV vaccine. This paper provides the most comprehensive analysis so far of variation in specific EBV genes relevant to these diseases and proposed EBV vaccines. By focusing on variation in LMP1, Zp, gp350, EBNA1, and the BART miRNA cluster 2, new relationships with the known

  20. Small molecule and peptide-mediated inhibition of Epstein-Barr virus nuclear antigen 1 dimerization

    SciTech Connect

    Kim, Sun Young; Song, Kyung-A; Samsung Biomedical Research Institute

    Highlights: Black-Right-Pointing-Pointer Evidence that targeting EBNA1 dimer, an EBV onco-antigen, can be achievable. Black-Right-Pointing-Pointer A small molecule and a peptide as EBNA1 dimerization inhibitors identified. Black-Right-Pointing-Pointer Both inhibitors associated with EBNA1 and blocked EBNA1 DNA binding activity. Black-Right-Pointing-Pointer Also, prevented its dimerization, and repressed viral gene transcription. -- Abstract: Latent Epstein-Barr virus (EBV) infection is associated with human B cell lymphomas and certain carcinomas. EBV episome persistence, replication, and gene expression are dependent on EBV-encoded nuclear antigen 1 (EBNA1)'s DNA binding domain (DBD)/dimerization domain (DD)-mediated sequence-specific DNA binding activity. Homodimerization of EBNA1 is essential for EBNA1 DNA binding and transactivation.more » In this study, we characterized a novel small molecule EBNA1 inhibitor EiK1, screened from the previous high throughput screening (HTS). The EiK1 compound specifically inhibited the EBNA1-dependent, OriP-enhanced transcription, but not EBNA1-independent transcription. A Surface Plasmon Resonance Biacore assay revealed that EiK1 associates with EBNA1 amino acid 459-607 DBD/DD. Consistent with the SPR data, in vitro gel shift assays showed that EiK1 suppressed the activity of EBNA1 binding to the cognate familial repeats (FR) sequence, but not control RBP-J{kappa} binding to the J{kappa} site. Subsequently, a cross-linker-mediated in vitro multimerization assay and EBNA1 homodimerization-dependent yeast two-hybrid assay showed that EiK1 significantly inhibited EBNA1 dimerization. In an attempt to identify more highly specific peptide inhibitors, small peptides encompassing the EBNA1 DBD/DD were screened for inhibition of EBNA1 DBD-mediated DNA binding function. The small peptide P85, covering EBNA1 a.a. 560-574, significantly blocked EBNA1 DNA binding activity in vitro, prevented dimerization in vitro and in vivo, associated

  1. Effect of Interleukins on Antibody Production by Epstein-Barr Virus Transformed B Cells.

    PubMed

    Ali, Aisheh I; Badran, Yousef R; Hassuneh, Mona R; Sanber, Khaled S; Ismail, Said I

    2015-06-01

    During the past few decades, monoclonal antibodies (MAbs) have become an increasingly used tool in diagnostics, therapeutics, and biomedical research. Several methods have been employed to produce MAbs, one of which is the immortalization of B cells by Epstein-Barr virus (EBV). Despite its simplicity, this procedure was never routinely adopted due to its poor efficiency and short-lived antibody (Ab) production. Various adjustments to the basic procedure were introduced, including the addition of certain cytokines and CpG oligodeoxynucleotides, which were shown to improve EBV infectivity and cloning efficiency. The objective of this study was to manipulate culture conditions of the EBV-transformed human lymphocytes, lymphoblastoid cell lines (LCLs), by the timely addition of stimuli including CpG and various interleukins. Such manipulations are aimed at improving LCL proliferative activity and enhancing the cell lines' immortalization potential as well as their Ab production. To accomplish this, IgG(+) B cells were isolated from peripheral blood of a hepatitis B vaccinated, anti-HB Ab-positive volunteer. These cells were infected with EBV and incubated in the presence of CpG DNA 2006 motifs, recombinant human interleukin-2 (rhIL-2), rhIL-4, rhIL-6, and rhIL-21, individually and in combinations. Cells were then restimulated for 2 weeks with the same ILs. The effect of these ILs on anti-HB Ab production and the proliferation of the EBV-transformed lymphocytes were investigated. The current study demonstrates that treatment of LCL cultures with rhIL-2, rh-IL4, rhIL-6, and rhIL-21, individually and in combination, increased to varying degrees the proliferative activity and Ab production of these cells. The addition of IL-4 alone was able to sustain increase in anti-HB Ab despite IL-4 withdrawal. This study suggests that with further optimization ILs can have an enhancing effect on LCL immortalization potential and Ab production capacity.

  2. The Minimal Replicator of Epstein-Barr Virus oriP

    PubMed Central

    Yates, John L.; Camiolo, Sarah M.; Bashaw, Jacqueline M.

    2000-01-01

    oriP is a 1.7-kb region of the Epstein-Barr virus (EBV) chromosome that supports the replication and stable maintenance of plasmids in human cells. oriP contains two essential components, called the DS and the FR, both of which contain multiple binding sites for the EBV-encoded protein, EBNA-1. The DS appears to function as the replicator of oriP, while the FR acts in conjunction with EBNA-1 to prevent the loss of plasmids from proliferating cells. Because of EBNA-1's role in stabilizing plasmids through the FR, it has not been entirely clear to what extent EBNA-1 might be required for replication from oriP per se, and a recent study has questioned whether EBNA-1 has any direct role in replication. In the present study we found that plasmids carrying oriP required EBNA-1 to replicate efficiently even when assayed only 2 days after plasmids were introduced into the cell lines 143B and 293. Significantly, using 293 cells it was demonstrated that the plasmid-retention function of EBNA-1 and the FR did not contribute significantly to the accumulation of replicated plasmids, and the DS supported efficient EBNA-1-dependent replication in the absence of the FR. The DS contains two pairs of closely spaced EBNA-1 binding sites, and a previous study had shown that both sites within either pair are required for activity. However, it was unclear from previous work what additional sequences within the DS might be required. We found that each “half” of the DS, including a pair of closely spaced EBNA-1 binding sites, had significant replicator activity when the other half had been deleted. The only significant DNA sequences that the two halves of the DS share in common, other than EBNA-1 binding sites, is a 9-bp sequence that is present twice in the “left half” and once in the “right half.” These nonamer repeats, while not essential for activity, contributed significantly to the activity of each half of the DS. Two thymines occur at unique positions within EBNA-1

  3. Epstein-Barr Virus, Human Papillomavirus and Mouse Mammary Tumour Virus as Multiple Viruses in Breast Cancer

    PubMed Central

    Glenn, Wendy K.; Heng, Benjamin; Delprado, Warick; Iacopetta, Barry; Whitaker, Noel J.; Lawson, James S.

    2012-01-01

    Background The purpose of this investigation is to determine if Epstein Barr virus (EBV), high risk human papillomavirus (HPV), and mouse mammary tumour viruses (MMTV) co-exist in some breast cancers. Materials and Methods All the specimens were from women residing in Australia. For investigations based on standard PCR, we used fresh frozen DNA extracts from 50 unselected invasive breast cancers. For normal breast specimens, we used DNA extracts from epithelial cells from milk donated by 40 lactating women. For investigations based on in situ PCR we used 27 unselected archival formalin fixed breast cancer specimens and 18 unselected archival formalin fixed normal breast specimens from women who had breast reduction surgery. Thirteen of these fixed breast cancer specimens were ductal carcinoma in situ (dcis) and 14 were predominantly invasive ductal carcinomas (idc). Results EBV sequences were identified in 68%, high risk HPV sequences in 50%, and MMTV sequences in 78% of DNA extracted from 50 invasive breast cancer specimens. These same viruses were identified in selected normal and breast cancer specimens by in situ PCR. Sequences from more than one viral type were identified in 72% of the same breast cancer specimens. Normal controls showed these viruses were also present in epithelial cells in human milk – EBV (35%), HPV, 20%) and MMTV (32%) of 40 milk samples from normal lactating women, with multiple viruses being identified in 13% of the same milk samples. Conclusions We conclude that (i) EBV, HPV and MMTV gene sequences are present and co-exist in many human breast cancers, (ii) the presence of these viruses in breast cancer is associated with young age of diagnosis and possibly an increased grade of breast cancer. PMID:23183846

  4. Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer.

    PubMed

    Glenn, Wendy K; Heng, Benjamin; Delprado, Warick; Iacopetta, Barry; Whitaker, Noel J; Lawson, James S

    2012-01-01

    The purpose of this investigation is to determine if Epstein Barr virus (EBV), high risk human papillomavirus (HPV), and mouse mammary tumour viruses (MMTV) co-exist in some breast cancers. All the specimens were from women residing in Australia. For investigations based on standard PCR, we used fresh frozen DNA extracts from 50 unselected invasive breast cancers. For normal breast specimens, we used DNA extracts from epithelial cells from milk donated by 40 lactating women. For investigations based on in situ PCR we used 27 unselected archival formalin fixed breast cancer specimens and 18 unselected archival formalin fixed normal breast specimens from women who had breast reduction surgery. Thirteen of these fixed breast cancer specimens were ductal carcinoma in situ (dcis) and 14 were predominantly invasive ductal carcinomas (idc). EBV sequences were identified in 68%, high risk HPV sequences in 50%, and MMTV sequences in 78% of DNA extracted from 50 invasive breast cancer specimens. These same viruses were identified in selected normal and breast cancer specimens by in situ PCR. Sequences from more than one viral type were identified in 72% of the same breast cancer specimens. Normal controls showed these viruses were also present in epithelial cells in human milk - EBV (35%), HPV, 20%) and MMTV (32%) of 40 milk samples from normal lactating women, with multiple viruses being identified in 13% of the same milk samples. We conclude that (i) EBV, HPV and MMTV gene sequences are present and co-exist in many human breast cancers, (ii) the presence of these viruses in breast cancer is associated with young age of diagnosis and possibly an increased grade of breast cancer.

  5. Effect of interferon-alpha therapy in a patient with common variable immunodeficiency and chronic Epstein-Barr virus infection.

    PubMed

    Toraldo, R; D'Avanzo, M; Tolone, C; Canino, G; Iafusco, F; Notarangelo, L D; Ugazio, A; Cirillo, C

    1995-01-01

    We report an 18-year-old boy with common variable immunodeficiency who presented with splenomegaly as well as left axillary and lateral cervical lymphadenopathy. Main laboratory investigations showed severe thrombocytopenia. Epstein-Barr virus (EBV) DNA was detected in the patient's throat-washing specimens and lymph node biopsy. Lymphocytes from the lymph node biopsy were also positive for EBV nuclear antigen. Serology for EBV and cytomegalovirus was negative. A therapeutic attempt with acyclovir did not influence the course of infection. Six months' treatment with human lymphoblastoid interferon-alpha (IFN alfa) brought about the normalization of clinical and hematologic conditions. Detection on throat-washing specimens carried out 1 year after therapy was negative. Our preliminary experience suggests that human lymphoblastoid IFN-alpha is a valid alternative in therapy of immunodeficient EB virus-infected patients.

  6. Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations

    PubMed Central

    2011-01-01

    Epstein-Barr virus (EBV) is a highly successful herpesvirus, colonizing more than 90% of the adult human population worldwide, although it is also associated with various malignant diseases. Primary infection is usually clinically silent, and subsequent establishment of latency in the memory B lymphocyte compartment allows persistence of the virus in the infected host for life. EBV is so markedly B-lymphotropic when exposed to human lymphocytes in vitro that the association of EBV with rare but distinct types of T and NK cell lymphoproliferations was quite unexpected. Whilst relatively rare, these EBV-associated T and NK lymphoproliferations can be therapeutically challenging and prognosis for the majority of patients is dismal. In this review, we summarize the current knowledge on the role of EBV in the pathogenesis of these tumours, and the implications for treatment. PMID:21899744

  7. Mutagenesis and Genome Engineering of Epstein-Barr Virus in Cultured Human Cells by CRISPR/Cas9.

    PubMed

    Yuen, Kit-San; Chan, Chi-Ping; Kok, Kin-Hang; Jin, Dong-Yan

    2017-01-01

    The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 nuclease (Cas9) system is a powerful genome-editing tool for both chromosomal and extrachromosomal DNA. DNA viruses such as Epstein-Barr virus (EBV), which undergoes episomal replication in human cells, can be effectively edited by CRISPR/Cas9. We have demonstrated targeted editing of the EBV genome by CRISPR/Cas9 in several lines of EBV-infected cells. CRISPR/Cas9-based mutagenesis and genome engineering of EBV provides a new method for genetic analysis, which has some advantages over bacterial artificial chromosome-based recombineering. This approach might also prove useful in the cure of EBV infection. In this chapter, we use the knockout of the BART promoter as an example to detail the experimental procedures for construction of recombinant EBV in human cells.

  8. Epstein-Barr virus associated modulation of Wnt pathway is not dependent on latent membrane protein-1.

    PubMed

    Webb, Natasha; Connolly, Geoff; Tellam, Judy; Yap, Alpha S; Khanna, Rajiv

    2008-09-22

    Previous studies have indicated that Epstein-Barr virus (EBV) can modulate the Wnt pathway in virus-infected cells and this effect is mediated by EBV-encoded oncogene latent membrane protein 1 (LMP1). Here we have reassessed the role of LMP1 in regulating the expression of various mediators of the canonical Wnt cascade. Contradicting the previous finding, we found that the levels of E-cadherin, beta-catenin, Glycogen Synthase Kinase 3ss (GSK3beta), axin and alpha-catenin were not affected by the expression of LMP1 sequences from normal B cells or nasopharyngeal carcinoma. Moreover, we also show that LMP1 expression had no detectable effect on the E-cadherin and beta-catenin interaction and did not induce transcriptional activation of beta-catenin. Taken together these studies demonstrate that EBV-mediated activation of Wnt pathway is not dependent on the expression of LMP1.

  9. Stress and the memory T-cell response to the Epstein-Barr virus in healthy medical students.

    PubMed

    Glaser, R; Pearson, G R; Bonneau, R H; Esterling, B A; Atkinson, C; Kiecolt-Glaser, J K

    1993-11-01

    This study investigated the memory T-cell proliferative response to several early and late Epstein-Barr virus (EBV) polypeptides. Blood samples were collected twice, 1 month before a 3-day block of examinations and again on the last day of the exam series. Ss were 25 healthy, EBV seropositive medical students. The proliferative response to 5 of the 6 EBV polypeptides significantly decreased during examinations. In addition, Ss high (above the median) in seeking support, as measured by the COPE, had lower proliferative responses to 3 EBV polypeptides (p17, p52/50, and p85), as well as higher levels of antibody to EBV virus capsid antigen. The data provide further evidence that psychological stress can modulate the cellular immune response to latent EBV.

  10. [Epstein-Barr virus associated gastric carcinoma: the genetic alteration and the expression of CD44 variant].

    PubMed

    Chong, J M; Fukayama, M

    1997-02-01

    Epstein-Barr virus (EBV), a ubiquitous human herpes virus, was recently identified in 2-16% of gastric carcinomas. EBV-encoded small RNA was found in nearly all of the carcinoma cells even at the intramucosal stage. EBV in EBV associated gastric carcinoma (EBVaGC) is monoclonal based on Southern blot hybridization using probes adjacent to the unique terminal repeat of EBV-DNA. Furthermore, the genetic pathway of this carcinogenesis is different of EBVaGC: deletion of 5q and/or 17p and microsatellite instability are extremely rare in EBVaGC, in contrast to their high frequency in EBV-negative carcinomas. We also examined the relationship between the expression of CD44 variants and EBVaGC, and found the expression of CD44 variants was significantly correlated with EBV-etiology.

  11. Co-infection with cytomegalovirus and Epstein-Barr virus in mononucleosis: case report and review of literature.

    PubMed

    Olson, Douglas; Huntington, Mark K

    2009-09-01

    A 25-year-old woman presented with infectious mononucleosis. Serological studies demonstrated elevated IgM titres to both cytomegalovirus (CMV) and Epstein-Barr virus (EBV). The role of each of these agents in infectious mononucleosis is reviewed, as are literature reports of co-infection by these two viruses. Both near-simultaneous infections and temporally remote sequential infections with acute CMV triggering an immunoreactivation of EBV are reported in the literature. We believe the current case is most consistent with the latter. Infectious mononucleosis is a common infection of childhood and young adulthood. Although a variety of agents may be associated with infectious mononucleosis, EBV is the most common etiology. We encountered a patient with serological findings that were suggestive of the simultaneous presence of two etiological agents of infectious mononucleosis: EBV and CMV. This prompted an inquiry into how commonly dual infections are encountered and their significance.

  12. Epstein-Barr Virus Latent Membrane Protein 1 Genetic Variability in Peripheral Blood B Cells and Oropharyngeal Fluids

    PubMed Central

    Renzette, Nicholas; Somasundaran, Mohan; Brewster, Frank; Coderre, James; Weiss, Eric R.; McManus, Margaret; Greenough, Thomas; Tabak, Barbara; Garber, Manuel; Kowalik, Timothy F.

    2014-01-01

    ABSTRACT We report the diversity of latent membrane protein 1 (LMP1) gene founder sequences and the level of Epstein-Barr virus (EBV) genome variability over time and across anatomic compartments by using virus genomes amplified directly from oropharyngeal wash specimens and peripheral blood B cells during acute infection and convalescence. The intrahost nucleotide variability of the founder virus was 0.02% across the region sequences, and diversity increased significantly over time in the oropharyngeal compartment (P = 0.004). The LMP1 region showing the greatest level of variability in both compartments, and over time, was concentrated within the functional carboxyl-terminal activating regions 2 and 3 (CTAR2 and CTAR3). Interestingly, a deletion in a proline-rich repeat region (amino acids 274 to 289) of EBV commonly reported in EBV sequenced from cancer specimens was not observed in acute infectious mononucleosis (AIM) patients. Taken together, these data highlight the diversity in circulating EBV genomes and its potential importance in disease pathogenesis and vaccine design. IMPORTANCE This study is among the first to leverage an improved high-throughput deep-sequencing methodology to investigate directly from patient samples the degree of diversity in Epstein-Barr virus (EBV) populations and the extent to which viral genome diversity develops over time in the infected host. Significant variability of circulating EBV latent membrane protein 1 (LMP1) gene sequences was observed between cellular and oral wash samples, and this variability increased over time in oral wash samples. The significance of EBV genetic diversity in transmission and disease pathogenesis are discussed. PMID:24429365

  13. Epstein-Barr virus latent membrane protein 1 genetic variability in peripheral blood B cells and oropharyngeal fluids.

    PubMed

    Renzette, Nicholas; Somasundaran, Mohan; Brewster, Frank; Coderre, James; Weiss, Eric R; McManus, Margaret; Greenough, Thomas; Tabak, Barbara; Garber, Manuel; Kowalik, Timothy F; Luzuriaga, Katherine

    2014-04-01

    We report the diversity of latent membrane protein 1 (LMP1) gene founder sequences and the level of Epstein-Barr virus (EBV) genome variability over time and across anatomic compartments by using virus genomes amplified directly from oropharyngeal wash specimens and peripheral blood B cells during acute infection and convalescence. The intrahost nucleotide variability of the founder virus was 0.02% across the region sequences, and diversity increased significantly over time in the oropharyngeal compartment (P = 0.004). The LMP1 region showing the greatest level of variability in both compartments, and over time, was concentrated within the functional carboxyl-terminal activating regions 2 and 3 (CTAR2 and CTAR3). Interestingly, a deletion in a proline-rich repeat region (amino acids 274 to 289) of EBV commonly reported in EBV sequenced from cancer specimens was not observed in acute infectious mononucleosis (AIM) patients. Taken together, these data highlight the diversity in circulating EBV genomes and its potential importance in disease pathogenesis and vaccine design. This study is among the first to leverage an improved high-throughput deep-sequencing methodology to investigate directly from patient samples the degree of diversity in Epstein-Barr virus (EBV) populations and the extent to which viral genome diversity develops over time in the infected host. Significant variability of circulating EBV latent membrane protein 1 (LMP1) gene sequences was observed between cellular and oral wash samples, and this variability increased over time in oral wash samples. The significance of EBV genetic diversity in transmission and disease pathogenesis are discussed.

  14. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus.

    PubMed

    Li, Feng-Yen; Chaigne-Delalande, Benjamin; Su, Helen; Uzel, Gulbu; Matthews, Helen; Lenardo, Michael J

    2014-04-03

    Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named "X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia" (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high-level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and has led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease.

  15. Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection

    PubMed Central

    Saburi, Masuho; Ogata, Masao; Satou, Takako; Yoshida, Natsumi; Nagamatsu, Kentaro; Nashimoto, Yuko; Moroga, Yui; Takano, Kuniko; Kohno, Kazuhiro; Shirao, Kuniaki

    2016-01-01

    A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations. PMID:27904117

  16. Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection.

    PubMed

    Saburi, Masuho; Ogata, Masao; Satou, Takako; Yoshida, Natsumi; Nagamatsu, Kentaro; Nashimoto, Yuko; Moroga, Yui; Takano, Kuniko; Kohno, Kazuhiro; Shirao, Kuniaki

    A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations.

  17. [A case of chronic active Epstein-Barr virus infection associated with recurrent cerebellar ataxia and skin eruptions].

    PubMed

    Araki, Katsuya; Okuno, Tatsusada; Honorat, Josephe Archie; Kinoshita, Makoto; Takahashi, Masanori P; Mizuki, Masao; Kitagawa, Kazuo; Mochizuki, Hideki

    2013-01-01

    A 62-year-old woman presented with subacute cerebellar ataxia, lymph node swelling and skin eruption. Laboratory tests revealed elevated titers of anti-VCA-IgG antibody and anti-EADR-IgG antibody, with Epstein-Barr virus (EBV) DNA detected from the blood and CSF by PCR. Since these data were highlighted with the diagnosis of chronic active EBV infection (CAEBV) and her ataxia improved concomitantly with the remission of other infectious mononucleosis-like symptoms, we supposed her ataxia is associated with CAEBV. Five years later, at the age of 67, her ataxia relapsed concurrently with skin eruptions, whereas MRI demonstrated progression of cerebellar atrophy. After high-dose intravenous methylprednisolone treatment, the clinical symptoms resolved. Initial infection of EBV in childhood often causes autoimmune acute cerebellitis but cerebellar ataxia has rarely been described in CAEBV. Furthermore, immunohistochemical analysis revealed a reactivity of the patient's serum and CSF on rat cerebellum, suggesting an autoimmune pathomechanism for the ataxia.

  18. An adult-onset case of chronic active Epstein-Barr virus infection with fulminant clinical course.

    PubMed

    Kaneko, Hiroto; Taniwaki, Masafumi; Matsumoto, Yosuke; Yoshida, Mihoko; Shimura, Kazuho; Fujino, Takahiro; Uchiyama, Hitoji; Kuroda, Junya

    2018-06-01

    A 56-year-old Japanese male with chronic active Epstein-Barr virus (EBV) infection (CAEBV) who developed systemic gamma-delta T-cell lymphoproliferative disease (LPD) is reported. Although immune cooling therapy was effective, he died of sudden and severe hypoxia and anemia soon after the initiation of cytotoxic chemotherapy that had been previously recommended. There might remain a difficulty to control fulminant adult-onset CAEBV. Additionally, we describe three types of lymphoid cells that were observed in his peripheral blood: morphologically normal lymphocytes, large blastic cells and mature ones with rough granules. Morphological observation appeared to be useful to estimate clinical manifestations. Since CAEBV is extremely rare disease in adult population, it is important to accumulate clinical data to more understand the pathogenesis or to establish treatment strategy. Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  19. Allogeneic peripheral blood stem cell transplantation for the treatment of chronic active Epstein-Barr virus infection.

    PubMed

    Fujii, N; Takenaka, K; Hiraki, A; Maeda, Y; Ikeda, K; Shinagawa, K; Ashiba, A; Munemasa, M; Sunami, K; Hiramatsu, Y; Ishimaru, F; Niiya, K; Yoshino, T; Harada, M

    2000-10-01

    The prognosis of chronic active Epstein-Barr virus infection (CAEBV) is very poor. We describe a 24-year-old male with severe CAEBV who was treated with allogeneic peripheral blood stem cell transplantation (allo-PBSCT). On admission, EBER-1 in lymphocytes infiltrating the liver, EBV-DNA in peripheral blood mononuclear cells (PBMC) and monoclonal NK cell proliferation were confirmed. After unsuccessful chemotherapy, he received an allo-PBSCT from his HLA-identical sister. Although he died of pulmonary hemorrhage on day +19, EBV-DNA was undetectable by PCR in PBMC, and the post-mortem liver showed no EBER-1-positive lymphocytes. This experience suggests that EBV-positive lymphocytes in CAEBV may be eradicated by allo-PBSCT, thereby raising the possibility of a new treatment modality. Bone Marrow Transplantation (2000) 26, 805-808.

  20. Fatal natural killer cell lymphoma arising in a patient with a crop of Epstein-Barr virus-associated disorders.

    PubMed

    Nitta, Yukiko; Iwatsuki, Keiji; Kimura, Hiroshi; Kojima, Seiji; Morishima, Tsuneo; Tsuji, Kazuhide; Oono, Takashi

    2005-01-01

    Natural killer (NK) lymphoma in Asia is frequently associated with latent Epstein-Barr (EBV) infection. Unlike the adult cases, EBV-associated NK/T cell lymphomas in children are often preceded by various EBV-related disorders, including chronic active EBV infection (CAEBV), hypersensitivity to mosquito bites (HMB), virus-associated haemophagocytic syndrome (VAHS), and hydroa vacciniforme (HV)-like eruptions. Here, we report a 14-year-old Japanese girl who sequentially developed all the symptoms related to EBV-associated NK/T cell lymphoproliferative disorders in a 12-year clinical course. Our observations confirm the spectrum of EBV-associated cutaneous disorders and indicate the importance of long-term follow-up.

  1. The unexpected finding of a splenic infarction in a patient with infectious mononucleosis due to Epstein-Barr virus.

    PubMed

    Machado, Catarina; Melo Salgado, Joana; Monjardino, Leonor

    2015-11-25

    The authors present a case of a 24-year-old man with infectious mononucleosis (IM) due to Epstein-Barr virus (EBV). Among his symptoms, he reported abdominal pain in the upper left quadrant. An abdominal ultrasound and CT revealed an extensive splenic infarction. During the acute stage of this disease, the thrombophilic screening revealed reduced free protein S and elevated factor VIII, with normalisation on re-evaluation 6 weeks later. Splenic infarction is a very rare complication of IM due to EBV but should be considered in patients presenting abdominal pain. A hypercoagulability state should be investigated. To our knowledge, this is the first described case of a splenic infarction in a patient with IM due to EBV associated with a transient reduction of protein S and elevation of factor VIII. Thus, this work promotes the importance of including these factors in the thrombophilic screening conducted during the investigation of similar cases. 2015 BMJ Publishing Group Ltd.

  2. Investigation of Epstein-Barr virus DNA in formalin-fixed and paraffin- embedded breast cancer tissues.

    PubMed

    Kalkan, Ahmet; Ozdarendeli, Aykut; Bulut, Yasemin; Yekeler, Hayrettin; Cobanoglu, Bengu; Doymaz, Mehmet Z

    2005-01-01

    To investigate etiological role of Epstein-Barr virus (EBV) DNA in breast cancer. The presence of EBV DNA in 57 breast cancer tissues was investigated with a sensitive PCR assay. The breast cancer tissues were from invasive ductular (n=28), lobular (n=20) and other miscellaneous carcinomas (n=9). Tissues from normal breasts and patients with various benign breast diseases (n=55): fibrocystic disease (n=34), fibroadenoma (n=16), hyperplasia, and granulomatous mastitis (n=5), were used as control samples. EBV DNA was detected in 13 (23%) cancerous tissues (7 ductular, 4 lobular, 2 other carcinoma) and 19 (35%) in the control tissues. The difference between EBV presence in malignant and benign tissues was not statistically significant (p>0.05). The presence of EBV DNA was detected almost equally in both breast cancer and normal tissues, which indicates no etiological role for EBV in breast cancer. We suggest further etiological studies. Copyright (c) 2005 S. Karger AG, Basel.

  3. A prospective follow-up of Epstein-Barr virus LMP1 genotypes in saliva and blood during infectious mononucleosis.

    PubMed

    Fafi-Kremer, Samira; Morand, Patrice; Germi, Raphaele; Ballout, Mirvat; Brion, Jean-Paul; Genoulaz, Odile; Nicod, Sandrine; Stahl, Jean-Paul; Ruigrok, Rob W H; Seigneurin, Jean-Marie

    2005-12-15

    To monitor multiple Epstein-Barr virus (EBV) infections during the early and convalescent stages of infectious mononucleosis (IM), a cloning and sequencing study of the LMP1 gene was conducted in saliva and peripheral blood mononuclear cells (PBMCs) from 23 patients with IM at day 0 (D0) and day 180 (D180) after the onset of the disease. Multiple EBV strains were detected in 9 (39%) of the patients during follow-up, with 7 of 9 cases detected as early as D0. Six of the nine patients harbored the same dominant strain in saliva and PBMCs during follow-up, with a trend toward a restriction of the number of EBV strains in saliva but not in PBMCs at D180. Furthermore, transmission of a minor strain was observed between partners in a heterosexual couple. There was no correlation between multiple infections and EBV DNA load in either compartment.

  4. Peripheral blood lymphocytes express recombination-activating genes 1 and 2 during Epstein-Barr virus-induced infectious mononucleosis.

    PubMed

    Wagner, Hans-Joachim; Scott, Rona S; Buchwald, Dedra; Sixbey, John W

    2004-09-01

    Implicit in the persistence of Epstein-Barr virus (EBV) in B lymphocytes is the successful circumvention of ongoing cell selection for competence of B cell receptors (BCRs). Because the EBV infection of B cells in vitro induces enzymatic machinery that is responsible for secondary immunoglobulin gene rearrangement, we examined the expression of the recombination-activating genes (RAGs) in peripheral blood mononuclear cells (PBMCs) from 26 patients with infectious mononucleosis (IM). RAG1 and/or RAG2 RNA was detected in PBMCs from 42% of patients with IM but not from healthy control subjects. EBV may usurp the cellular mechanism that diversifies the BCR, to guarantee a level of survival signaling sufficient for its own persistence.

  5. The unexpected finding of a splenic infarction in a patient with infectious mononucleosis due to Epstein-Barr virus

    PubMed Central

    Machado, Catarina; Melo Salgado, Joana; Monjardino, Leonor

    2015-01-01

    The authors present a case of a 24-year-old man with infectious mononucleosis (IM) due to Epstein-Barr virus (EBV). Among his symptoms, he reported abdominal pain in the upper left quadrant. An abdominal ultrasound and CT revealed an extensive splenic infarction. During the acute stage of this disease, the thrombophilic screening revealed reduced free protein S and elevated factor VIII, with normalisation on re-evaluation 6 weeks later. Splenic infarction is a very rare complication of IM due to EBV but should be considered in patients presenting abdominal pain. A hypercoagulability state should be investigated. To our knowledge, this is the first described case of a splenic infarction in a patient with IM due to EBV associated with a transient reduction of protein S and elevation of factor VIII. Thus, this work promotes the importance of including these factors in the thrombophilic screening conducted during the investigation of similar cases. PMID:26607191

  6. Evidence that amphotericin B mediates reactivation of latent Epstein-Barr virus in Hodgkin's lymphoma allowing cytotoxicity by acyclovir.

    PubMed

    Kast, Richard E

    2006-04-30

    This brief communication focuses on aspects of a recent case report (Yonsei Med J 2005;46:425-30) on a full and sustained remission of Hodgkin's lymphoma (HL) after a single day of chemotherapy. A septic episode required stopping chemotherapy and starting amphotericin B and acyclovir. Remission evidence was seen within days of starting these. A review of research supporting the notion that amphotericin B can reactivate latent Epstein-Barr virus and thus allow acyclovir to kill infected HL cells is given. Experimental work is required to confirm or refute this possibility. If successful, amphotericin B and acyclovir treatment could be extended to other EBV-driven cancers such as Burkitt's lymphoma, nasopharyngeal carcinoma and the occasional EBV-related epithelial cancer of the breast, colon, prostate, and others.

  7. Development of Extranodal NK/T-cell Lymphoma Nasal Type in Cerebrum Following Epstein-Barr Virus-positive Uveitis.

    PubMed

    Imai, Ayano; Takase, Hiroshi; Imadome, Ken-Ichi; Matsuda, Go; Ohnishi, Iichiro; Yamamoto, Kouhei; Kudo, Takumi; Tanaka, Yoji; Maehara, Taketoshi; Miura, Osamu; Arai, Ayako

    2017-01-01

    A 74-year-old woman developed bilateral uveitis with high Epstein-Barr virus (EBV) DNA load in the vitreous fluid without lymphoma cells. Four years after the onset, T2-weighted contrast-enhanced MRI revealed hyperintense lesions in the right occipital and parietal lobe. A biopsy resulted in the diagnosis of extranodal NK/T-cell lymphoma nasal type (ENKL). The repeat region of LMP1, an EBV gene, detected in the brain lesion was identical to that detected in the vitreous fluid. ENKL of the central nervous system is quite rare, and the pathogenesis has not been determined. The lymphoma in this case might have been closely associated with the EBV-positive uveitis.

  8. Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Uhlin, Michael; Wikell, Helena; Sundin, Mikael; Blennow, Ola; Maeurer, Markus; Ringden, Olle; Winiarski, Jacek; Ljungman, Per; Remberger, Mats; Mattsson, Jonas

    2014-02-01

    Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (P<0.001), serological Epstein-Barr virus mismatch recipient-/donor+ (P<0.001), use of reduced intensity conditioning (P=0.002), acute graft-versus-host disease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (P<0.001). The study identifies patients at risk of post-transplant lymphoproliferative disease after transplantation in need of pre-emptive measures.

  9. Response and survival benefit with chemoimmunotherapy in Epstein-Barr virus-positive diffuse large B-cell lymphoma.

    PubMed

    Beltran, Brady E; Quiñones, Pilar; Morales, Domingo; Malaga, Jose M; Chavez, Julio C; Sotomayor, Eduardo M; Castillo, Jorge J

    2018-02-01

    Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a haematologic malignancy with poor prognosis when treated with chemotherapy. We evaluated response and survival benefits of chemoimmunotherapy in EBV-positive DLBCL patients. A total of 117 DLBCL patients were included in our retrospective analysis; 33 were EBV-positive (17 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] and 16 with CHOP), and 84 were EBV-negative (all treated with R-CHOP). The outcomes of interest were complete response (CR) and overall survival (OS) in EBV-positive DLBCL patients (R-CHOP versus CHOP) and in DLBCL patients treated with R-CHOP (EBV-positive vs EBV-negative). There were no differences in the clinical characteristics between EBV-positive and EBV-negative DLBCL patients. Among EBV-positive DLBCL patients, R-CHOP was associated with higher odds of CR (OR 3.14, 95% CI 0.75-13.2; P = .10) and better OS (hazard ratio 0.30, 95% confidence interval [CI] 0.09-0.94; P = .04). There were no differences in CR rate (OR 0.52, 95% CI 0.18-1.56; P = .25) or OS (hazard ratio 0.93, 95% CI 0.32-2.67; P = .89) between EBV-positive and EBV-negative DLBCL patients treated with R-CHOP. Based on our study, the addition of rituximab to CHOP is associated with improved response and survival in EBV-positive DLBCL patients. Epstein-Barr virus status does not seem to affect response or survival in DLBCL patients treated with R-CHOP. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor

    PubMed Central

    Noda, Chieko; Narita, Yohei; Watanabe, Takahiro; Yoshida, Masahiro; Ashio, Keiji; Sato, Yoshitaka; Goshima, Fumi; Kanda, Teru; Yoshiyama, Hironori; Tsurumi, Tatsuya; Kimura, Hiroshi

    2016-01-01

    ABSTRACT Latent membrane protein 1 (LMP1) is a major oncogene essential for primary B cell transformation by Epstein-Barr virus (EBV). Previous studies suggested that some transcription factors, such as PU.1, RBP-Jκ, NF-κB, and STAT, are involved in this expression, but the underlying mechanism is unclear. Here, we identified binding sites for PAX5, AP-2, and EBF in the proximal LMP1 promoter (ED-L1p). We first confirmed the significance of PU.1 and POU domain transcription factor binding for activation of the promoter in latency III. We then focused on the transcription factors AP-2 and early B cell factor (EBF). Interestingly, among the three AP-2-binding sites in the LMP1 promoter, two motifs were also bound by EBF. Overexpression, knockdown, and mutagenesis in the context of the viral genome indicated that AP-2 plays an important role in LMP1 expression in latency II in epithelial cells. In latency III B cells, on the other hand, the B cell-specific transcription factor EBF binds to the ED-L1p and activates LMP1 transcription from the promoter. IMPORTANCE Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is crucial for B cell transformation and oncogenesis of other EBV-related malignancies, such as nasopharyngeal carcinoma and T/NK lymphoma. Its expression is largely dependent on the cell type or condition, and some transcription factors have been implicated in its regulation. However, these previous reports evaluated the significance of specific factors mostly by reporter assay. In this study, we prepared point-mutated EBV at the binding sites of such transcription factors and confirmed the importance of AP-2, EBF, PU.1, and POU domain factors. Our results will provide insight into the transcriptional regulation of the major oncogene LMP1. PMID:26819314

  11. Glypican-4 gene polymorphism (rs1048369) and susceptibility to Epstein-Barr virus-associated and -negative gastric carcinoma.

    PubMed

    Zhao, Danrui; Liu, Shuzhen; Sun, Lingling; Zhao, Zhenzhen; Liu, Song; Kuang, Xiaojing; Shu, Jun; Luo, Bing

    2016-07-15

    Gastric cancer (GC) is one of the most common malignant tumors in China and single nucleotide polymorphisms (SNPs) have been found to be highly related to GC carcinogenesis. Glypican-4 (GPC4), a member of the heparan sulphate proteoglycan family, plays an important role in the regulation of cell growth and differentiation. However, little is known about polymorphisms of GPC4 gene and their associated susceptibility to GC, especially to Epstein-Barr virus-associated GC (EBVaGC). Here we studied the GPC4 polymorphism (rs1048369) in GC individuals, especially those with EBVaGC, and we explored an association between the GPC4 gene polymorphism (rs1048369) and susceptibility to EBVaGC and Epstein-Barr virus-negative GC (EBVnGC) in a population from Northern China. The GPC4 gene polymorphism (rs1048369) was detected in 54 cases of EBVaGC and 73 cases of EBVnGC using polymerase chain reaction (PCR). One hundred and seven peripheral blood samples from healthy individuals were also measured as a control group. There were significant differences in both the genotype and allelic frequency of GPC4 gene (rs1048369) between the EBVaGC and EBVnGC patients. Meanwhile, the distribution of genotype and allelic frequency of GPC4 (rs1048369) differed between EBVaGC and control groups. Distribution of the GPC4 genotype also revealed differences between EBVnGC and control groups, no significant differences in the allelic frequency of the GPC4 gene (rs1048369) were observed. The frequency of the T allele in EBVaGC group was significantly higher than that in control and EBVnGC groups. The GPC4 gene polymorphism and the allele of GPC4 are both associated with susceptibility to EBVaGC. The T allele of GPC4 may represent a risk factor for EBVaGC. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Low rate of apoptosis and overexpression of bcl-2 in Epstein-Barr virus-associated gastric carcinoma.

    PubMed

    Kume, T; Oshima, K; Shinohara, T; Takeo, H; Yamashita, Y; Shirakusa, T; Kikuchi, M

    1999-06-01

    Epstein-Barr virus (EBV) has been demonstrated in about 10% of gastric carcinomas. However, the pathogenetic role of EBV in gastric carcinoma is uncertain. We compared the rate of apoptotic cell death, cell proliferation and the expression of apoptosis-related proteins in gastric carcinomas with or without EBV. Epstein-Barr virus was detected in 40 gastric carcinomas by EBV-encoded small RNA-1 in-situ hybridization. Apoptotic cell death, MIB-1, p53, bcl-2 and bcl-x were examined by the terminal deoxynucleotidyl-mediated dUTP-nick end labelling method and immunohistochemistry. We also included 40 age-, sex- and disease stage-matched EBV-negative cases as a control. The number of apoptotic cells was significantly lower in EBV-positive (20 +/- 15. 1/1000 cells) and bcl-2-positive (17 +/- 12.9/1000 cells) tumours than in EBV-negative (43 +/- 37.1) and bcl-2-negative tumours (38 +/- 32.1, P < 0.001, P < 0.001, respectively). bcl-2 immunostaining was significantly higher in EBV-positive tumours (24 cases) than in EBV-negative tumours (12 cases, P < 0.05). There was no significant difference in bcl-x and p53 expression between EBV-positive and -negative tumours. The number of MIB-1-positive cells in EBV-positive tumours (237 +/- 161/1000) was significantly lower than in EBV-negative tumours (480 +/- 208/1000 cells, P < 0.001). A low rate of apoptosis and high bcl-2 expression were recognized in EBV-positive gastric carcinomas, suggesting that bcl-2 protein is the main inhibitor of apoptosis in EBV-positive carcinomas. In addition, the low apoptotic and proliferative activities may reflect a low biological activity in EBV-positive gastric carcinomas.

  13. Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus*

    PubMed Central

    Bagdonaite, Ieva; Nordén, Rickard; Joshi, Hiren J.; King, Sarah L.; Vakhrushev, Sergey Y.; Olofsson, Sigvard; Wandall, Hans H.

    2016-01-01

    Herpesviruses are among the most complex and widespread viruses, infection and propagation of which depend on envelope proteins. These proteins serve as mediators of cell entry as well as modulators of the immune response and are attractive vaccine targets. Although envelope proteins are known to carry glycans, little is known about the distribution, nature, and functions of these modifications. This is particularly true for O-glycans; thus we have recently developed a “bottom up” mass spectrometry-based technique for mapping O-glycosylation sites on herpes simplex virus type 1. We found wide distribution of O-glycans on herpes simplex virus type 1 glycoproteins and demonstrated that elongated O-glycans were essential for the propagation of the virus. Here, we applied our proteome-wide discovery platform for mapping O-glycosites on representative and clinically significant members of the herpesvirus family: varicella zoster virus, human cytomegalovirus, and Epstein-Barr virus. We identified a large number of O-glycosites distributed on most envelope proteins in all viruses and further demonstrated conserved patterns of O-glycans on distinct homologous proteins. Because glycosylation is highly dependent on the host cell, we tested varicella zoster virus-infected cell lysates and clinically isolated virus and found evidence of consistent O-glycosites. These results present a comprehensive view of herpesvirus O-glycosylation and point to the widespread occurrence of O-glycans in regions of envelope proteins important for virus entry, formation, and recognition by the host immune system. This knowledge enables dissection of specific functional roles of individual glycosites and, moreover, provides a framework for design of glycoprotein vaccines with representative glycosylation. PMID:27129252

  14. Epstein-Barr virus DNA loads in adult human immunodeficiency virus type 1-infected patients receiving highly active antiretroviral therapy

    NASA Technical Reports Server (NTRS)

    Ling, Paul D.; Vilchez, Regis A.; Keitel, Wendy A.; Poston, David G.; Peng, Rong Sheng; White, Zoe S.; Visnegarwala, Fehmida; Lewis, Dorothy E.; Butel, Janet S.

    2003-01-01

    Patients with human immunodeficiency virus type 1 (HIV-1) infection are at high risk of developing Epstein-Barr virus (EBV)-associated lymphoma. However, little is known of the EBV DNA loads in patients receiving highly active antiretroviral therapy (HAART). Using a real-time quantitative polymerase chain reaction assay, we demonstrated that significantly more HIV-1-infected patients receiving HAART than HIV-1-uninfected volunteers had detectable EBV DNA in blood (57 [81%] of 70 vs. 11 [16%] of 68 patients; P=.001) and saliva (55 [79%] of 68 vs. 37 [54%] of 68 patients; P=.002). The mean EBV loads in blood and saliva samples were also higher in HIV-1-infected patients than in HIV-1-uninfected volunteers (P=.001). The frequency of EBV detection in blood was associated with lower CD4+ cell counts (P=.03) among HIV-1-infected individuals, although no differences were observed in the EBV DNA loads in blood or saliva samples in the HIV-1-infected group. Additional studies are needed to determine whether EBV-specific CD4+ and CD8+ cells play a role in the pathogenesis of EBV in HIV-1-infected patients receiving HAART.

  15. Retrospective analysis of oncogenic human papilloma virus and Epstein-Barr virus prevalence in Turkish nasopharyngeal cancer patients.

    PubMed

    Tatlı Doğan, Hayriye; Kılıçarslan, Aydan; Doğan, Mehmet; Süngü, Nuran; Güler Tezel, Gaye; Güler, Gülnur

    2016-11-01

    Nasopharyngeal carcinoma (NPC) is associated with the Epstein-Barr virus (EBV). Human papilloma virus (HPV) has also been detected in NPC cases. In this retrospective study, we analyze the frequency of EBV and HPV infection in 82 Turkish patients with NPC. A total of 82 were evaluated for EBV and HPV. In situ hybridization (ISH) was performed for EBV. HPV-ISH and P16 immunohistochemistry used to determine the HPV status. Seventy-two of the 82 (87%) NPC patients were EBV-positive. The highest rate of EBV-positivity was found in undifferentiated NPC patients, which accounted for 65 of 68 (95.6%) undifferentiated cases. One of the 82 NPC patients whose tumor was non-keratinizing differentiated, contained HPV. Our data shows that EBV is closely associated with NPC in Turkey. We found lower rates of HPV-positivity in NPC patients than in North American populations. In addition, both EBV and HPV-negativity were more associated with decreased survival than EBV-positive cases. Copyright © 2016 Elsevier GmbH. All rights reserved.

  16. Low intrathecal antibody production despite high seroprevalence of Epstein-Barr virus in multiple sclerosis: a review of the literature.

    PubMed

    Ruprecht, Klemens; Wildemann, Brigitte; Jarius, Sven

    2018-02-01

    Patients with multiple sclerosis (MS) frequently have an intrathecal production of antibodies to different common viruses, which can be detected by elevated antiviral antibody indices (AIs). There is a strong and consistent association of MS and Epstein-Barr virus (EBV) infection. To systematically compare the frequencies of intrathecal antibody production to EBV, measles virus, rubella virus, varicella zoster virus (VZV) and herpes simplex virus (HSV) in patients with MS. Review of the English and German literature on the frequencies of intrathecal immunoglobulin (Ig)G antibody production, as defined by an elevated AI, to EBV, measles virus, rubella virus, VZV and HSV in adult and pediatric patients with MS. In nine original studies identified, the frequencies of an intrathecal production of antibodies to Epstein-Barr nuclear antigen-1 (33/340, 9.7%), EBV viral capsid antigen (12/279, 4.3%) and antigens from EBV-infected cell lines (14/90, 15.6%) in adult patients with MS were clearly lower (p ≤ 0.03 for all pairwise comparisons) than the frequencies of an intrathecal production of antibodies to measles virus (612/922, 66.4%), rubella virus (521/922, 56.5%), VZV (470/922, 51%; data from 17 original studies) and HSV (78/291, 26.8%; data from 6 original studies). Though based on a lower number of original studies and patients, findings in children with MS were essentially similar. As in adults and children with MS the seroprevalence of EBV is higher than the seroprevalences of the other investigated viruses, the lower frequency of elevated EBV AIs became even more pronounced after correction of the frequencies of elevated antiviral AIs for the seroprevalences of the respective viruses. Given the very high seroprevalence of EBV in MS, the frequency of intrathecally produced antibodies to EBV in patients with MS is paradoxically low compared to that of other common viruses. These findings are compatible with the recently proposed hypothesis that in individuals

  17. Urgent liver transplantation for acute liver failure due to parvovirus B19 infection complicated by primary Epstein-Barr virus and cytomegalovirus infections and aplastic anaemia.

    PubMed

    So, K; Macquillan, G; Garas, G; Delriviere, L; Mitchell, A; Speers, D; Mews, C; Augustson, B; de Boer, W B; Baker, D; Jeffrey, G P

    2007-03-01

    An 11-year-old boy presented with hepatic failure secondary to parvovirus B19 infection, requiring urgent liver transplantation. His recovery was complicated by primary Epstein-Barr virus and cytomegalovirus infections. He subsequently developed aplastic anaemia that has been refractory to antithymocyte globulin and cyclosporine therapy and may now require bone marrow transplantation. We present this case to emphasize parvovirus as a rare cause of hepatic failure and of aplastic anaemia as a complication of the virus.

  18. Correlation between Epstein-Barr Virus Infection and Disease Activity of Systemic Lupus Erythematosus: a Cross-Sectional Study

    PubMed

    Piroozmand, Ahmad; Haddad Kashani, Hamed; Zamani, Batool

    2017-02-01

    Background: Systemic lupus erythematosus (SLE) is an autoimmune disease for whose pathogenesis viral infections are important. The Epstein-Barr virus (EBV) is the main infectious etiological agent. This study aimed to quantitative evaluation of EBV in SLE patients. Materials and Methods: In this cross-sectional study, 40 patients with SLE diagnosed based on American College of Rheumatology criteria were selected using purposive sampling. All were included in the study after obtaining informed consent for participation. Whole blood samples were taken and buffy coat preparations were isolated to determine viral load using the real-time polymerase chain reaction method and assessment with the SLE disease activity index (SLE-DAI). Results: From a total of 40 patients, 37 cases (92.5%) were women. The EBV test was positive in 67.5% and mean viral load was 5396 ± 1891.9 copy/ml. Twenty of forty patients had active and 50% inactive disease, mean EBV viral loads being 6798 and 28.25 copy/ml, respectively (P-value = 0.003). In terms of the severity of disease activity, 17.5 % of female patients had mild to moderate activity, whilst 32.5% of them had severe activity, with respective viral loads of 5,803.3 and 29.73 copy/ml (P-value = 0.003). Conclusion: The Epstein-Barr viral load in SLE patients with active disease was found to be markedly higher than in inactive cases. Thus, EBV may have an important role in the pathogenesis and activity of SLE. Creative Commons Attribution License

  19. A Rare Case of Chronic Active Epstein-Barr Virus (EBV) Infection Accompanied by the Infiltration of EBV-infected CD8+ T Cells into the Muscle.

    PubMed

    Kobayashi, Nobuhiko; Mitsui, Takeki; Ogawa, Yoshiyuki; Iriuchishima, Hirono; Takizawa, Makiko; Yokohama, Akihiko; Saitoh, Takayuki; Koiso, Hiromi; Tsukamoto, Norifumi; Murakami, Hirokazu; Nojima, Yoshihisa; Handa, Hiroshi

    2018-04-01

    We describe a rare case of chronic active Epstein-Barr virus (CAEBV) infection, with infiltration of the skeletal muscle. A 19-year-old woman with swollen cervical lymph nodes and a fever was referred to our hospital. Swelling of the trapezium muscle and elevation of creatinine kinase level were observed. Biopsy results of the brachialis muscle revealed infiltration of Epstein-Barr virus (EBV)-encoded RNA-positive CD8 T lymphocytes. The EBV virus load in the peripheral blood was high, and EBV monoclonality was determined by Southern blot analysis. Owing to the rarity of CAEBV with skeletal muscle infiltration, this case alerts physicians to the potential diagnostic pitfalls of CAEBV.

  20. Structure of Epstein-Barr Virus Glycoprotein 42 Suggests a Mechanism for Triggering Receptor-Activated Virus Entry

    SciTech Connect

    Kirschner, Austin N.; Sorem, Jessica; Longnecker, Richard

    Epstein-Barr virus requires glycoproteins gH/gL, gB, and gp42 to fuse its lipid envelope with B cells. Gp42 is a type II membrane protein consisting of a flexible N-terminal region, which binds gH/gL, and a C-terminal lectin-like domain that binds to the B-cell entry receptor human leukocyte antigen (HLA) class II. Gp42 triggers membrane fusion after HLA binding, a process that requires simultaneous binding to gH/gL and a functional hydrophobic pocket in the lectin domain adjacent to the HLA binding site. Here we present the structure of gp42 in its unbound form. Comparisons to the previously determined structure of a gp42:HLAmore » complex reveals additional N-terminal residues forming part of the gH/gL binding site and structural changes in the receptor binding domain. Although the core of the lectin domain remains similar, significant shifts in two loops and an {alpha} helix bordering the essential hydrophobic pocket suggest a structural mechanism for triggering fusion.« less

  1. Pediatric epstein-barr virus carriers with or without tonsillar enlargement may substantially contribute to spreading of the virus.

    PubMed

    Hug, Martina; Dorner, Marcus; Fröhlich, Franziska Zucol; Gysin, Claudine; Neuhaus, Diego; Nadal, David; Berger, Christoph

    2010-10-15

    Human-to-human transmission of the persistent infection establishing Epstein-Barr virus (EBV) occurs via saliva. Tonsils act as important portal of entry and exit of EBV. The contagiousness of pediatric EBV carriers and the role played by tonsillar enlargement (TE) are not known. We compared EBV shedding in mouthwash samples from pediatric EBV carriers with or without TE to that in mouthwash samples from pediatric patients with infectious mononucleosis (IM), the symptomatic form of primary infection if delayed after the age of 5 years. EBV DNA was quantified by polymerase chain reaction, and contagiousness was assessed using the cord lymphocyte transformation assay. EBV carriers with TE shed EBV DNA at an almost similar frequency (although in lower amounts) as pediatric patients with acute IM but more frequently (P <.001) and in higher amounts (P = .038) than EBV carriers without TE. EBV DNA levels in mouthwash samples from EBV carriers with TE mirrored levels in tonsils and gradually declined after tonsillectomy. Almost half of the mouthwash samples from pediatric EBV carriers contained infectious EBV. Pediatric EBV carriers--in particular, those with TE-may considerably contribute to the spreading of EBV in industrialized countries.

  2. Knockout of Epstein-Barr virus BPLF1 retards B-cell transformation and lymphoma formation in humanized mice.

    PubMed

    Whitehurst, Christopher B; Li, Guangming; Montgomery, Stephanie A; Montgomery, Nathan D; Su, Lishan; Pagano, Joseph S

    2015-10-20

    BPLF1 of Epstein-Barr virus (EBV) is classified as a late lytic cycle protein but is also found in the viral tegument, suggesting its potential involvement at both initial and late stages of viral infection. BPLF1 possesses both deubiquitinating and deneddylating activity located in its N-terminal domain and is involved in processes that affect viral infectivity, viral DNA replication, DNA repair, and immune evasion. A recently constructed EBV BPLF1-knockout (KO) virus was used in conjunction with a humanized mouse model that can be infected with EBV, enabling the first characterization of BPLF1 function in vivo. Results demonstrate that the BPLF1-knockout virus is approximately 90% less infectious than wild-type (WT) virus. Transformation of human B cells, a hallmark of EBV infection, was delayed and reduced with BPLF1-knockout virus. Humanized mice infected with EBV BPLF1-knockout virus showed less weight loss and survived longer than mice infected with equivalent infectious units of WT virus. Additionally, splenic tumors formed in 100% of mice infected with WT EBV but in only 25% of mice infected with BPLF1-KO virus. Morphological features of spleens containing tumors were similar to those in EBV-induced posttransplant lymphoproliferative disease (PTLD) and were almost identical to cases seen in human diffuse large B-cell lymphoma. The presence of EBV genomes was detected in all mice that developed tumors. The results implicate BPLF1 in human B-cell transformation and tumor formation in humanized mice. Epstein-Barr virus infects approximately 90% of the world's population and is the causative agent of infectious mononucleosis. EBV also causes aggressive lymphomas in individuals with acquired and innate immune disorders and is strongly associated with diffuse large B-cell lymphomas, classical Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal carcinoma (NPC). Typically, EBV initially infects epithelial cells in the oropharynx, followed by a lifelong

  3. Immunologic Difference between Hypersensitivity to Mosquito Bite and Hemophagocytic Lymphohistiocytosis Associated with Epstein-Barr Virus Infection

    PubMed Central

    Hsieh, Meng-Ying; Lin, Syh-Jae; Jaing, Tang-Her; Chen, Shih-Hsiang; Hung, Iou-Jih; Yang, Chao-Ping; Chen, Chin-Jung; Huang, Yhu-Chering; Li, Shin-Pai; Huang, Jing-Long

    2013-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, virus-triggered immune disease. Hypersensitivity to mosquito bite (HMB), a presentation of Chronic Active Epstein-Barr Virus infection (CAEBV), may progress to HLH. This study aimed to investigate the immunologic difference between the HMB episodes and the HLH episodes associated with EBV infection. Immunologic changes of immunoglobulins, lymphocyte subsets, cytotoxicity, intracellular perforin and granzyme expressions, EBV virus load and known candidate genes for hereditary HLH were evaluated and compared. In 12 HLH episodes (12 patients) and 14 HMB episodes (4 patients), there were both decreased percentages of CD4+ and CD8+ and increased memory CD4+ and activated (CD2+HLADR+) lymphocytes. In contrast to HMB episodes that had higher IgE levels and EBV virus load predominantly in NK cells, those HLH episodes with virus load predominantly in CD3+ lymphocyte had decreased perforin expression and cytotoxicity that were recovered in the convalescence period. However, there was neither significant difference of total virus load in these episodes nor candidate genetic mutations responsible for hereditary HLH. In conclusion, decreased perforin expression in the HLH episodes with predominant-CD3+ EBV virus load is distinct from those HMB episodes with predominant-NK EBV virus load. Whether the presence of non-elevated memory CD4+ cells or activated lymphocytes (CD2+HLADR+) increases the mortality rate in the HLH episodes remains to be further warranted through larger-scale studies. PMID:24204658

  4. Fulminant Epstein-Barr virus - infectious mononucleosis in an adult with liver failure, splenic rupture, and spontaneous esophageal bleeding with ensuing esophageal necrosis: a case report.

    PubMed

    Busch, Daniel; Hilswicht, Sarah; Schöb, Dominik S; von Trotha, Klaus T; Junge, Karsten; Gassler, Nikolaus; Truong, Son; Neumann, Ulf P; Binnebösel, Marcel

    2014-02-05

    Infectious mononucleosis is a clinical syndrome most commonly associated with primary Epstein-Barr virus infection. The majority of patients with infectious mononucleosis recovers without apparent sequelae. However, infectious mononucleosis may be associated with several acute complications. In this report we present a rare case of esophageal rupture that has never been described in the literature before. We present the case of an 18-year-old Caucasian man affected by severe infectious mononucleosis complicated by fulminant hepatic failure, splenic rupture and esophageal necrosis. Although primary Epstein-Barr virus infection is rarely fatal, fulminant infection may occur - in this case leading to hepatic failure, splenic rupture and esophageal necrosis, subsequently making several surgical interventions necessary. We show here that infectious mononucleosis is not only a strictly medical condition, but can also lead to severe surgical complications.

  5. Human papilloma virus, herpes simplex virus and epstein barr virus in oral squamous cell carcinoma from eight different countries.

    PubMed

    Jalouli, Jamshid; Jalouli, Miranda M; Sapkota, Dipak; Ibrahim, Salah O; Larsson, Per-Anders; Sand, Lars

    2012-02-01

    Oral squamous cell carcinoma (OSCC) is a major health problem in many parts of the world, and the major causative agents are thought to be the use of alcohol and tobacco. Oncogenic viruses have also been suggested to be involved in OSCC development. This study investigated the prevalence of human papillomaviruses (HPV), herpes simplex virus (HSV) and Epstein-Barr virus (EBV) in 155 OSCC from eight different countries from different ethnic groups, continents and with different socioeconomic backgrounds. 41 A total of OSCCs were diagnosed in the tongue (26%) and 23 in the floor of the mouth (15%); the other 91 OSCCs were diagnosed in other locations (59%). The patients were also investigated regarding the use of alcohol and smoking and smokeless tobacco habits. Tissue samples were obtained from formalin-fixed, paraffin-embedded samples of the OSCC. DNA was extracted and the viral genome was examined by single, nested and semi-nested PCR assays. Sequencing of double-stranded DNA from the PCR product was carried out. Following sequencing of the HPV-, HSV- and EBV-positive PCR products, 100% homology between the sampels was found. Of all the 155 OSCCs examined, 85 (55%) were positive for EBV, 54 (35%) for HPV and 24 (15%) for HSV. The highest prevalence of HPV was seen in Sudan (65%), while HSV (55%) and EBV (80%) were most prevalent in the UK. In 34% (52/155) of all the samples examined, co-infection by two (46/155=30%) or three (6/155=4%) virus specimens was detected. The most frequent double infection was HPV with EBV in 21% (32/155) of all OSCCs. There was a statistically significant higher proportion of samples with HSV (p=0.026) and EBV (p=0.015) in industrialized countries (Sweden, Norway, UK and USA) as compared to developing countries (Sudan, India, Sri Lanka and Yemen). Furthermore, there was a statistically significant higher co-infection of HSV and EBV in samples from industrialized countries (p=0.00031). No firm conclusions could be drawn regarding the

  6. Co-infection with Helicobacter pylori and Epstein-Barr virus in benign upper digestive diseases: An endoscopic and serologic pilot study.

    PubMed

    Buzás, György M; Konderák, Judith

    2016-06-01

    Some gastric cancers are Epstein-Barr virus associated. To assess the prevalence of Helicobacter pylori and viral co-infection in benign upper digestive diseases. One hundred and four outpatients were included in a prospective endoscopic-serologic study. Epstein-Barr virus immunoglobulin G (IgG), immunoglobulin M and viral capsid antigen titres were assayed with an ELISA test. Helicobacter pylori was determined by the modified Giemsa stain and by IgG-chemiluminescence. The overall prevalence of Helicobacter pylori was 56.7%. Duodenal ulcer patients were infected in 72.5 % of the cases, with the prevalence being 33.3% in functional dyspepsia (p = 0.0008) and 25.8% in reflux patients (p = 0.0001). Epstein-Barr virus IgG was detected in 70.1% of the whole group, 75% of duodenal ulcer patients, 51.2% of functional dyspepsia patients (p = 0.04) and 51.6% of the reflux disease cases (p = 0.04). Co-infection with both agents was detected in 60% of duodenal ulcer patients, 18.1% of functional dyspepsia (p = 0.00014) and 12.9% of reflux disease patients (p = 0.00012). Anti-viral IgG titre displayed a 31.7 ± 3.0 cut-off index in duodenal ulcer, 20.5 ± 3.5 in functional dyspepsia (p = 0.01) and 21.4 ± 3.6 in reflux cases (p = 0.03). Both Helicobacter pylori and Epstein-Barr virus, and co-infection with these agents, were significantly more prevalent in duodenal ulcer patients than in dyspeptic/reflux patients.

  7. Primary Epstein-Barr virus infection and probable parvovirus B19 reactivation resulting in fulminant hepatitis and fulfilling five of eight criteria for hemophagocytic lymphohistiocytosis.

    PubMed

    Karrasch, Matthias; Felber, Jörg; Keller, Peter M; Kletta, Christine; Egerer, Renate; Bohnert, Jürgen; Hermann, Beate; Pfister, Wolfgang; Theis, Bernhard; Petersen, Iver; Stallmach, Andreas; Baier, Michael

    2014-11-01

    A case of primary Epstein-Barr virus (EBV) infection/parvovirus B19 reactivation fulfilling five of eight criteria for hemophagocytic lymphohistiocytosis (HLH) is presented. Despite two coinciding viral infections, massive splenomegaly, and fulminant hepatitis, the patient had a good clinical outcome, probably due to an early onset form of HLH with normal leukocyte count, normal natural killer (NK) cell function, and a lack of hemophagocytosis.

  8. Association of monoclonal expansion of Epstein-Barr virus-negative CD158a+ NK cells secreting large amounts of gamma interferon with hemophagocytic lymphohistiocytosis.

    PubMed

    López-Alvarez, María R; Martínez-Sánchez, María V; Salgado-Cecilia, María G; Campillo, José A; Heine-Suñer, Damian; Villar-Permuy, Florentina; Fuster, José L; Bas, Agueda; Gil-Herrera, Juana; Muro, Manuel; García-Alonso, Ana M; Alvarez-López, María R; Minguela, Alfredo

    2009-01-01

    We report the first case of hemophagocytic lymphohistiocytosis (HLH) induced by the monoclonal expansion of Epstein-Barr virus (EBV)-negative NK cells. Consanguinity of the patient's parents made it necessary to discard familial HLH in the patient and her sister with identical HLA markers and demonstrate that no cause other than the expansion of NK cells, which secrete high levels of gamma interferon, was inducing HLH in this patient.

  9. Anti-MuSK myasthenia gravis presenting with Epstein-Barr virus-associated mononucleosis and immune-mediated diabetes mellitus.

    PubMed

    Bhibhatbhan, Arunee; Kline, Gregory; Vincent, Angela; Toth, Cory

    2007-08-01

    We report a young woman with the abrupt onset of infectious mononucleosis due to Epstein-Barr virus associated with a subsequent autoimmune form of diabetes mellitus and myasthenia gravis with anti-muscle-specific kinase (MuSK) antibodies. The simultaneous onset of these two autoimmune diseases preceded by a systemic viral illness supports a causal relationship between MuSK antibodies and myasthenia gravis and suggests the possibility of a viral trigger in some cases.

  10. Pembrolizumab, Capecitabine, and Radiation Therapy in Treating Patients With Mismatch-Repair Deficient and Epstein-Barr Virus Positive Gastric Cancer

    ClinicalTrials.gov

    2017-11-15

    Epstein-Barr Virus Positive; Gastric Adenocarcinoma; Mismatch Repair Protein Deficiency; Stage IB Gastric Cancer AJCC v7; Stage II Gastric Cancer AJCC v7; Stage IIA Gastric Cancer AJCC v7; Stage IIB Gastric Cancer AJCC v7; Stage III Gastric Cancer AJCC v7; Stage IIIA Gastric Cancer AJCC v7; Stage IIIB Gastric Cancer AJCC v7; Stage IIIC Gastric Cancer AJCC v7

  11. Detection and quantification of virus DNA in plasma of patients with Epstein-Barr virus-associated diseases.

    PubMed Central

    Yamamoto, M; Kimura, H; Hironaka, T; Hirai, K; Hasegawa, S; Kuzushima, K; Shibata, M; Morishima, T

    1995-01-01

    Epstein-Barr virus (EBV) causes various diseases, such as infectious mononucleosis (IM), fatal IM, EBV-associated hemophagocytic syndrome (EBVAHS), and chronic active EBV infection (CAEBV). In the present study, cell-free EBV DNA was detected in the plasma of patients with EBV-associated diseases by PCR assay. The patients included 20 patients with IM, 2 patients with fatal IM, 4 patients with EBVAHS, 4 patients with CAEBV, and 38 healthy children (20 EBV seropositive and 18 EBV seronegative). In patients with IM, plasma samples were positive for EBV DNA in all patients (100%) in the acute phase and in 44% of the patients in the convalescent phase, but plasma samples from the 38 healthy control children were negative (0%) for EBV DNA. Quantitative PCR assay revealed that plasma from patients with IM contained the highest amount of virus DNA within 7 days following the onset of disease (mean, 6 x 10(4) copies per ml). The EBV DNA concentration decreased thereafter as the patients recovered. Plasma from patients with fatal IM contained more than 100 times more copies of EBV DNA (3 x 10(7) copies per ml) than plasma from patients with IM. Plasma from patients with the acute phase of EBVAHS contained 10 times more copies of EBV DNA (5 x 10(5) copies per ml) than plasma from IM, and then patients with the number of copies decreased similarly in both groups of patients in the convalescent phase (2 x 10(4) copies per ml). The amount of virus DNA in patients with CAEBV (6 x 10(4) copies per ml) was similar to that noted in patients with IM; however, it became higher (1 x 10(6) copies per ml) when the patients' clinical status deteriorated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7665644

  12. Detection of Active Epstein-Barr Virus Infection in Duodenal Mucosa of Patients With Refractory Celiac Disease.

    PubMed

    Perfetti, Vittorio; Baldanti, Fausto; Lenti, Marco Vincenzo; Vanoli, Alessandro; Biagi, Federico; Gatti, Marta; Riboni, Roberta; Dallera, Elena; Paulli, Marco; Pedrazzoli, Paolo; Corazza, Gino Roberto

    2016-08-01

    Refractory celiac disease is characterized by mucosal damage in patients with celiac disease despite a gluten-free diet. Little is known about the mechanisms that cause persistent intestinal inflammation in these patients. We performed a case-control study of 17 consecutive patients diagnosed with refractory celiac disease from 2001 through 2014 (median age, 51 y; 10 women) and 24 patients with uncomplicated celiac disease (controls) to determine whether refractory disease is associated with infection by lymphotropic oncogenic viruses. We performed real-time PCR analyses of duodenal biopsy samples from all patients to detect Epstein-Barr virus (EBV), human herpesvirus-8, and human T-cell lymphotropic virus-I, -II, or -III. We used in situ hybridization and immunohistochemical analyses to identify infected cells and viral proteins. We did not detect human herpesvirus-8 or human T-cell lymphotropic viruses in any of the biopsy specimens. However, 12 of 17 (70.5%) biopsy specimens from patients with refractory celiac disease were positive for EBV, compared with 4 of 24 (16.6%) biopsy specimens from controls (P < .001). EBV was detected in inflammatory cells and enterocytes. An analysis of latency- and replication-associated proteins confirmed active infection. Further studies are needed to determine whether EBV infection contributes to the pathogenesis of refractory celiac disease and enteropathy-associated T-cell lymphoma. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

  13. Structural and Functional Basis for an EBNA1 Hexameric Ring in Epstein-Barr Virus Episome Maintenance.

    PubMed

    Deakyne, Julianna S; Malecka, Kimberly A; Messick, Troy E; Lieberman, Paul M

    2017-10-01

    Epstein-Barr virus (EBV) establishes a stable latent infection that can persist for the life of the host. EBNA1 is required for the replication, maintenance, and segregation of the latent episome, but the structural features of EBNA1 that confer each of these functions are not completely understood. Here, we have solved the X-ray crystal structure of an EBNA1 DNA-binding domain (DBD) and discovered a novel hexameric ring oligomeric form. The oligomeric interface pivoted around residue T585 as a joint that links and stabilizes higher-order EBNA1 complexes. Substitution mutations around the interface destabilized higher-order complex formation and altered the cooperative DNA-binding properties of EBNA1. Mutations had both positive and negative effects on EBNA1-dependent DNA replication and episome maintenance with OriP. We found that one naturally occurring polymorphism in the oligomer interface (T585P) had greater cooperative DNA binding in vitro , minor defects in DNA replication, and pronounced defects in episome maintenance. The T585P mutant was compromised for binding to OriP in vivo as well as for assembling the origin recognition complex subunit 2 (ORC2) and trimethylated histone 3 lysine 4 (H3K4me3) at OriP. The T585P mutant was also compromised for forming stable subnuclear foci in living cells. These findings reveal a novel oligomeric structure of EBNA1 with an interface subject to naturally occurring polymorphisms that modulate EBNA1 functional properties. We propose that EBNA1 dimers can assemble into higher-order oligomeric structures important for diverse functions of EBNA1. IMPORTANCE Epstein-Barr virus is a human gammaherpesvirus that is causally associated with various cancers. Carcinogenic properties are linked to the ability of the virus to persist in the latent form for the lifetime of the host. EBNA1 is a sequence-specific DNA-binding protein that is consistently expressed in EBV tumors and is the only viral protein required to maintain the viral

  14. An Epstein-Barr Virus MicroRNA Blocks Interleukin-1 (IL-1) Signaling by Targeting IL-1 Receptor 1.

    PubMed

    Skinner, Camille M; Ivanov, Nikita S; Barr, Sarah A; Chen, Yan; Skalsky, Rebecca L

    2017-11-01

    Epstein-Barr virus (EBV) encodes >44 viral microRNAs (miRNAs) that are differentially expressed throughout infection, can be detected in Epstein-Barr virus (EBV)-positive tumors, and manipulate several biological processes, including cell proliferation, apoptosis, and immune responses. Here, we show that EBV BHRF1-2 miRNAs block NF-κB activation following treatment with proinflammatory cytokines, specifically interleukin-1β (IL-1β). Analysis of EBV PAR-CLIP miRNA targetome data sets combined with pathway analysis revealed multiple BHRF1-2 miRNA targets involved in interleukin signaling pathways. By further analyzing changes in cellular gene expression patterns, we identified the IL-1 receptor 1 (IL1R1) as a direct target of miR-BHRF1-2-5p. Targeting the IL1R1 3' untranslated region (UTR) by EBV miR-BHRF1-2-5p was confirmed using 3'-UTR luciferase reporter assays and Western blot assays. Manipulation of EBV BHRF1-2 miRNA activity in latently infected B cells altered steady-state cytokine levels and disrupted IL-1β responsiveness. These studies demonstrate functionally relevant BHRF1-2 miRNA interactions during EBV infection, which is an important step in understanding their roles in pathogenesis. IMPORTANCE IL-1 signaling plays an important role in inflammation and early activation of host innate immune responses following virus infection. Here, we demonstrate that a viral miRNA downregulates the IL-1 receptor 1 during EBV infection, which consequently alters the responsiveness of cells to IL-1 stimuli and changes the cytokine expression levels within infected cell populations. We postulate that this viral miRNA activity not only disrupts IL-1 autocrine and paracrine signaling loops that can alert effector cells to sites of infection but also provides a survival advantage by dampening excessive inflammation that may be detrimental to the infected cell. Copyright © 2017 American Society for Microbiology.

  15. The Epstein-Barr Virus (EBV) in T Cell and NK Cell Lymphomas: Time for a Reassessment

    PubMed Central

    Gru, A. A.; Haverkos, B. H.; Freud, A. G.; Hastings, J.; Nowacki, N. B.; Barrionuevo, C.; Vigil, C. E.; Rochford, R.; Natkunam, Y.; Baiocchi, R. A.

    2015-01-01

    While Epstein-Barr virus (EBV) was initially discovered and characterized as an oncogenic virus in B cell neoplasms, it also plays a complex and multifaceted role in T/NK cell lymphomas. In B cell lymphomas, EBV-encoded proteins have been shown to directly promote immortalization and proliferation through stimulation of the NF-κB pathway and increased expression of anti-apoptotic genes. In the context of mature T/NK lymphomas (MTNKL), with the possible exception on extranodal NK/T cell lymphoma (ENKTL), the virus likely plays a more diverse and nuanced role. EBV has been shown to shape the tumor microenvironment by promoting Th2-skewed T cell responses and by increasing the expression of the immune checkpoint ligand PD-L1. The type of cell infected, the amount of plasma EBV DNA, and the degree of viral lytic replication have all been proposed to have prognostic value in T/NK cell lymphomas. Latency patterns of EBV infection have been defined using EBV-infected B cell models and have not been definitively established in T/NK cell lymphomas. Identifying the expression profile of EBV lytic proteins could allow for individualized therapy with the use of antiviral medications. More work needs to be done to determine whether EBV-associated MTNKL have distinct biological and clinical features, which can be leveraged for risk stratification, disease monitoring, and therapeutic purposes. PMID:26449716

  16. How compelling are the data for Epstein-Barr virus being a trigger for systemic lupus and other autoimmune diseases?

    PubMed

    Draborg, Anette; Izarzugaza, Jose M G; Houen, Gunnar

    2016-07-01

    Systemic lupus erythematosus (SLE) is caused by a combination of genetic and acquired immunodeficiencies and environmental factors including infections. An association with Epstein-Barr virus (EBV) has been established by numerous studies over the past decades. Here, we review recent experimental studies on EBV, and present our integrated theory of SLE development. SLE patients have dysfunctional control of EBV infection resulting in frequent reactivations and disease progression. These comprise impaired functions of EBV-specific T-cells with an inverse correlation to disease activity and elevated serum levels of antibodies against lytic cycle EBV antigens. The presence of EBV proteins in renal tissue from SLE patients with nephritis suggests direct involvement of EBV in SLE development. As expected for patients with immunodeficiencies, studies reveal that SLE patients show dysfunctional responses to other viruses as well. An association with EBV infection has also been demonstrated for other autoimmune diseases, including Sjögren's syndrome, rheumatoid arthritis, and multiple sclerosis. Collectively, the interplay between an impaired immune system and the cumulative effects of EBV and other viruses results in frequent reactivation of EBV and enhanced cell death, causing development of SLE and concomitant autoreactivities.

  17. Epstein-Barr Virus EBNA1 Protein Regulates Viral Latency through Effects on let-7 MicroRNA and Dicer

    PubMed Central

    Mansouri, Sheila; Pan, Qun; Blencowe, Benjamin J.; Claycomb, Julie M.

    2014-01-01

    ABSTRACT The EBNA1 protein of Epstein-Barr virus (EBV) plays multiple roles in EBV latent infection, including altering cellular pathways relevant for cancer. Here we used microRNA (miRNA) cloning coupled with high-throughput sequencing to identify the effects of EBNA1 on cellular miRNAs in two nasopharyngeal carcinoma cell lines. EBNA1 affected a small percentage of cellular miRNAs in both cell lines, in particular, upregulating multiple let-7 family miRNAs, including let-7a. The effects of EBNA1 on let-7a were verified by demonstrating that EBNA1 silencing in multiple EBV-positive carcinomas downregulated let-7a. Accordingly, the let-7a target, Dicer, was found to be partially downregulated by EBNA1 expression (at the mRNA and protein levels) and upregulated by EBNA1 silencing in EBV-positive cells. Reporter assays based on the Dicer 3′ untranslated region with and without let-7a target sites indicated that the effects of EBNA1 on Dicer were mediated by let-7a. EBNA1 was also found to induce the expression of let-7a primary RNAs in a manner dependent on the EBNA1 transcriptional activation region, suggesting that EBNA1 induces let-7a by transactivating the expression of its primary transcripts. Consistent with previous reports that Dicer promotes EBV reactivation, we found that a let-7a mimic inhibited EBV reactivation to the lytic cycle, while a let-7 sponge increased reactivation. The results provide a mechanism by which EBNA1 could promote EBV latency by inducing let-7 miRNAs. IMPORTANCE The EBNA1 protein of Epstein-Barr virus (EBV) contributes in multiple ways to the latent mode of EBV infection that leads to lifelong infection. In this study, we identify a mechanism by which EBNA1 helps to maintain EBV infection in a latent state. This involves induction of a family of microRNAs (let-7 miRNAs) that in turn decreases the level of the cellular protein Dicer. We demonstrate that let-7 miRNAs inhibit the reactivation of latent EBV, providing an explanation for

  18. Viral reprogramming of the Daxx histone H3.3 chaperone during early Epstein-Barr virus infection.

    PubMed

    Tsai, Kevin; Chan, Lilian; Gibeault, Rebecca; Conn, Kristen; Dheekollu, Jayaraju; Domsic, John; Marmorstein, Ronen; Schang, Luis M; Lieberman, Paul M

    2014-12-01

    Host chromatin assembly can function as a barrier to viral infection. Epstein-Barr virus (EBV) establishes latent infection as chromatin-assembled episomes in which all but a few viral genes are transcriptionally silent. The factors that control chromatin assembly and guide transcription regulation during the establishment of latency are not well understood. Here, we demonstrate that the EBV tegument protein BNRF1 binds the histone H3.3 chaperone Daxx to modulate histone mobility and chromatin assembly on the EBV genome during the early stages of primary infection. We demonstrate that BNRF1 substitutes for the repressive cochaperone ATRX to form a ternary complex of BNRF1-Daxx-H3.3-H4, using coimmunoprecipitation and size-exclusion chromatography with highly purified components. FRAP (fluorescence recovery after photobleaching) assays were used to demonstrate that BNRF1 promotes global mobilization of cellular histone H3.3. Mutation of putative nucleotide binding motifs on BNRF1 attenuates the displacement of ATRX from Daxx. We also show by immunofluorescence combined with fluorescence in situ hybridization that BNRF1 is important for the dissociation of ATRX and Daxx from nuclear bodies during de novo infection of primary B lymphocytes. Virion-delivered BNRF1 suppresses Daxx-ATRX-mediated H3.3 loading on viral chromatin as measured by chromatin immunoprecipitation assays and enhances viral gene expression during early infection. We propose that EBV tegument protein BNRF1 replaces ATRX to reprogram Daxx-mediated H3.3 loading, in turn generating chromatin suitable for latent gene expression. Epstein-Barr Virus (EBV) is a human herpesvirus that efficiently establishes latent infection in primary B lymphocytes. Cellular chromatin assembly plays an important role in regulating the establishment of EBV latency. We show that the EBV tegument protein BNRF1 functions to regulate chromatin assembly on the viral genome during early infection. BNRF1 alters the host cellular

  19. Clinical manifestations and quantitative analysis of virus load in Taiwanese children with Epstein-Barr virus-associated infectious mononucleosis.

    PubMed

    Cheng, Chia Chi; Chang, Luan Yin; Shao, Pei Lan; Lee, Ping Ing; Chen, Jong Min; Lu, Chun Yi; Lee, Chin Yun; Huang, Li Min

    2007-06-01

    To delineate the clinical manifestations in different age groups and to define the viral load in patients with Epstein-Barr virus-associated infectious mononucleosis (EBV-associated IM). We reviewed data on 69 children with EBV-associated IM from November 2001 to October 2005. Clinical features were evaluated among four age groups: <3 years, 3 to 5 years, 6 to 9 years and 10 to 18 years. EBV viral load was measured by quantitative real-time polymerase chain reaction (PCR) in 13 patients with 15 specimens. Majority of the children were younger than 7 years of age (76.8%) and the male-to-female ratio was 1.6:1. The symptoms and signs included fever (91.3%), tonsillopharyngitis (88.4%), lymphadenopathy (78.3%) and hepatitis (75.4%). The younger age group had higher monocyte count, lower occurrence of hepatitis, and lower glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels than the older age group. The median (range) EBV viral load of peripheral blood mononuclear cells (PBMCs) and plasma in IM patients was 738 (0-7455) copies/mug DNA and 51 (0-957) copies/mL plasma, respectively. The PBMC detection rate was high in the early (within 10 days after onset) and late phase (>10 days after onset) [90-100%]. The plasma detection rate in the early phase (66.7%) was higher than that in the late phase (40%). The younger age group of EBV-associated IM patients had higher monocyte count, lower occurrence of hepatitis, and lower GOT and GPT levels than the older age group. The PBMC detection rate was almost equally high in both the early and late phases, while the plasma detection rate was higher in the early phase. Quantitative real-time PCR of EBV DNA is useful for diagnosing and monitoring EBV-associated IM, especially in younger children.

  20. Kinetics of Epstein-Barr virus load and virus-specific CD8+ T cells in acute infectious mononucleosis.

    PubMed

    Hoshino, Yo; Nishikawa, Kazuo; Ito, Yoshinori; Kuzushima, Kiyotaka; Kimura, Hiroshi

    2011-03-01

    During the convalescent phase of acute infectious mononucleosis (AIM), Epstein-Barr virus (EBV) load shrinks rapidly in association with a rapid decline in the number of EBV-specific CD8(+) T cells. The actual contribution of EBV-specific CD8(+) T cells in reducing EBV load, however, is not known. To clarify the impact of EBV-specific CD8(+) T cells on the contraction of EBV load in AIM, we estimated half-lives of both EBV load and EBV-specific CD8(+) T cells. Blood was serially taken from five pediatric patients with AIM during the convalescent period, including the very early phase, and both EBV load and EBV-specific CD8(+) T cell numbers were assayed. EBV load declined rapidly (half-life 1.5 d) during the first 2 weeks after onset of symptoms. This half-life was seven-fold shorter than that reported for CD27(+) memory B cells. Subsequently, the EBV load declined much more slowly, with a half-life of 38.7 d. EBV-specific CD8(+) T cell numbers also declined concomitantly with the decrease in EBV load. The half-life of EBV-specific CD8(+) T cells during first 2 weeks was 2.9 d. The number of EBV-specific CD8(+) T cells and the rate of change of viral load correlated significantly (R(2) ≥ 0.8; p ≤ 0.02). The short half-life of EBV load, together with the strong correlation between the number of EBV-specific CD8(+) T cells and the rate of change of viral load indicates an active role for EBV-specific CD8(+) T cells in elimination of EBV in AIM. Copyright © 2010 Elsevier B.V. All rights reserved.

  1. Performance of the Epstein-Barr Virus and Herpes Simplex Virus Immunoglobulin M Assays on the Liaison Platform with Sera from Patients Displaying Acute Parvovirus B19 Infection▿

    PubMed Central

    Costa, Elisa; Tormo, Nuria; Clari, María Ángeles; Bravo, Dayana; Muñoz-Cobo, Beatriz; Navarro, David

    2009-01-01

    Acute parvovirus B19 infection has been reported to cause false-positive results frequently in the Epstein-Barr (EBV) and herpes simplex virus (HSV) immunoglobulin M (IgM) assays from DiaSorin performed on the Liaison platform. We tested 65 sera from patients with a presumptive or conclusive diagnosis of acute parvovirus B19 infection in both assays and obtained no false-positive results in the EBV IgM test and 10.4% nonspecific reactivities in the HSV IgM assay. Our data support the specificity of both assays in this clinical setting. PMID:19571110

  2. Epstein-Barr virus-positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection-associated T/NK-cell lymphoproliferative disorder: a case report.

    PubMed

    Kato, Seiichi; Miyata, Tomoko; Takata, Katsuyoshi; Shimada, Satoko; Ito, Yoshinori; Tomita, Akihiro; Elsayed, Ahmed Ali; Takahashi, Emiko; Asano, Naoko; Kinoshita, Tomohiro; Kimura, Hiroshi; Nakamura, Shigeo

    2013-12-01

    A 30-year-old female patient presented with intestinal Epstein-Barr virus (EBV)-positive cytotoxic T-cell lymphoma (EBV+ CTL), which was surgically resected. Fourteen years later, she returned to our hospital with hypersensitivity to mosquito bites and was diagnosed with chronic active EBV infection-associated T/NK-cell lymphoproliferative disorder (CAEBV/TNK-LPD). She developed systemic EBV+ CTL at age 47 years during the 2.5-year clinical course of CAEBV/TNK-LPD, despite multiagent chemotherapy and allogeneic stem cell transplantation. Afterward, she had a rapidly deteriorating clinical course and died at age 48 years. The immunophenotype of the EBV+ CTL was consistently a CD3, CD8, and cytotoxic molecule-positive type with the same clonality in polymerase chain reaction analysis of T-cell receptor-γ chain gene rearrangement. This is the first reported case of EBV+ CTL preceding the clinical presentation of CAEBV/TNK-LPD. The present case was unique in suggesting a close relationship between EBV+ CTL and chronic active EBV infection. © 2013.

  3. Comparison of two automated instruments for Epstein-Barr virus serology in a large adult hospital and implementation of an Epstein-Barr virus nuclear antigen-based testing algorithm.

    PubMed

    Al Sidairi, Hilal; Binkhamis, Khalifa; Jackson, Colleen; Roberts, Catherine; Heinstein, Charles; MacDonald, Jimmy; Needle, Robert; Hatchette, Todd F; LeBlanc, Jason J

    2017-11-01

    Serology remains the mainstay for diagnosis of Epstein-Barr virus (EBV) infection. This study compared two automated platforms (BioPlex 2200 and Architect i2000SR) to test three EBV serological markers: viral capsid antigen (VCA) immunoglobulins of class M (IgM), VCA immunoglobulins of class G (IgG) and EBV nuclear antigen-1 (EBNA-1) IgG. Using sera from 65 patients at various stages of EBV disease, BioPlex demonstrated near-perfect agreement for all EBV markers compared to a consensus reference. The agreement for Architect was near-perfect for VCA IgG and EBNA-1 IgG, and substantial for VCA IgM despite five equivocal results. Since the majority of testing in our hospital was from adults with EBNA-1 IgG positive results, post-implementation analysis of an EBNA-based algorithm showed advantages over parallel testing of the three serologic markers. This small verification demonstrated that both automated systems for EBV serology had good performance for all EBV markers, and an EBNA-based testing algorithm is ideal for an adult hospital.

  4. Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue repository during 1979-2009.

    PubMed

    Mbulaiteye, Sam M; Pullarkat, Sheeja T; Nathwani, Bharat N; Weiss, Lawrence M; Rao, Nagesh; Emmanuel, Benjamin; Lynch, Charles F; Hernandez, Brenda; Neppalli, Vishala; Hawes, Debra; Cockburn, Myles G; Kim, Andre; Williams, Makeda; Altekruse, Sean; Bhatia, Kishor; Goodman, Marc T; Cozen, Wendy

    2014-01-01

    Burkitt lymphoma (BL) occurs at all ages, but the patterns of Epstein-Barr virus (EBV) positivity in relation to human immunodeficiency virus (HIV), immunoprofiles and age have not been fully explored. BL tissues from residual tissue repositories, and two academic centers in the United States were examined by expert hematopathologists for morphology, immunohistochemistry, MYC rearrangement, EBV-encoded RNA (EBER), and diagnosed according to the 2008 WHO lymphoma classification. Analysis was done using frequency tables, Chi-squared statistics, and Student's t-test. Of 117 cases examined, 91 were confirmed as BL. The age distribution was 26%, 15%, 19%, and 29% for 0-19, 20-34, 35-59, 60+ years, and missing in 11%. MYC rearrangement was found in 89% and EBER positivity in 29% of 82 cases with results. EBER positivity varied with age (from 13% in age group 0-19 to 55% in age group 20-34, and fell to 25% in age group 60+ years, p = 0.08); with race (56% in Blacks/Hispanics vs 21% in Whites/Asians/Pacific Islanders, p = 0.006); and by HIV status (64% in HIV positive vs 22% in HIV negative cases, p = 0.03). EBER positivity was demonstrated in about one-third of tumors and it was strongly associated with race and HIV status, and marginally with age-group. © 2013 APMIS Published by Blackwell Publishing Ltd.

  5. Pathogenesis of chronic active Epstein-Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency?

    PubMed

    Kimura, Hiroshi

    2006-01-01

    Chronic active Epstein-Barr virus infection (CAEBV) is characterised by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, hepatosplenomegaly, persistent hepatitis and extensive lymphadenopathy. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Nearly three decades have passed since this disease was first identified, and recent advances in technology have increased our understanding of CAEBV pathophysiology. There is accumulating evidence that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. EBV-infected T or NK cells are able to evade the host cellular immune system due to the limited expression of viral proteins of reduced antigenicity. Recent studies suggest that infection of T or NK cells is a common event during primary EBV infection. A defect or single nucleotide polymorphism in host immune-modulating genes may allow for the expansion of virus infected cells giving rise to CAEBV. In this review, I summarise our current understanding of the pathogenesis of CAEBV and propose a model of CAEBV pathogenicity.

  6. Demonstration of the Burkitt's lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cells in vivo

    PubMed Central

    Hochberg, Donna; Middeldorp, Jaap M.; Catalina, Michelle; Sullivan, John L.; Luzuriaga, Katherine; Thorley-Lawson, David A.

    2004-01-01

    Epstein-Barr virus (EBV) is a herpesvirus that establishes a lifelong, persistent infection. It was first discovered in the tumor Burkitt's lymphoma (BL). Despite intensive study, the role of EBV in BL remains enigmatic. One striking feature of the tumor is the unique pattern of viral latent protein expression, which is restricted to EBV-encoded nuclear antigen (EBNA) 1. EBNA1 is required to maintain the viral genome but is not recognized by cytotoxic T cells. Consequently, it was proposed that this expression pattern was used by latently infected B cells in vivo. This would be the site of long-term, persistent infection by the virus and, by implication, the progenitor of BL. We now know that EBV persists in memory B cells in the peripheral blood and that BL is a tumor of memory cells. However, a normal B cell expressing EBNA1 alone has been elusive. Here we show that most infected cells in the blood express no detectable latent mRNA or proteins. The exception is that when infected cells divide they express EBNA1 only. This is the first detection of the BL viral phenotype in a normal, infected B cell in vivo. It suggests that BL may be a tumor of a latently infected memory B cell that is stuck proliferating because it is a tumor and, therefore, constitutively expressing only EBNA1. PMID:14688409

  7. An ELISA method to compute endpoint titers to Epstein-Barr virus and cytomegalovirus: application to population-based studies.

    PubMed

    Stowe, Raymond P; Ruiz, R Jeanne; Fagundes, Christopher P; Stowe, Robin H; Chen, Min; Glaser, Ronald

    2014-06-01

    Indirect fluorescence analysis (IFA), the gold standard for determining herpesvirus antibody titers, is labor-intensive and poorly suited for large population-based studies. The enzyme-linked immunosorbent assay (ELISA) is used widely for measuring antiviral antibodies but also suffers drawbacks such as reduced specificity and the qualitative nature of the results due to limited interpretation of the optical density (OD) units. This paper describes a method to titer herpesvirus antibodies using microplates coated with virally-infected cells in which a standard curve, derived from IFA-scored samples, allowed OD units to be converted into titers. A LOOKUP function was created in order to report the data as traditional IFA-based (i.e., 2-fold) titers. The modified ELISA correlated significantly with IFA and was subsequently used to compute endpoint antibody titers to Epstein-Barr virus (EBV)-virus capsid antigen (VCA) and cytomegalovirus (CMV) in blood samples taken from 398 pregnant Hispanic women. Four women were EBV negative (1%), while 58 women were CMV negative (14.6%). EBV VCA antibody titers were significantly higher than CMV antibody titers (p<0.001). This method allows titering of herpesvirus antibodies by ELISA suitable for large population-based studies. In addition, the LOOKUP table enables conversion from OD-derived titers into 2-fold titers for comparison of results with other studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Epstein-Barr Virus (EBV) DNA in plasma is not encapsidated in patients with EBV-related malignancies.

    PubMed

    Ryan, Julie L; Fan, Hongxin; Swinnen, Lode J; Schichman, Steven A; Raab-Traub, Nancy; Covington, Mary; Elmore, Sandra; Gulley, Margaret L

    2004-06-01

    Epstein-Barr Virus (EBV), a ubiquitous gamma herpes virus, infects more than 95% of the human population before adulthood. Life-long persistence, usually without adverse health consequences, relies on a balance between viral latency, viral replication, and host immune response. Patients with EBV-related disease often have high levels of EBV DNA in their plasma. This study addresses whether this circulating, cell-free EBV DNA is encapsidated in virions or exists as naked genomes. First, an assay was developed, combining DNase I and quantitative real-time PCR, to discriminate encapsidated from naked EBV DNA. EBV DNA was almost always naked in the plasma of AIDS-related lymphoma patients (n = 11) and immunosuppressed/posttransplantation patients (n = 8). In contrast, infectious mononucleosis patients (n = 30) often had a mixture of encapsidated and naked EBV DNA. These findings may be important in understanding how viral load relates to disease status and in predicting response to nucleoside analogs and other antiviral therapies.

  9. Rapid CRISPR/Cas9-Mediated Cloning of Full-Length Epstein-Barr Virus Genomes from Latently Infected Cells.

    PubMed

    Yajima, Misako; Ikuta, Kazufumi; Kanda, Teru

    2018-04-03

    Herpesviruses have relatively large DNA genomes of more than 150 kb that are difficult to clone and sequence. Bacterial artificial chromosome (BAC) cloning of herpesvirus genomes is a powerful technique that greatly facilitates whole viral genome sequencing as well as functional characterization of reconstituted viruses. We describe recently invented technologies for rapid BAC cloning of herpesvirus genomes using CRISPR/Cas9-mediated homology-directed repair. We focus on recent BAC cloning techniques of Epstein-Barr virus (EBV) genomes and discuss the possible advantages of a CRISPR/Cas9-mediated strategy comparatively with precedent EBV-BAC cloning strategies. We also describe the design decisions of this technology as well as possible pitfalls and points to be improved in the future. The obtained EBV-BAC clones are subjected to long-read sequencing analysis to determine complete EBV genome sequence including repetitive regions. Rapid cloning and sequence determination of various EBV strains will greatly contribute to the understanding of their global geographical distribution. This technology can also be used to clone disease-associated EBV strains and test the hypothesis that they have special features that distinguish them from strains that infect asymptomatically.

  10. Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection.

    PubMed

    Price, Alexander M; Dai, Joanne; Bazot, Quentin; Patel, Luv; Nikitin, Pavel A; Djavadian, Reza; Winter, Peter S; Salinas, Cristina A; Barry, Ashley Perkins; Wood, Kris C; Johannsen, Eric C; Letai, Anthony; Allday, Martin J; Luftig, Micah A

    2017-04-20

    Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFκB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFκB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.

  11. Rapid CRISPR/Cas9-Mediated Cloning of Full-Length Epstein-Barr Virus Genomes from Latently Infected Cells

    PubMed Central

    Ikuta, Kazufumi; Kanda, Teru

    2018-01-01

    Herpesviruses have relatively large DNA genomes of more than 150 kb that are difficult to clone and sequence. Bacterial artificial chromosome (BAC) cloning of herpesvirus genomes is a powerful technique that greatly facilitates whole viral genome sequencing as well as functional characterization of reconstituted viruses. We describe recently invented technologies for rapid BAC cloning of herpesvirus genomes using CRISPR/Cas9-mediated homology-directed repair. We focus on recent BAC cloning techniques of Epstein-Barr virus (EBV) genomes and discuss the possible advantages of a CRISPR/Cas9-mediated strategy comparatively with precedent EBV-BAC cloning strategies. We also describe the design decisions of this technology as well as possible pitfalls and points to be improved in the future. The obtained EBV-BAC clones are subjected to long-read sequencing analysis to determine complete EBV genome sequence including repetitive regions. Rapid cloning and sequence determination of various EBV strains will greatly contribute to the understanding of their global geographical distribution. This technology can also be used to clone disease-associated EBV strains and test the hypothesis that they have special features that distinguish them from strains that infect asymptomatically. PMID:29614006

  12. Evaluation of the presence of Epstein-Barr virus (EBV) in Iranian patients with thyroid papillary carcinoma.

    PubMed

    Homayouni, Maryam; Mohammad Arabzadeh, Seyed Ali; Nili, Fatemeh; Razi, Farideh; Amoli, Mahsa Mohammad

    2017-07-01

    Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. EBV is one of the most important viruses related to different types of malignancies. This study investigated the relationship between EBV and papillary thyroid carcinoma. In this study the presence of Epstein-Barr Nuclear Antigen 1 (EBNA1) gene in papillary thyroid carcinoma tissues were examined by nested-PCR method. Paraffin-embedded tissues (N=41) blocks of thyroid cancer were used. DNA was extracted from all samples and then samples were evaluated for the presence of EBV gene. In 41 samples, EBNA1 was detected in 65.8% of patients with papillary thyroid carcinoma which was significantly higher in younger ages. The significant presence of EBV genome in papillary thyroid carcinoma suggests that this virus may play a role in this cancer especially in younger ages. As a result, monitoring of patients with EBV latent infection for PTC can be very important. Copyright © 2017 Elsevier GmbH. All rights reserved.

  13. Prevalence of human papillomavirus and Epstein-Barr virus DNA in Chinese children with tonsillar and/or adenoidal hypertrophy.

    PubMed

    Xue, Xiao-cheng; Chen, Xiao-ping; Yao, Wen-hao; Zhang, Yi; Sun, Guang-bin; Tan, Xue-jun

    2014-06-01

    Tonsillar and adenoidal hypertrophy are prevalent otolaryngologic disorders in children, but their pathogenesis is largely unknown. The presence of human papillomavirus (HPV) and Epstein-Barr virus (EBV) DNA in 146 tonsil and/or adenoid tissue specimens from 104 Chinese children with tonsillar and/or adenoidal hypertrophy were screened using flow-through hybridization gene-chip technology and real-time fluorescence-based quantitative PCR. Then, the relationships between the prevalence of the viruses and other clinical characteristics of tonsillar and/or adenoidal hypertrophy were analyzed. No patient had HPV DNA. EBV DNA was detected in 19/42 (45.2%) tonsil tissues and 72/104 (69.2%) adenoid tissue specimens (P < 0.05). EBV DNA was not related to the patients' age, gender, disease course, or nationality, but children positive for EBV were less likely to snore; 14/15 (93.3%) patients who did not snore and 59/89 (66.3%) patients who snored were EBV positive. EBV DNA, but not HPV DNA was detected in Chinese children with tonsillar and/or adenoidal hypertrophy. Adenoid tissues might more susceptible than tonsil tissues to EBV infection. In addition, EBV infection did not aggravate snoring in patients with tonsillar and/or adenoidal hypertrophy. © 2014 Wiley Periodicals, Inc.

  14. Antigen-inducing ability of herpesvirus papio in human and baboon lymphoma lines, compared to Epstein-Barr virus.

    PubMed

    Klein, G; Falk, L; Falk, K

    1978-01-01

    Herpesvirus papio(HVP)-carrying baboon lymphoblastoid lines do not express a nuclear antigen like the Epstein-Barr virus(EBV)-determined nuclear antigen (EBNA), as judged by in situ anticomplement fluorescence staining, although the carry multiple viral genomes and, in the case of producerlines, early antigen (EA) and viral capsid antigen (VCA) that cross-react with the corresponding human EBV-determined antigens. To test whether the lack of in situ nuclear antigen expression is a property innate to the baboon virus or the baboon cell, nonproducer HVP-carrying baboon lymphoid cells of the 26 CB-1 line were superinfected with two human EBV strains. B95-8-derived EBV induced brilliant EBNA staining, proving that the baboon lymphoid cell was competent to synthesize EBNA. In the mirror experiment, HVP derived from the 9B or the 18C baboon line was added to the EBV-carrying Raji line, the EBV-negative Ramos and BJAB lines and the HVP-carrying nonproducer 26 CB-1 line, respectively. HVP induced EA and VCA in Raji, and EA in BJAB and 26 CB-1. EBNA was not induced in any of the three EBNA-negative lines, BJAB, Ramos and 26 CB-1. It is concluded that the lack of in situ nuclear staining in HVP-carrying baboon lines is a HVP-associated property and is not due to any innate inability of the baboon lymphoid cell to synthesize an antigen of the EBNA type.

  15. Epstein-Barr virus and human immunodeficiency virus serological responses and viral burdens in HIV-infected patients treated with HAART

    NASA Technical Reports Server (NTRS)

    O'Sullivan, Cathal E.; Peng, RongSheng; Cole, Kelly Stefano; Montelaro, Ronald C.; Sturgeon, Timothy; Jenson, Hal B.; Ling, Paul D.; Butel, J. S. (Principal Investigator)

    2002-01-01

    Epstein-Barr virus (EBV) associated non-Hodgkin lymphoma is recognized as a complication of human immunodeficiency virus (HIV) infection. Little is known regarding the influence of highly active antiretroviral therapy (HAART) on the biology of EBV in this population. To characterize the EBV- and HIV-specific serological responses together with EBV DNA levels in a cohort of HIV-infected adults treated with HAART, a study was conducted to compare EBV and HIV serologies and EBV DNA copy number (DNAemia) over a 12-month period after the commencement of HAART. All patients were seropositive for EBV at baseline. Approximately 50% of patients had detectable EBV DNA at baseline, and 27/30 had detectable EBV DNA at some point over the follow-up period of 1 year. Changes in EBV DNA copy number over time for any individual were unpredictable. Significant increases in the levels of Epstein-Barr nuclear antigen (EBNA) and Epstein-Barr early antigen (EA) antibodies were demonstrated in the 17 patients who had a good response to HAART. Of 29 patients with paired samples tested, four-fold or greater increases in titers were detected for EA in 12/29 (41%), for EBNA in 7/29 (24%), for VCA-IgG in 4/29 (14%); four-fold decreases in titers were detected in 2/29 (7%) for EA and 12/29 (41%) for EBNA. A significant decline in the titer of anti-HIV antibodies was also demonstrated. It was concluded that patients with advanced HIV infection who respond to HAART have an increase in their EBV specific antibodies and a decrease in their HIV-specific antibodies. For the cohort overall, there was a transient increase in EBV DNA levels that had declined by 12 months. Copyright 2002 Wiley-Liss, Inc.

  16. Knockout of Epstein-Barr Virus BPLF1 Retards B-Cell Transformation and Lymphoma Formation in Humanized Mice

    PubMed Central

    Li, Guangming; Montgomery, Stephanie A.; Montgomery, Nathan D.; Su, Lishan; Pagano, Joseph S.

    2015-01-01

    ABSTRACT BPLF1 of Epstein-Barr virus (EBV) is classified as a late lytic cycle protein but is also found in the viral tegument, suggesting its potential involvement at both initial and late stages of viral infection. BPLF1 possesses both deubiquitinating and deneddylating activity located in its N-terminal domain and is involved in processes that affect viral infectivity, viral DNA replication, DNA repair, and immune evasion. A recently constructed EBV BPLF1-knockout (KO) virus was used in conjunction with a humanized mouse model that can be infected with EBV, enabling the first characterization of BPLF1 function in vivo. Results demonstrate that the BPLF1-knockout virus is approximately 90% less infectious than wild-type (WT) virus. Transformation of human B cells, a hallmark of EBV infection, was delayed and reduced with BPLF1-knockout virus. Humanized mice infected with EBV BPLF1-knockout virus showed less weight loss and survived longer than mice infected with equivalent infectious units of WT virus. Additionally, splenic tumors formed in 100% of mice infected with WT EBV but in only 25% of mice infected with BPLF1-KO virus. Morphological features of spleens containing tumors were similar to those in EBV-induced posttransplant lymphoproliferative disease (PTLD) and were almost identical to cases seen in human diffuse large B-cell lymphoma. The presence of EBV genomes was detected in all mice that developed tumors. The results implicate BPLF1 in human B-cell transformation and tumor formation in humanized mice. PMID:26489865

  17. Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.

    PubMed

    Speck, Olga; Tang, Weihua; Morgan, Douglas R; Kuan, Pei Fen; Meyers, Michael O; Dominguez, Ricardo L; Martinez, Enrique; Gulley, Margaret L

    2015-10-01

    Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.

  18. The Immunomodulatory Capacity of an Epstein-Barr Virus Abortive Lytic Cycle: Potential Contribution to Viral Tumorigenesis

    PubMed Central

    2018-01-01

    Epstein-Barr virus (EBV) is characterized by a bipartite life cycle in which latent and lytic stages are alternated. Latency is compatible with long-lasting persistency within the infected host, while lytic expression, preferentially found in oropharyngeal epithelial tissue, is thought to favor host-to-host viral dissemination. The clinical importance of EBV relates to its association with cancer, which we think is mainly a consequence of the latency/persistency mechanisms. However, studies in murine models of tumorigenesis/lymphomagenesis indicate that the lytic cycle also contributes to cancer formation. Indeed, EBV lytic expression is often observed in established cell lines and tumor biopsies. Within the lytic cycle EBV expresses a handful of immunomodulatory (BCRF1, BARF1, BNLF2A, BGLF5 & BILF1) and anti-apoptotic (BHRF1 & BALF1) proteins. In this review, we discuss the evidence supporting an abortive lytic cycle in which these lytic genes are expressed, and how the immunomodulatory mechanisms of EBV and related herpesviruses Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV) result in paracrine signals that feed tumor cells. An abortive lytic cycle would reconcile the need of lytic expression for viral tumorigenesis without relaying in a complete cycle that would induce cell lysis to release the newly formed infective viral particles. PMID:29601503

  19. Human NF-κB1 Haploinsufficiency and Epstein-Barr Virus-Induced Disease-Molecular Mechanisms and Consequences.

    PubMed

    Hoeger, Birgit; Serwas, Nina Kathrin; Boztug, Kaan

    2017-01-01

    Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κB1)-related human primary immune deficiencies have initially been characterized as defining a subgroup of common variable immunodeficiencies (CVIDs), representing intrinsic B-cell disorders with antibody deficiency and recurrent infections of various kind. Recent evidence indicates that NF-κB1 haploinsufficiency underlies a variable type of combined immunodeficiency (CID) affecting both B and T lymphocyte compartments, with a broadened spectrum of disease manifestations, including Epstein-Barr virus (EBV)-induced lymphoproliferative disease and immediate life-threatening consequences. As part of this review series focused on EBV-related primary immunodeficiencies, we discuss the current clinical and molecular understanding of monoallelic NFKB1 germline mutations with special focus on the emerging context of EBV-associated disease. We outline mechanistic implications of dysfunctional NF-κB1 in B and T cells and discuss the fatal relation of impaired T-cell function with the inability to clear EBV infections. Finally, we compare common and suggested treatment angles in the context of this complex disease.

  20. Serum BAFF levels, Methypredsinolone therapy, Epstein-Barr Virus and Mycobacterium avium subsp. paratuberculosis infection in Multiple Sclerosis patients.

    PubMed

    Mameli, Giuseppe; Cocco, Eleonora; Frau, Jessica; Arru, Giannina; Caggiu, Elisa; Marrosu, Maria Giovanna; Sechi, Leonardo A

    2016-07-07

    Elevated B lymphocyte activating factor BAFF levels have been reported in multiple sclerosis (MS) patients; moreover, disease-modifying treatments (DMT) have shown to influence blood BAFF levels in MS patients, although the significance of these changes is still controversial. In addition, BAFF levels were reported increased during infectious diseases. In our study, we wanted to investigate on the serum BAFF concentrations correlated to the antibody response against Mycobacterium avium subspecies paratuberculosis (MAP), Epstein-Barr virus (EBV) and their human homologous epitopes in MS and in patients affected with other neurological diseases (OND), divided in Inflammatory Neurological Diseases (IND), Non Inflammatory Neurological Diseases (NIND) and Undetermined Neurological Diseases (UND), in comparison to healthy controls (HCs). Our results confirmed a statistically significant high BAFF levels in MS and IND patients in comparison to HCs but not NIND and UND patients. Interestingly, BAFF levels were inversely proportional to antibodies level against EBV and MAP peptides and the BAFF levels significantly decreased in MS patients after methylprednisolone therapy. These results implicate that lower circulating BAFF concentrations were present in MS patients with humoral response against MAP and EBV. In conclusion MS patients with no IgGs against EBV and MAP may support the hypothesis that elevated blood BAFF levels could be associated with a more stable disease.

  1. Epstein-Barr virus associated T-cell lymphoproliferative disease misdiagnosed as ulcerative colitis: a case report.

    PubMed

    Zheng, Xiaodan; Xie, Jianlan; Zhou, Xiaoge

    2015-01-01

    Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disease (LPD) is not uncommon in China, but gastrointestinal involvement is very rare. We report on an immunocompetent patient with EBV-associated T-cell LPD of the colon. The 26-year-old man was initially misdiagnosed with ulcerative colitis (UC). A colon biopsy revealed the presence of small to medium-sized lymphoid cells infiltrating the intestinal wall. The neoplastic cells expressed CD3, CD5, and granzyme B, not CD56. EBV-encoded small ribonucleic acid was detected in the tumor cells of the colon as well as the lymph node, and the T-cell receptor gene rearrangement result displayed δ gene monoclonal rearrangement. The patient died 2 moths after the diagnosis. The clinical course of EBV-associated T-cell LPD is aggressive and the prognosis is poor, the wrong diagnosis may delay treatment. Therefore, we should be very careful to prevent misdiagnosis. When patients have multiple intestinal ulcers that are not typical of UC and the clinical course is unusual, although morphology looks like inflammatory change, pathologist should consider the possibility of EBV-associated LPD. The treatment strategy and prognosis of these two diseases are different.

  2. In vivo dynamics of EBNA1-oriP interaction during latent and lytic replication of Epstein-Barr virus.

    PubMed

    Daikoku, Tohru; Kudoh, Ayumi; Fujita, Masatoshi; Sugaya, Yutaka; Isomura, Hiroki; Tsurumi, Tatsuya

    2004-12-24

    The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is required for maintenance of the viral genome DNA during the latent phase of EBV replication but continues to be synthesized after the induction of viral productive replication. An EBV genome-wide chromatin immunoprecipitation assay revealed that EBNA1 constantly binds to oriP of the EBV genome during not only latent but also lytic infection. Although the total levels of EBNA1 proved constant throughout the latter, the levels of the oriP-bound form were increased as lytic infection proceeded. EBV productive DNA replication occurs at discrete sites in nuclei, called replication compartments, where viral replication proteins are clustered. Confocal laser microscopic analyses revealed that whereas EBNA1 was distributed broadly in nuclei as fine punctate dots during the latent phase of infection, the protein became redistributed to the viral replication compartments and localized as distinct spots within and/or nearby the compartments after the induction of lytic replication. Taking these findings into consideration, oriP regions of the EBV genome might be organized by EBNA1 into replication domains that may set up scaffolding for lytic replication and transcription.

  3. Epstein-Barr virus-induced gene 3 (EBI3) polymorphisms and expression are associated with susceptibility to pulmonary tuberculosis.

    PubMed

    Zheng, Ruijuan; Liu, Haipeng; Song, Peng; Feng, Yonghong; Qin, Lianhua; Huang, Xiaochen; Chen, Jianxia; Yang, Hua; Liu, Zhonghua; Cui, Zhenglin; Hu, Zhongyi; Ge, Baoxue

    2015-07-01

    Tuberculosis (TB) remains a major global health problem and host genetic factors play a critical role in susceptibility and resistance to TB. The aim of this study was to identify novel candidate genes associated with TB susceptibility. We performed a population-based case-control study to genotype 13 tag SNPs spanning Epstein-Barr virus-induced gene 3 (EBI3), colony stimulating factor 2 (CSF2), IL-4, interferon beta 1 (IFNB1), chemokine (C-X-C motif) ligand 14 (CXCL14) and myeloid differentiation primary response gene 88 (Myd88) genes in 435 pulmonary TB patients and 375 health donors from China. We observed that EBI3 gene rs4740 polymorphism was associated with susceptibility to pulmonary tuberculosis (PTB) and the allele G was associated with a protective effect against PTB. Furthermore, EBI3 deficiency led to reduced bacterial burden and histopathological impairment in the lung of mice infected with Mycobacterium bovis BCG. Meanwhile, higher abundance of EBI3 was observed in the granuloma of PTB patients and in the lung tissue of BCG-infected mice. Of note, the expression of EBI3 in macrophages was remarkably induced by mycobacteria infection at both mRNA and protein level. In conclusion, EBI3 gene rs4740 polymorphism is closely associated with susceptibility to PTB and the elevation and enrichment of EBI3 in the lung which at least partially derived from macrophages may contribute to the exacerbation of mycobacterial infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Orbital Epstein-Barr Virus-Positive Polymorphic B-Cell Lymphoproliferative Disorder in an Apparently Immunocompetent Woman.

    PubMed

    Abendroth, Michael D; Bayerl, Michael G; Wilkinson, Michael J; Claxton, David F; Specht, Charles S

    2017-12-01

    We report a rare case of Epstein-Barr virus (EBV)-positive polymorphic B-cell lymphoproliferative disorder (LPD) involving the lacrimal gland of a 28-year-old, apparently immunocompetent woman. She presented with a chief complaint of orbital swelling and tenderness and was found to have a lesion involving the right lacrimal gland and distal superior and lateral rectus muscles. Histology of the lesion revealed histiocytes with pleomorphic nuclei, reactive lymphocytes, and scattered cells that resembled the Reed-Sternberg (R-S) cells of classical Hodgkin lymphoma. The R-S-like cells were positive for PAX5 and CD30 and negative for CD15, supporting a diagnosis of polymorphic B-cell LPD. In situ hybridization for EBV-encoded RNA demonstrated the presence of EBV. Most EBV-positive polymorphic B-cell LPDs are associated with immunodeficiency. However, the patient described is HIV-negative and has no identifiable defects in immunoglobulin levels or cell-mediated immunity. This raises the question of whether she has an underlying immunodeficiency resulting from subtle changes in T-cell physiology, or whether chronic EBV infection contributed to her immune dysfunction through an unclear mechanism. The orbital mass partially regressed with chemotherapy, and the patient has done well clinically with no recurrence of this EBV-LPD for over 2 years.

  5. [Recurrence of chronic active Epstein-Barr virus infection presenting with myelopathy after umbilical cord blood transplantation].

    PubMed

    Watanabe, Shohei; Okada, Masaya; Tokugawa, Tazuko; Sawada, Akihiro; Ogawa, Hiroyasu; Yoshikawa, Hiroo

    2014-01-01

    A 38-year-old man was admitted to our hospital with neck pain, dysesthesia of both hands, and weakness of the left upper limb. He had been diagnosed with a chronic active Epstein-Barr virus infection (CAEBV) at the age of 34 and had undergone umbilical cord blood transplantation at the age of 37. MRI of the spinal cord revealed an intramedullary hyperintense lesion on T₂-weighted images with gadolinium enhancement. Because his laboratory tests revealed proliferation of CD19(+) lymphocytes in the peripheral blood, and EBV DNA was detected in both peripheral blood and CSF, he was diagnosed as having post-transplant EBV associated lymphoproliferative disease. However, chemotherapy did not alleviate his symptoms. At a later time, quantitative chimerism analysis of his CSF showed a higher proportion of lymphocytes that had originated from the recipient. Finally, he was diagnosed as having a recurrence of CAEBV in the central nervous system, and his symptoms were restored by intrathecal chemotherapy (methotrexate, cytosine arabinoside, and prednisolone). Quantitative chimerism analysis of CSF was useful for diagnosing the recurrence of CAEBV in the central nervous system.

  6. The Spectrum of Epstein-Barr Virus-Associated Lymphoproliferative Disease in Korea: Incidence of Disease Entities by Age Groups

    PubMed Central

    Cho, Eun-Yoon; Kim, Ki-Hyun; Kim, Won-Seog; Yoo, Keon Hee; Koo, Hong-Hoe

    2008-01-01

    This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma. PMID:18436998

  7. Alterations in ATR in nasal NK/T-cell lymphoma and chronic active Epstein-Barr virus infection.

    PubMed

    Liu, Angen; Takakuwa, Tetsuya; Luo, Wen-Juan; Fujita, Shigeki; Aozasa, Katsuyuki

    2006-07-01

    Nasal natural killer (NK)/T-cell lymphoma (NKTCL) and chronic active Epstein-Barr virus infection (CAEBV) are relatively frequent, especially in Asia, and are poor in prognosis. Both diseases are proliferative diseases of NK/T cells that show highly complicated karyotypes, suggesting the involvement of chromosomal instability. ATR is an important gene for DNA damage response and chromosomal stability. To evaluate the role of ATR gene alterations in the pathogenesis of NKTCL and CAEBV, the whole coding region of the ATR gene was examined in cell lines derived from NKTCL and CAEBV, as well as tumor samples from patients. ATR alterations were detected in two of eight NKTCL and in one of three CAEBV lines. Most aberrant transcripts observed were deletions resulting from aberrant splicing. ATR alterations were also detected in four of 10 NKTCL clinical samples. Both NKTCL and CAEBV cell lines with ATR alterations showed a delay or abrogation in repair of ionizing radiation-induced DNA double-strand breaks and ultraviolet-induced DNA single-strand breaks, and both exhibited a defect in p53 accumulation. These findings show that alterations in the ATR gene result in an abnormal response to DNA double-strand break and single-strand break repair, suggesting a role for ATR gene alterations in NKTCL lymphomagenesis.

  8. Chronic active Epstein-Barr virus infection with marked pericardial effusion successfully treated with allogeneic peripheral blood stem cell transplantation.

    PubMed

    Matsui, Shinichiro; Takeda, Yusuke; Isshiki, Yusuke; Yamazaki, Atsuko; Nakao, Sanshiro; Takaishi, Koji; Nagao, Yuhei; Hasegawa, Nagisa; Togasaki, Emi; Shimizu, Ryoh; Kawajiri, Chika; Sakai, Shio; Mimura, Naoya; Takeuchi, Masahiro; Ohwada, Chikako; Sakaida, Emiko; Iseki, Tohru; Imadome, Ken-Ichi; Nakaseko, Chiaki

    2016-05-01

    A 23-year-old woman presented with a persistent fever and shortness of breath. Computed tomography showed marked pericardial effusion, hepatosplenomegaly, and cervical and mediastinal lymph node swelling. Epstein-Barr virus (EBV) antibody titers were abnormally elevated, and the copy number of EBV-DNA was increased in peripheral blood. Based on these observations, she was diagnosed with chronic active EBV infection (CAEBV). The EBV-infected cells in her peripheral blood were CD4(+)T lymphocytes. Fever and pericardial effusion improved following treatment with a combination of prednisolone, etoposide, and cyclosporine; however, peripheral blood EBV-DNA levels remained high. The patient underwent allogeneic peripheral blood stem cell transplantation from an EBV-seronegative, HLA-matched sibling donor, with fludarabine and melphalan conditioning. The post-transplantation course was uneventful, except for mild skin acute graft-versus-host disease (grade 2). EBV-DNA became undetectable in peripheral blood 98 days post transplantation. She has since been in good health without disease recurrence. CAEBV is a potentially fatal disease caused by persistent EBV infection of T lymphocytes or natural killer cells, thus requiring prompt treatment and allogeneic transplantation. Pericardial effusion is rarely observed in CAEBV and can impede its diagnosis. Therefore, we should be aware that patients may present with marked pericardial effusion as an initial manifestation of CAEBV.

  9. An autopsy case of chronic active Epstein-Barr virus infection (CAEBV): distribution of central nervous system (CNS) lesions.

    PubMed

    Kobayashi, Zen; Tsuchiya, Kuniaki; Takahashi, Makoto; Yokota, Osamu; Sasaki, Atsushi; Bhunchet, Ekapot; Arai, Tetsuaki; Akiyama, Haruhiko; Kamoshita, Masaharu; Kotera, Minoru; Mizusawa, Hidehiro

    2008-12-15

    A 27-year-old Japanese man developed recurrent respiratory and central nervous system (CNS) symptoms, and hemophagocytic syndromes with a clinical course of 6 years. CT demonstrated multiple nodular lesions in the bilateral lungs, and MRI revealed multiple abnormal intensity areas in the brain and spinal cord. Cerebrospinal fluid (CSF) examination disclosed mild pleocytosis and the presence of Epstein-Barr virus (EBV)-DNA detected by polymerase chain reaction (PCR). The patient died of a hemorrhagic shock associated with a hemophagocytic syndrome. A postmortem study revealed massive hemorrhage in the abdominal cavity and iliopsoas muscles, as well as diffuse infiltration of lymphocytes and/or macrophages into the lungs, liver, kidneys, spleen, cardiac muscle, bone marrow, and CNS. The severe involvement was demonstrated in the CNS, especially in the spinal cord and brainstem. The CD3 positive cells of the brainstem were EBV-encoded RNA 1 positive. This is the first autopsy case of chronic active EBV infection (CAEBV) in which severe and extensive CNS involvement was demonstrated.

  10. Differences between T cell-type and natural killer cell-type chronic active Epstein-Barr virus infection.

    PubMed

    Kimura, Hiroshi; Hoshino, Yo; Hara, Shinya; Sugaya, Naomi; Kawada, Jun-Ichi; Shibata, Yukiko; Kojima, Seiji; Nagasaka, Tetsuro; Kuzushima, Kiyotaka; Morishima, Tsuneo

    2005-02-15

    Infections of T cells and natural killer (NK) cells play a central role in the pathogenesis of chronic active Epstein-Barr virus (CAEBV) infection. To characterize the virologic and cytokine profiles of T cell-type and NK cell-type infection, 39 patients with CAEBV infection were analyzed. Patients with T cell-type infection had higher titers of immunoglobulin G against early and late EBV antigens, suggesting lytic cycle infection. However, the pattern of EBV gene expression was latency type II; BZLF1, which is a hallmark of lytic cycle infection, could not be detected in any patients, regardless of infection type. Patients with CAEBV infection had high concentrations of proinflammatory, T helper cell type 1, and anti-inflammatory cytokines. The cytokine profile in patients with NK cell-type infection was similar to that in patients with T cell-type infection, but the concentration of IL-13 was high in patients with NK cell-type infection. These findings should help to clarify the pathogenesis of CAEBV infection and facilitate the development of more-effective treatments.

  11. [An autopsied case of chronic active Epstein-Barr virus infection complicated in systemic lupus erythematosus and antiphospholipid antibody syndrome].

    PubMed

    Ogawa, Jun; Koike, Ryuji; Sugihara, Takahiko; Hagiyama, Hiroyuki; Nishio, Junko; Kohsaka, Hitoshi; Kubota, Tetsuo; Kawachi, Hiroshi; Kasahara, Ichiro; Miyasaka, Nobuyuki

    2002-12-01

    We have experienced a case of chronic active Epstein-Barr virus infection (CAEBV) complicated in systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS). A 35-year-old woman was admitted to our hospital with complaints of fever and dyspnea on exertion. She was diagnosed as having SLE on the basis of arthritis, oropharyngeal ulcer, lymphopenia, and positive autoantibodies against DNA, RNP and SSA. The diagnosis of APS was also made because of positive anti-cardiolipin IgG antibodies and the existence of multiple pulmonary infarction with pulmonary hypertension. The administration of 30 mg/day of prednisolone and anti-coagulation significantly improved clinical symptoms. However, she was again admitted to the hospital four months later because of progressive liver damage and pancytopenia. Increment of prednisolone did not improve the clinical situation and she expired because of pulmonary hemorrhage. At autopsy, there were a significant increase of histiocytes with hemophagocytosis and a dense infiltration of atypical lymphocytes in the liver, spleen, lymph nodes and bone marrow. Infiltrated lymphocytes were positive for CD 3 and EBER 1 in immunohistochemical staining and EBVmRNA was detected by in situ hybridization. Final pathological diagnosis was CAEBV with hemophagocytic syndrome in association with lupus nephritis, pulmonary hemorrhage and pulmonary infarction.

  12. Epstein-Barr virus-associated T-cell lymphoproliferative disorder affecting skin and lung in an elderly patient.

    PubMed

    Hoshino, Tomomi; Tatsuno, Kazuki; Shimauchi, Takatoshi; Okada, Satoko; Ito, Taisuke; Ono, Takaaki; Ohshima, Koichi; Tokura, Yoshiki

    2014-09-01

    A 70-year-old man presented with papular skin lesions and was diagnosed with Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder (T-LPD). The patient showed infiltration of a large number of EBV-encoded RNA-positive T cells in the skin and lung, presence of EBV load in the peripheral blood, and expansion of clonal EBV-infected γδ T cells and CD8(+) T cells in the blood and skin, as assessed by EBV-terminal repeat Southern blot, T-cell receptor polymerase chain reaction and flow cytometric analyses. In the Japanese or East Asian fatal cases of EBV-associated T/natural killer (NK)-LPD, there are two peaks in age at death, approximately 20 years and 60 years. The former age group is associated with chronic active EBV infection (CAEBV), and the latter group typically suffers from extranodal NK/T-cell lymphoma. Our case is characterized not only by the unique skin and lung manifestations but also the late onset age of the disease, indicating that the skin manifestation of CAEBV can be seen even in elderly patients. © 2014 Japanese Dermatological Association.

  13. The spectrum of Epstein-Barr virus-associated lymphoproliferative disease in Korea: incidence of disease entities by age groups.

    PubMed

    Cho, Eun-Yoon; Kim, Ki-Hyun; Kim, Won-Seog; Yoo, Keon Hee; Koo, Hong-Hoe; Ko, Young-Hyeh

    2008-04-01

    This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma.

  14. [A Case of Acute Acalculous Cholecystitis During Infectious Mononucleosis Caused by the Epstein-Barr Virus in a Young Woman].

    PubMed

    Ono, Shiro; Kobayashi, Tadanao; Nishio, Kenji

    2016-05-01

    Infection with the Epstein-Barr virus (EBV) is a common disease and is mainly asymptomatic during childhood, whereas infectious mononucleosis with clinical signs such as fever, pharyngitis, lymphadenopathy and hepatosplenomegaly often occurs in adolescents and adults with primary infection. Acalculous cholecystitis has been reported as a rare complication. We report herein a case of acalculous cholecystitis accompanied by infectious mononucleosis by EBV, which was treated successfully by medical treatment. A 33-year-old woman who had been admitted by fever, pharyngitis and lymphadenopathy developed a right upper quadrant pain, that was diagnosed as acalculous cholecystitis based on an imaging study. Antibiotic treatment did not resolve the symptoms, and surgical intervention was considered. We diagnosed her as having infectious mononucleosis based on a typical physical presentation and seropositivity for the EBV viral capsid antigen, suggesting that the acalculous cholecystatis might have been a complication of the EBV infection. After the administration of glucocorticoid and acyclovir, the patient became afebrile and the abdominal pain disappeared. Though acalculous cholecystitis rarely accompanies infectious mononucleosis caused by EBV, clinicians should be aware of this complication to avoid unnecessary cholecystectomy.

  15. Use of the lymphocyte count as a diagnostic screen in adults with suspected Epstein-Barr virus infectious mononucleosis.

    PubMed

    Biggs, Timothy C; Hayes, Stephen M; Bird, Jonathan H; Harries, Philip G; Salib, Rami J

    2013-10-01

    To evaluate the predictive diagnostic accuracy of the lymphocyte count in Epstein-Barr virus-related infectious mononucleosis (IM). Retrospective case note and blood results review within a university-affiliated teaching hospital. A retrospective review of 726 patients undergoing full blood count and Monospot testing was undertaken. Monospot testing outcomes were compared with the lymphocyte count, examining for significant statistical correlations. With a lymphocyte count of ≤4 × 10(9) /L, 99% of patients had an associated negative Monospot result (sensitivity of 84% and specificity of 94%). A group subanalysis of the population older than 18 years with a lymphocyte count ≤4 × 10(9) /L revealed that 100% were Monospot negative (sensitivity of 100% and specificity of 97%). A lymphocyte count of ≤4 × 10(9) /L correlated significantly with a negative Monospot result. A lymphocyte count of ≤4 × 10(9) /L appears to be a highly reliable predictor of a negative Monospot result, particularly in the population aged >18 years. Pediatric patients, and adults with strongly suggestive symptoms and signs of IM, should still undergo Monospot testing. However, in adults with more subtle symptoms and signs, representing the vast majority, Monospot testing should be restricted to those with a lymphocyte count >4 × 10(9) /L. NA Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

  16. On optimizing the blocking step of indirect enzyme-linked immunosorbent assay for Epstein-Barr virus serology.

    PubMed

    Lim, Chun Shen; Krishnan, Gopala; Sam, Choon Kook; Ng, Ching Ching

    2013-01-16

    Because blocking agent occupies most binding surface of a solid phase, its ability to prevent nonspecific binding determines the signal-to-noise ratio (SNR) and reliability of an enzyme-linked immunosorbent assay (ELISA). We demonstrate a stepwise approach to seek a compatible blocking buffer for indirect ELISA, via a case-control study (n=176) of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC). Regardless of case-control status, we found that synthetic polymer blocking agents, mainly Ficoll and poly(vinyl alcohol) (PVA) were able to provide homogeneous backgrounds among samples, as opposed to commonly used blocking agents, notably nonfat dry milk (NFDM). The SNRs for NPC samples that correspond to blocking using PVA were approximately 3-fold, on average, higher than those blocking using NFDM. Both intra- and inter-assay precisions of PVA-based assays were <14%. A blocking agent of choice should have tolerable sample backgrounds from both cases and controls to ensure the reliability of an immunoassay. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Epstein-Barr virus-infected Akata cells are sensitive to histone deacetylase inhibitor TSA-provoked apoptosis.

    PubMed

    Kook, Sung-Ho; Son, Young-Ok; Han, Seong-Kyu; Lee, Hyung-Soon; Kim, Beom-Tae; Jang, Yong-Suk; Choi, Ki-Choon; Lee, Keun-Soo; Kim, So-Soon; Lim, Ji-Young; Jeon, Young-Mi; Kim, Jong-Ghee; Lee, Jeong-Chae

    2005-11-30

    Epstein-Barr virus (EBV) infects more than 90 % of the world's population and has a potential oncogenic nature. A histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), has shown potential ability in cancer chemoprevention and treatment, but its effect on EBV-infected Akata cells has not been examined. This study investigated the effect of TSA on the proliferation and apoptosis of the cells. TSA inhibited cell growth and induced cytotoxicity in the EBV-infected Akata cells. TSA treatment sensitively induced apoptosis in the cell, which was demonstrated by the increased number of positively stained cells in the TUNEL assay, the migration of many cells to the sub-G0/G1 phase in flow cytometric analysis, and the ladder formation of genomic DNA. Western blot analysis showed that caspase-dependent pathways are involved in the TSA-induced apoptosis of EBV-infected Akata cells. Overall, this study shows that EBV-infected B lymphomas are quite sensitive to TSA-provoked apoptosis.

  18. Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel

    PubMed Central

    Munger, K. L.; Levin, L. I.; O’Reilly, E. J.; Falk, K. I.; Ascherio, A.

    2011-01-01

    Background Elevated Epstein-Barr virus (EBV) antibody titers are risk factors for MS, but the strength and consistency this association are not well characterized. Objectives To determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS. Methods We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks. Results MS risk increased with increasing titers of anti-EBNA complex (p<10−9) and anti-EBNA-1 (p=5.8E-9) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95%CI:9.6-136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95%CI:2.6-23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the ROC curves were 0.67 for EBNA complex and 0.65 for EBNA-1. Conclusions Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score. PMID:21685232

  19. Epstein-Barr virus nuclear antigen-1 is highly colocalized with interphase chromatin and its newly replicated regions in particular.

    PubMed

    Ito, Sayuri; Gotoh, Eisuke; Ozawa, Shigeru; Yanagi, Kazuo

    2002-10-01

    Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1), which binds to both the EBV origin of replication (oriP) and metaphase chromosomes, is essential for the replication/retention and segregation/partition of oriP-containing plasmids. Here the chromosomal localization of EBNA-1 fused to green fluorescent protein (GFP-EBNA-1) is examined by confocal microscopy combined with a 'premature chromosome condensation' (PCC) procedure. Analyses show that GFP-EBNA-1 expressed in living cells that lack oriP plasmids is associated with cellular chromatin that has been condensed rapidly by the PCC procedure into identifiable forms that are unique to each phase of interphase as well as metaphase chromosomes. Studies of cellular chromosomal DNAs labelled with BrdU or Cy3-dUTP indicate that GFP-EBNA-1 colocalizes highly with the labelled, newly replicated regions of interphase chromatin in cells. These results suggest that EBNA-1 is associated not only with cellular metaphase chromosomes but also with condensing chromatin/chromosomes and probably with interphase chromatin, especially with its newly replicated regions.

  20. Effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine on several parameters of Epstein-Barr virus infection.

    PubMed

    Zhang, Z X; Liu, Y X; Chen, H C; Allaudeen, H S; De Clercq, E

    1984-01-01

    The selective and potent anti-herpesvirus drug, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), has been examined for its inhibitory effects on several parameters of Epstein-Barr virus (EBV) infection in the lymphoblastoid cell lines Raji, P3HR-1, B-95-8 and P3 hybrid cells (a human embryo oropharyngeal cell line fused with a nasopharyngeal carcinoma cell line). At a dosage of 0.03 to 0.1 mM, BVdU caused a marked inhibition of (i) spontaneous viral capsid antigen (VCA) expression in B-95-8 and P3 hybrid cells, (ii) VCA expression and DNA synthesis in B-95-8 cells induced with croton oil and n-butyrate, (iii) early antigen (EA) expression and DNA synthesis in Raji cells superinfected with EBV, and (iv) VCA expression and DNA synthesis in B-95-8 cells superinfected with EBV. In its inhibitory effects on these various parameters of EBV infection, BVdU appears to be comparable to acyclovir [9-(2-hydroxyethoxymethyl)guanine], another selective anti-herpesvirus drug which has been previously recognized as an effective inhibitor of EBV replication.

  1. Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students.

    PubMed

    Balfour, Henry H; Odumade, Oludare A; Schmeling, David O; Mullan, Beth D; Ed, Julie A; Knight, Jennifer A; Vezina, Heather E; Thomas, William; Hogquist, Kristin A

    2013-01-01

    University students were studied prospectively to determine the incidence of and risk factors for acquisition of primary Epstein-Barr virus (EBV) infection and the virologic and immune correlates of disease severity. EBV antibody-negative freshmen participated in monthly surveillance until graduation. If antibodies developed, proximate samples were assayed for viral load by polymerase chain reaction. Lymphocyte and natural killer (NK) cell numbers and activation were measured by flow cytometry, and plasma cytokine levels were measured by a multiplex assay. Of 546 students screened, 202 (37%) were antibody negative; 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. Increases were observed in numbers of NK cells and CD8(+) T-cells but not in numbers of CD4(+) T-cells during acute infection. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003). Kissing was a significant risk for primary EBV infection. A total of 89% of infections were symptomatic, and blood viral load and CD8(+) lymphocytosis correlated with disease severity.

  2. Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers

    PubMed Central

    Cohen, Jeffrey I.; Dropulic, Lesia; Hsu, Amy P.; Zerbe, Christa S.; Krogmann, Tammy; Dowdell, Kennichi; Hornung, Ronald L.; Lovell, Jana; Hardy, Nancy; Hickstein, Dennis; Cowen, Edward W.; Calvo, Katherine R.; Pittaluga, Stefania; Holland, Steven M.

    2016-01-01

    Background. Most patients infected with Epstein-Barr virus (EBV) are asymptomatic, have nonspecific symptoms, or have self-limiting infectious mononucleosis. EBV, however, may result in severe primary disease or cancer. Methods. We report EBV diseases associated with GATA2 deficiency at one institution and describe the hematology, virology, and cytokine findings. Results. Seven patients with GATA2 deficiency developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme–like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor α, interferon γ, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. Conclusions. GATA2 is the first gene associated with EBV hydroa vacciniforme–like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts. PMID:27169477

  3. Validation of Roche LightCycler Epstein-Barr virus quantification reagents in a clinical laboratory setting.

    PubMed

    Gulley, Margaret L; Fan, Hongxin; Elmore, Sandra H

    2006-11-01

    Epstein-Barr virus (EBV) is associated with a wide range of benign and malignant diseases, including infectious mononucleosis, lymphoma, posttransplant lymphoproliferative disorder, and nasopharyngeal carcinoma. Measurement of EBV viral load in plasma is increasingly used for rapid assessment of disease status. We evaluated the performance characteristics of an EBV polymerase chain reaction assay that uses commercial reagents and instruments from Roche Diagnostics (Indianapolis, IN). DNA was extracted from plasma using a MagNaPure instrument, and viral load was measured by real-time polymerase chain reaction on a LightCycler. Analyte-specific reagents included primers and hybridization probes targeting the EBV LMP2 gene and a spiked control sequence. Accuracy and reproducibility were established using DNA from three cell lines. The assay was sensitive to approximately 750 copies of EBV DNA per milliliter of plasma and was linear across at least four orders of magnitude. The assay detected EBV DNA in three of five samples from nasopharyngeal carcinoma patients, seven of nine infectious mononucleosis samples, and 34/34 samples from immunosuppressed patients with clinically significant EBV-related disease, whereas EBV DNA was undetectable in plasma from 21 individuals without EBV-related disease. In conclusion, this LightCycler EBV assay is rapid, sensitive, and linear for quantifying EBV viral load. The assay appears to be useful for measuring clinically significant EBV levels in immunodeficient patients.

  4. Chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis exacerbation in a patient with systemic lupus erythematosus.

    PubMed

    Yamashita, H; Shimizu, A; Tsuchiya, H; Takahashi, Y; Kaneko, H; Kano, T; Mimori, A

    2014-07-01

    Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic infectious mononucleosis-like symptoms. We report a very rare case with autoimmune hepatitis (AIH) complicated by CAEBV. A 50-year-old woman with systemic lupus erythematosus (SLE) complicated by AIH began to suffer from acute respiratory failure and her clinical symptoms improved rapidly in response to steroid treatment. However, during the gradual tapering of the steroid dose, a steady increase of the serum hepatobiliary enzyme levels subsequently was observed and the patient began to have continuous fever. Moreover, upper gastrointestinal endoscopy revealed multiple intractable gastric ulcers. When EBER-ISH was performed on liver biopsy and gastric mucosal biopsy specimens, EBER-positive lymphocytes were observed. When peripheral blood was examined, 2.1 × 10(6) copies/µg of EBV-DNA were observed in the CD4-positive T cells, confirming the diagnosis of CAEBV. A cooling therapy was started by steroid and cyclosporine. Thereafter, despite the start of CHOP therapy, she developed a malignant lymphoma (PTCL-NOS) and died of hepatic failure. When treatment-resistant AIH patients are encountered, not only AIH exacerbation but also CAEBV should be considered in the differential diagnosis. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  5. Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A.

    PubMed

    Minamitani, Takeharu; Yasui, Teruhito; Ma, Yijie; Zhou, Hufeng; Okuzaki, Daisuke; Tsai, Chiau-Yuang; Sakakibara, Shuhei; Gewurz, Benjamin E; Kieff, Elliott; Kikutani, Hitoshi

    2015-09-15

    Epstein-Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells can cause B-cell malignancies in humans with T- or natural killer-cell deficiency. We now find that EBV-encoded latent membrane protein 2A (LMP2A) mimics B-cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B-cell differentiation in mice that conditionally express LMP2A in GC B cells or all B-lineage cells found LMP2A expression enhanced not only BCR signals but also plasma cell differentiation in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody-producing B cells despite apparently normal GC formation. GC B-cell-specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the zinc finger and bric-a-brac, tramtrack domain-containing protein 20 locus. We conclude that LMP2A reduces the stringency of GC B-cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with excessive prosurvival effects.

  6. Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma.

    PubMed

    Farina, Antonella; Cirone, Mara; York, Michael; Lenna, Stefania; Padilla, Cristina; Mclaughlin, Sarah; Faggioni, Alberto; Lafyatis, Robert; Trojanowska, Maria; Farina, Giuseppina A

    2014-04-01

    Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-β1 (TGFβ1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.

  7. The Epstein-Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim.

    PubMed

    Desbien, Anthony L; Kappler, John W; Marrack, Philippa

    2009-04-07

    Current knowledge suggests that the balance between life and death within a cell can be controlled by the stable engagement of Bcl-2-related proapoptotic proteins such as Bak, Bax, and Bim by survival proteins such as Bcl-2. BHRF1 is a prosurvival molecule from Epstein-Barr virus that has a high degree of homology to Bcl-2. To understand how BHRF1 blocks apoptosis, BHRF1 and mutants of BHRF1 were expressed in primary cells and an IL-2-dependent T cell line. BHRF1 bound the Executioner Bak and, when cells were cultured without cytokines, BHRF1 associated with Bim. A point mutation that lost the ability to bind Bak retained its ability to bind Bim and to protect cells. This result demonstrated that it was the capacity of BHRF1 to bind Bim, not Bak, that provided protection. Interestingly, the amount of Bim bound by BHRF1 was minimal when compared with the amount of Bim induced by apoptosis. Thus, BHRF1 does not act by simply absorbing the excess Bim produced while cells prepare for death. Rather, BHRF1 may act either by binding preferentially the most lethal form of Bim o