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1.  Development of Drugs for Epstein - Barr virus using High-Throughput in silico Virtual Screening 
Expert opinion on drug discovery  2010;5(12):10.1517/17460441.2010.524640.
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.
doi:10.1517/17460441.2010.524640
PMCID: PMC3816986  PMID: 22822721
Epstein-Barr virus (EBV); DNA polymerase; LMP1; EBNA1; computational screening
2.  The Importance Of Epigenetic Alterations In The Development Of Epstein-Barr Virus-Related Lymphomas 
Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with a series of malignant tumors. These include lymphomas (Burkitt’s lymphoma, Hodgkin’s disease, T/NK-cell lymphoma, post-transplant lymphoproliferative disease, AIDS-associated lymphoma, X-linked lymphoproliferative syndrome), carcinomas (nasopharyngeal carcinoma, gastric carcinoma, carcinomas of major salivary glands, thymic carcinoma, mammary carcinoma) and a sarcoma (leiomyosarcoma). The latent EBV genomes persist in the tumor cells as circular episomes, co-replicating with the cellular DNA once per cell cycle. The expression of latent EBV genes is cell type specific due to the strict epigenetic control of their promoters. DNA methylation, histone modifications and binding of key cellular regulatory proteins contribute to the regulation of alternative promoters for transcripts encoding the nuclear antigens EBNA1 to 6 and affect the activity of promoters for transcripts encoding transmembrane proteins (LMP1, LMP2A, LMP2B). In addition to genes transcribed by RNA polymerase II, there are also two RNA polymerase III transcribed genes in the EBV genome (EBER 1 and 2). The 5′ and internal regulatory sequences of EBER 1 and 2 transcription units are invariably unmethylated. The highly abundant EBER 1 and 2 RNAs are not translated to protein. Based on the cell type specific epigenetic marks associated with latent EBV genomes one can distinguish between viral epigenotypes that differ in transcriptional activity in spite of having an identical (or nearly identical) DNA sequence. Whereas latent EBV genomes are regularly targeted by epigenetic control mechanisms in different cell types, EBV encoded proteins may, in turn, affect the activity of a set of cellular promoters by interacting with the very same epigenetic regulatory machinery. There are EBNA1 binding sites in the human genome. Because high affinity binding of EBNA1 to its recognition sites is known to specify sites of DNA demethylation, we suggest that binding of EBNA1 to its cellular target sites may elicit local demethylation and contribute thereby to the activation of silent cellular promoters. EBNA2 interacts with histone acetyltransferases, and EBNALP (EBNA5) coactivates transcription by displacing histone deacetylase 4 from EBNA2-bound promoter sites. EBNA3C (EBNA6) seems to be associated both with histone acetylases and deacetylases, although in separate complexes. LMP1, a transmembrane protein involved in malignant transformation, can affect both alternative systems of epigenetic memory, DNA methylation and the Polycomb-trithorax group of protein complexes. In epithelial cells LMP1 can up-regulate DNA methyltransferases and, in Hodgkin lymphoma cells, induce the Polycomb group protein Bmi-1. In addition, LMP1 can also modulate cellular gene expression programs by affecting, via the NF-κB pathway, levels of cellular microRNAs miR-146a and miR-155. These interactions may result in epigenetic dysregulation and subsequent cellular dysfunctions that may manifest in or contribute to the development of pathological changes (e.g. initiation and progression of malignant neoplasms, autoimmune phenomena, immunodeficiency). Thus, Epstein-Barr virus, similarly to other viruses and certain bacteria, may induce pathological changes by epigenetic reprogramming of host cells. Elucidation of the epigenetic consequences of EBV-host interactions (within the framework of the emerging new field of patho-epigenetics) may have important implications for therapy and disease prevention, because epigenetic processes are reversible and continuous silencing of EBV genes contributing to patho-epigenetic changes may prevent disease development.
doi:10.4084/MJHID.2009.012
PMCID: PMC3033174  PMID: 21416002
3.  Association between Epstein-Barr Virus Infection and Chemoresistance to Docetaxel in Gastric Carcinoma 
Molecules and Cells  2011;32(2):173-179.
Epstein-Barr virus (EBV) is associated with human cancers such as nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s disease, and gastric carcinoma (GC). EBV is associated with about 10% of all GC cases globally. EBV-associated GC has distinct features from EBV-negative GC. However, it is still unclear if EBV infection has any effect on GC chemoresistance. Cell proliferation assay, cell cycle analysis, and active caspase Western blot revealed that the EBV-positive GC cell line (AGS-EBV) showed chemoresistance to docetaxel compared to the EBV-negative GC cell line (AGS). Docetaxel treatment increased expression of Bax similarly in AGS and AGS-EBV cell lines. However, Bcl-2 induction was markedly higher in AGS-EBV cells, after docetaxel treatment. Although docetaxel increased the expression of p53 to a similar extent in both cell lines, induction of p21 in AGS-EBV cells was lower than in AGS cells. Furthermore, expression of survivin was higher in AGS-EBV cells than in AGS cells following docetaxel treatment as well as at basal state. EBVlytic gene expression was induced by docetaxel treatment in AGS-EBV cells. The results suggest that EBV infection and lytic induction confers chemoresistance to GC, possibly by regulating cellular and EBV latent and lytic gene expression.
doi:10.1007/s10059-011-0066-y
PMCID: PMC3887666  PMID: 21626300
apoptosis; cell cycle related genes; chemoresistance; docetaxel; EBV-positive gastric carcinoma
4.  Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells*  
Epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world’s population, is associated with malignant tumors such as Burkitt’s lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.
doi:10.1631/jzus.B1200189
PMCID: PMC3542954  PMID: 23303627
Epstein-Barr virus; Bcl family members; Apoptosis; Drugs therapy
5.  Immune escape by Epstein Barr virus associated malignancies 
Seminars in cancer biology  2008;18(6):381-387.
Persistent Epstein-Barr virus (EBV) infection remains asymptomatic in the majority of virus carriers, despite the potent growth transforming potential of this virus. The increased frequency of EBV associated B cell lymphomas in immune compromised individuals suggests that tumor-free chronic infection with this virus is in part due to immune control. Here we discuss the evidence that loss of selective components of EBV specific immunity might contribute to EBV associated malignancies, like Nasopharyngeal Carcinoma, Burkitt’s and Hodgkin’s lymphoma, in otherwise immune competent patients. Furthermore, we discuss how current vaccine approaches against EBV might be able to target these selective deficiencies.
doi:10.1016/j.semcancer.2008.10.002
PMCID: PMC2615476  PMID: 18996483
Nasopharyngeal carcinoma; Hodgkin’s lymphoma; Burkitt’s lymphoma; T cells; malaria; HIV
6.  Lack of evidence for an association of Epstein–Barr virus infection with breast carcinoma 
Breast Cancer Research  2002;5(1):R13-R17.
Background
Epstein–Barr virus (EBV) is a ubiquitous human γ-herpes virus infecting more than 90% of the population worldwide. EBV is associated with certain malignancies (e.g. Burkitt lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma). Recent studies have raised the possibility that EBV may also be involved in the pathogenesis of breast carcinoma, the most common carcinoma of females. If substantiated, this finding would have major implications regarding prevention and therapy of the disease. The studies published so far have employed diverse methods, however, and the results have been controversial.
Methods
Using the EBV DNA PCR, EBV DNA in situ hybridisation and in situ hybridisation for the detection of the EBV-encoded RNAs, and using immunohistochemistry for the demonstration of the EBV-encoded nuclear antigen 1, we have studied a series of 59 invasive breast carcinomas for evidence of EBV infection.
Results
EBV-encoded RNA-specific in situ hybridisation and EBV-encoded nuclear antigen 1 immunohistochemistry were negative in all cases. Using the PCR, EBV DNA was detected in four out of 59 cases. These cases were further studied by EBV DNA in situ hybridisation, showing an absence of viral DNA from the tumour cells.
Conclusion
These results indicate that breast carcinoma is not an EBV-associated tumour.
doi:10.1186/bcr561
PMCID: PMC154138  PMID: 12559053
breast carcinoma; Epstein–Barr virus; immunohistology; in situ hybridisation
7.  The Ying-Yang of the virus-host interaction: Control of the DNA damage response 
Future microbiology  2011;6(4):379-383.
Viruses have evolved elegant strategies to manipulate the host while the host counters with defense systems including the interferon response, apoptosis, and the DNA damage response (DDR). Viruses have multiple strategies for manipulating the DDR and even the same virus can activate or inhibit the DDR at different stages of infection. Epstein-Barr virus (EBV) is a virus implicated in several human cancers including Burkitt’s lymphoma, nasopharyngeal carcinoma, post-transplant lymphoproliferative disease, and HIV associated lymphomas. Although multiple viral proteins have been implicated in EBV associated malignancies, the cellular pathways that control EBV-induced transformation and tumorigenesis remain incompletely understood. In this study, Nikitin et al demonstrate that early EBV infection induces a cellular DDR which restricts virus-mediated transformation. The EBV encoded EBNA3C protein subsequently attenuates this response to favor transformation and immortalization of host cells.
doi:10.2217/fmb.11.16
PMCID: PMC3169440  PMID: 21526939
ATM/CHK2; B cell transformation; DNA damage response; Epstein-Barr virus; tumorigenesis
8.  Macrophage involvement in Epstein-Barr virus-related tumors 
Epstein-Barr virus (EBV) is known as a causative agent of Burkitt’s lymphoma, nasopharyngeal carcinoma and approximately 10% of stomach carcinoma cases. In other human cancers, EBV gene expression including lytic infection protein detected using in situ hybridization and immunofluorescence staining has been reported. Moreover, the expression and replication of EBV genes in cultured normal macrophages and in histiocytes of Langerhans’ cell histiocytosis have been identified. The aim of this study was to examine EBV expression in macrophages in other EBV-associated human tumors. Forty-one cases of EBV-associated tumors, which had been confirmed to express EBV, were examined. Tissue sections after in situ hybridization were double-stained immunohistochemically with the monoclonal anti-CD68 antibody. EBV expression in macrophages in the lesions of nasopharyngeal carcinoma, oral cancer, thyroid carcinoma, renal cell carcinoma, testicular carcinoma, uterine carcinoma, cutaneous T-cell lymphoma and anaplastic large-cell lymphoma was identified, whereas macrophages in normal or non-cancerous lesions showed no EBV expression. Many tumor-associated macrophages in EBV-related tumors carry EBV, which appears to induce the EBV lytic infection of macrophages. Therefore, the possibility that the lytic infection of macrophages by EBV and the resulting inflammation play certain roles in the oncogenesis of EBV-associated human tumors was raised.
doi:10.3892/etm_00000044
PMCID: PMC3445936  PMID: 22993541
macrophage; Epstein-Barr virus; inflammation; in situ hybridization
9.  Dasatinib therapy results in decreased B cell proliferation, splenomegaly, and tumor growth in a murine model of lymphoma expressing Myc and Epstein-Barr virus LMP2A 
Antiviral Research  2012;95(1):49-56.
Epstein-Barr virus (EBV) infection and latency has been associated with malignant diseases including nasopharyngeal carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and immune deficiency associated lymphoproliferative diseases. EBV-encoded latent membrane protein 2A (LMP2A) recruits Lyn and Syk kinases via its SH2-domain binding motifs, and modifies their signaling pathways. LMP2A transgenic mice develop hyperproliferative bone marrow B cells and immature peripheral B cells through modulation of Lyn kinase signaling. LMP2A/λ-MYC double transgenic mice develop splenomegaly and cervical lymphomas starting at 8 weeks of age. We reasoned that targeting Lyn in LMP2A-expressing B cells with dasatinib would provide a therapeutic option for EBV-associated malignancies. Here, we show that dasatinib inhibits B cell colony formation by LMP2A transgenic bone marrow cells, and reverses splenomegaly and tumor growth in both a pre-tumor and a syngeneic tumor transfer model of EBV-associated Burkitt lymphoma. Our data support the idea that dasatinib may prove to be an effective therapeutic molecule for the treatment of EBV-associated malignancies.
doi:10.1016/j.antiviral.2012.05.003
PMCID: PMC3377840  PMID: 22609829
Burkitt lymphoma; dasatinib; Epstein-Barr virus (EBV); latent membrane protein 2A (LMP2A); Lyn; post-transplant lymphoproliferative diseases (PTLD)
10.  Phase I Clinical Trial of Valacyclovir and Standard of Care Cyclophosphamide in Children With Endemic Burkitt Lymphoma in Malawi 
Treatment options for Epstein-Barr virus (EBV)-associated Burkitt lymphoma in Africa are limited because of chemotherapy-associated toxicity. Since other EBV-associated diseases respond to antiviral agents, we investigated adding an antiviral agent, valacyclovir, to the current chemotherapy regimen in Malawi. In this phase I safety study, we showed that cyclophosphamide combined with valacyclovir was safe. Phase II efficacy trials should now be undertaken.
Background
Nucleoside analogues, including acyclovir, ganciclovir, and their precursors, have shown some efficacy against several Epstein-Barr virus (EBV)-associated diseases, including active EBV infection and posttransplantation lymphoproliferative disorder (PTLD). They have also been proposed as a possible treatment for EBV-associated malignancies, including endemic Burkitt lymphoma. The safety of nucleoside analogues in combination with chemotherapy in the developing world has not been studied and is necessary before any large scale efficacy trials are conducted.
Patients and Methods
Children 3–15 years old meeting inclusion criteria were assigned to a 3+3 dose escalation trial of combination valacyclovir (15 and 30 mg/kg, 3 times daily for 40 days) and cyclophosphamide (CPM) (40 mg/kg day 1, 60 mg/kg on days 8, 18, and 28) or CPM monotherapy. Subjects were monitored for clinical and laboratory toxicity and had EBV levels measured regularly. Dose-limiting toxicity (DLT) was our primary outcome.
Results
We found that the combination of valacyclovir and CPM was safe and did not lead to any DLT compared with CPM monotherapy. The most common side effects were vomiting, abdominal pain, and tumor site pain, which were similar in both arms. Patients with measurable serum EBV showed decreased loads over their treatment course.
Conclusions
We recommend a phase II valacyclovir dose of 30 mg/kg 3 times daily for 40 days. We also observed that 6 of our 12 patients with presumed Burkitt lymphoma had measurable EBV viral loads that decreased over the course of their treatment, suggesting that phase II studies should investigate this correlation further. This study paves the way for a phase II efficacy trial of combined valacyclovir and CPM in the treatment of endemic Burkitt lymphoma.
doi:10.1016/j.clml.2012.11.003
PMCID: PMC3654008  PMID: 23260601
11.  Rapamycin reverses splenomegaly and inhibits tumor development in a transgenic model of Epstein-Barr Virus-related Burkitt’s lymphoma 
Molecular cancer therapeutics  2011;10(4):679-686.
Epstein-Barr virus (EBV) infection and latency has been associated with malignancies including nasopharyngeal carcinoma and Burkitt’s lymphoma. EBV encoded latent membrane protein 2A (LMP2A) is expressed in most EBV-associated malignancies and as such provides a therapeutic target. Burkitt’s lymphoma is a hematopoietic cancer associated with the translocation of c-MYC to one of the immunoglobulin gene promoters leading to abnormally high expression of MYC and development of lymphoma. Our laboratory has developed a murine model of EBV-associated Burkitt’s lymphoma by crossing LMP2A transgenic mice with MYC transgenic mice. Since LMP2A has been shown to activate PI3K/Akt/mTOR pathway, we tested the therapeutic efficacy of mTOR inhibitor rapamycin on the tumors and splenomegaly in this double transgenic mice (Tg6/λ-MYC). We found that rapamycin reversed splenomegaly in Tg6/λ-MYC mice prior to tumor formation by targeting B cells. In a tumor transfer model, we also found that rapamycin significantly decreased tumor growth, splenomegaly, and metastasis of tumor cells into bone marrow of tumor recipients. Our data show that rapamycin may be a valuable candidate for the development of a treatment modality for EBV positive lymphomas such as Burkitt’s lymphoma, and more importantly, provides a basis to develop inhibitors that specifically target viral gene function in tumor cells that depend on LMP2A signaling for survival and/or growth.
doi:10.1158/1535-7163.MCT-10-0833
PMCID: PMC3073035  PMID: 21282357
EBV; LMP2A; Burkitt’s lymphoma; tumor; splenomegaly; rapamycin
12.  An Epstein-Barr Virus Encoded Inhibitor of Colony Stimulating Factor-1 Signaling Is an Important Determinant for Acute and Persistent EBV Infection 
PLoS Pathogens  2012;8(12):e1003095.
Acute Epstein-Barr virus (EBV) infection is the most common cause of Infectious Mononucleosis. Nearly all adult humans harbor life-long, persistent EBV infection which can lead to development of cancers including Hodgkin Lymphoma, Burkitt Lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and lymphomas in immunosuppressed patients. BARF1 is an EBV replication-associated, secreted protein that blocks Colony Stimulating Factor 1 (CSF-1) signaling, an innate immunity pathway not targeted by any other virus species. To evaluate effects of BARF1 in acute and persistent infection, we mutated the BARF1 homologue in the EBV-related herpesvirus, or lymphocryptovirus (LCV), naturally infecting rhesus macaques to create a recombinant rhLCV incapable of blocking CSF-1 (ΔrhBARF1). Rhesus macaques orally challenged with ΔrhBARF1 had decreased viral load indicating that CSF-1 is important for acute virus infection. Surprisingly, ΔrhBARF1 was also associated with dramatically lower virus setpoints during persistent infection. Normal acute viral load and normal viral setpoints during persistent rhLCV infection could be restored by Simian/Human Immunodeficiency Virus-induced immunosuppression prior to oral inoculation with ΔrhBARF1 or infection of immunocompetent animals with a recombinant rhLCV where the rhBARF1 was repaired. These results indicate that BARF1 blockade of CSF-1 signaling is an important immune evasion strategy for efficient acute EBV infection and a significant determinant for virus setpoint during persistent EBV infection.
Author Summary
Epstein-Barr virus (EBV) is a herpesvirus that persistently infects nearly all humans by adulthood. Acute and persistent phases of EBV infection are associated with a variety of human diseases, including infectious mononucleosis and cancer. To investigate how EBV interacts with the host to successfully establish acute and persistent infection, we combined the power of the rhesus macaque animal model for EBV infection with genetic engineering of the EBV-related herpesvirus, or lymphocryptovirus (LCV), that naturally infects rhesus macaques. We created a recombinant rhLCV carrying a mutated EBV BARF1 homologue, a replication-associated viral protein that is secreted and blocks Colony Stimulating Factor-1 (CSF-1) signaling, a cytokine important for innate immunity. Oral inoculation of rhesus macaques showed that the virus' ability to block CSF-1 was important for achieving the normally high viral loads during acute infection, and surprisingly, was also needed to establish normal levels of virus infection, or viral setpoint, during persistent infection. These studies show that virus-mediated interruption of innate immunity is critical for both acute and persistent phases of EBV infection. Understanding how EBV successfully infects humans and how the natural history of EBV infection can be disrupted will aid in development of vaccines to prevent EBV-associated diseases.
doi:10.1371/journal.ppat.1003095
PMCID: PMC3531511  PMID: 23300447
13.  Epstein-Barr Virus (EBV) detection and typing by PCR: a contribution to diagnostic screening of EBV-positive Burkitt's lymphoma 
Diagnostic Pathology  2006;1:17.
Background
Epstein-Barr virus (EBV) is associated to the etio-pathogenesis of an increasing number of tumors. Detection of EBV in pathology samples is relevant since its high prevalence in some cancers makes the virus a promising target of specific therapies. RNA in situ hybridization (RISH) is the standard diagnostic procedure, while polymerase chain reaction (PCR)-based methods are used for strain (EBV type-1 or 2) distinction. We performed a systematic comparison between RISH and PCR for EBV detection, in a group of childhood B-cell Non-Hodgkin lymphomas (NHL), aiming to validate PCR as a first, rapid method for the diagnosis of EBV-associated B-cell NHL.
Methods
EBV infection was investigated in formalin fixed paraffin-embedded tumor samples of 41 children with B-cell NHL, including 35 Burkitt's lymphoma (BL), from Rio de Janeiro, Brazil, by in situ hybridization of EBV-encoded small RNA (EBER-RISH) and PCR assays based on EBNA2 amplification.
Results
EBV genomes were detected in 68% of all NHL. Type 1 and 2 accounted for 80% and 20% of EBV infection, respectively. PCR and RISH were highly concordant (95%), as well as single- and nested-PCR results, allowing the use of a single PCR round for diagnostic purposes. PCR assays showed a sensitivity and specificity of 96% and 100%, respectively, with a detection level of 1 EBV genome in 5,000–10,000 EBV-negative cells, excluding the possibility of detecting low-number EBV-bearing memory cells.
Conclusion
We describe adequate PCR conditions with similar sensitivity and reliability to RISH, to be used for EBV diagnostic screening in high grade B-NHL, in "at risk" geographic regions.
doi:10.1186/1746-1596-1-17
PMCID: PMC1559641  PMID: 16893464
14.  A monkey model for Epstein Barr virus-associated lymphomagenesis in human acquired immunodeficiency syndrome [published erratum appears in J Exp Med 1992 Aug 1;176(2):following 634] 
High-grade malignant nonHodgkin's lymphomas--five lymphoblastic, three pleomorphic, and two immunoblastic--developed in 10/25 cynomolgus monkeys (Macaca fascicularis) followed for up to 746 d after infection with simian immunodeficiency virus, strain SIVsm. These lymphomas were shown to be associated with an Epstein-Barr (EB)-like cynomolgus B- lymphotropic herpesvirus (CBLV) by electron microscopy, by Southern blot hybridization with probes against human EBV, and by the expression of antigens corresponding to EBV-associated nuclear antigens (EBNAs) involved in human B cells transformation. Southern blot demonstration of immunoglobulin gene rearrangements and homogeneous EBV episomes indicated that all the lymphomas were CBLV-associated monoclonal B cell proliferations. Our findings suggest that these tumors correspond to the EBV-associated malignant lymphomas in acquired immunodeficiency syndrome with respect to clinical, morphological, phenotypic, and genotypic characteristics. The particular susceptibility of SIVsm immunodeficient cynomolgus monkeys for CBLV-associated lymphomagenesis appears therefore a useful model for EBV-associated lymphomas in humans.
PMCID: PMC2119285  PMID: 1319458
15.  Accumulation of Cytoplasmic β-Catenin and Nuclear Glycogen Synthase Kinase 3β in Epstein-Barr Virus-Infected Cells 
Journal of Virology  2004;78(21):11648-11655.
Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with cancers in immunocompromised populations. EBV establishes a latent infection and immortalizes and transforms B lymphocytes. Several latent proteins have profound effects on cellular growth, including activation of NF-κB, phosphatidylinositol 3′-OH kinase (PI3K) signaling, and notch signaling. Activation of PI3K can affect the activity of β-catenin, the target of the wnt signaling pathway. Deregulation of β-catenin is associated with a number of malignancies. To determine if β-catenin is regulated by EBV infection, EBV-infected cells were examined for β-catenin levels and localization. β-Catenin was increased in EBV-positive tumor cell lines compared to EBV-negative lines, in EBV-infected Burkitt's lymphoma cell lines, and in EBV-transformed lymphoblastoid cell lines (LCL). In contrast to wnt signaling, EBV consistently induced the accumulation of β-catenin in the cytoplasm but not the nucleus. The β-catenin regulating kinase, glycogen synthase kinase 3β (GSK3β), was shown to be phosphorylated and inactivated in EBV-infected lymphocytes. Inactivated GSK3β was localized to the nucleus of EBV-infected LCL. Neither the cytoplasmic accumulation of β-catenin nor the nuclear inactivation of GSK3β was affected by the inhibition of PI3K signaling. These data indicate that latent infection with EBV has unique effects on β-catenin signaling that are distinct from activation of wnt and independent of its effects on PI3K.
doi:10.1128/JVI.78.21.11648-11655.2004
PMCID: PMC523297  PMID: 15479806
16.  The Spectrum of Epstein-Barr Virus-Associated Lymphoproliferative Disease in Korea: Incidence of Disease Entities by Age Groups 
Journal of Korean Medical Science  2008;23(2):185-192.
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.
doi:10.3346/jkms.2008.23.2.185
PMCID: PMC2526432  PMID: 18436998
Lymphoma; Epstein-Barr Virus; Lymphohistiocytosis, Hemophagocytic
17.  EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors 
The Journal of Clinical Investigation  2012;122(4):1487-1502.
Epstein-Barr virus (EBV) persistently infects more than 90% of the human population and is etiologically linked to several B cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B cell lymphoma (DLBCL). Despite its growth transforming properties, most immune-competent individuals control EBV infection throughout their lives. EBV encodes various oncogenes, and of the 6 latency-associated EBV-encoded nuclear antigens, only EBNA3B is completely dispensable for B cell transformation in vitro. Here, we report that infection with EBV lacking EBNA3B leads to aggressive, immune-evading monomorphic DLBCL-like tumors in NOD/SCID/γc–/– mice with reconstituted human immune system components. Infection with EBNA3B-knockout EBV (EBNA3BKO) induced expansion of EBV-specific T cells that failed to infiltrate the tumors. EBNA3BKO-infected B cells expanded more rapidly and secreted less T cell–chemoattractant CXCL10, reducing T cell recruitment in vitro and T cell–mediated killing in vivo. B cell lines from 2 EBV-positive human lymphomas encoding truncated EBNA3B exhibited gene expression profiles and phenotypic characteristics similar to those of tumor-derived lines from the humanized mice, including reduced CXCL10 secretion. Screening EBV-positive DLBCL, HL, and BL human samples identified additional EBNA3B mutations. Thus, EBNA3B is a virus-encoded tumor suppressor whose inactivation promotes immune evasion and virus-driven lymphomagenesis.
doi:10.1172/JCI58092
PMCID: PMC3314448  PMID: 22406538
18.  Epstein-Barr virus-driven lymphomagenesis in the context of human immunodeficiency virus type 1 infection 
Epstein–Barr virus (EBV) is a ubiquitous human γ-herpes virus which establishes a life-long asymptomatic infection in immunocompetent hosts. In human immunodeficiency virus type 1 (HIV-1) infected patients, the impaired immunosurveillance against EBV may favor the development of EBV-related diseases, ranging from lymphoproliferative disorders to B cell non-Hodgkin’s lymphomas (NHL). Antiretroviral therapy (ART) has significantly modified the natural course of HIV-1 infection, resulting in decreased HIV-1 plasmaviremia, increased CD4 lymphocytes, and decreased opportunistic infections, indicating a restoration of immune functions. However, the impact of ART appears to be less favorable on EBV-related malignancies than on other AIDS-defining tumors, such as Kaposi’s sarcoma, and NHL remains the most common cancer during the ART era. EBV-driven tumors are associated with selective expression of latent oncogenic proteins, but uncontrolled lytic cycle with virus replication and/or reactivation may favor cell transformation, at least in the early phases. Several host’s factors may promote EBV reactivation and replication; besides immunodepression, inflammation/chronic immune stimulation may play an important role. Microbial pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, through Toll-like receptors, activate the immune system and may promote EBV reactivation and/or polyclonal expansion of EBV-infected cells. A body of evidence suggests that chronic immune stimulation is a hallmark of HIV-1 pathogenesis and may persist even in ART-treated patients. This review focuses on lymphomagenesis driven by EBV both in the context of the natural history of HIV-1 infection and in ART-treated patients. Understanding the mechanisms involved in the expansion of EBV-infected cells is a premise for the identification of prognostic markers of EBV-associated malignancies.
doi:10.3389/fmicb.2013.00311
PMCID: PMC3799006  PMID: 24151490
EBV; HIV-1; B cell activation; chronic immune activation; EBV-related malignancies; antiretroviral therapy; EBV lytic reactivation
19.  Dithiocarbamates and Viral IL-10 Collaborate in the Immortalization and Evasion of Immune Response in EBV-infected Human B Lymphocytes 
Chemico-biological interactions  2007;172(1):81-92.
Epstein-Barr Virus (EBV) is implicated in the development of a number of human malignancies including several subtypes of non-Hodgkin lymphoma (NHL) [1]. Lymphoproliferative disease and NHL occurring in severely immunosuppressed individuals almost all involve EBV and have been extensively studied and modeled in vitro. EBV has also been causally associated with some cases of NHL occurring in otherwise immunocompetent individuals. However, a direct role for EBV in the pathogenesis of neoplasms developing in the presence of an otherwise competent immune system has not been established. We investigated potential interactions between dithiocarbamates (DTC), an important class of thiono-sulfur compounds, and EBV leading to immortalization of human B lymphocytes and evasion of cell-mediated immune response in culture. Primary lymphocyte cultures employing wild-type and recombinant EBV mutants were used to assess the respective roles of DTC and viral genes in lymphocyte transformation and survival. Pretreatment of EBV-infected human B lymphocytes with DTC directly enhanced transformation in the absence of T cells (5 nM) and independently increased survival of transformed cells in the presence of competent autologous T cells (10 nM). Both DTC-induced transformation and immortalization of EBV-infected B lymphocytes were dependent on the expression of viral IL-10. These results provide a biological basis for studying collaborations between chemical and virus that alter lymphocyte biology, and provide a rationale for further molecular epidemiology studies to better understand the potential influence of these interactions on the development of NHL and perhaps other viral-associated malignancies.
doi:10.1016/j.cbi.2007.11.005
PMCID: PMC2293282  PMID: 18163983
dithiocarbamates; Epstein-Barr virus; IL-10; immune evasion; B lymphocytes
20.  Epstein-Barr virus and human diseases: recent advances in diagnosis. 
Clinical Microbiology Reviews  1988;1(3):300-312.
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
PMCID: PMC358052  PMID: 2848624
21.  Transcriptional profiling of Epstein–Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection 
British Journal of Cancer  2006;94(4):599-608.
Nasal NK/T-cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein–Barr virus (EBV). The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. To understand the pathogenesis of EBV-associated NK/T-cell lymphoproliferative disorders (LPD) and design new therapies, we employed a novel EBV DNA microarray to compare patterns of EBV expression in six cell lines established from EBV-associated NK/T-cell LPD. We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was expressed in SNK/T cells and the expression levels were preferentially high in cell lines from CAEBV infection. We also analyzsd the gene expression patterns of host cellular genes using a human oligonucleotide DNA microarray. We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression, which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.
doi:10.1038/sj.bjc.6602968
PMCID: PMC2361178  PMID: 16449999
Epstein Barr virus; nasal NK/T-cell lymphoma; EBV DNA microarray; CAEBV infection
22.  Immunotherapy for Epstein-Barr Virus-Related Lymphomas 
Latent EBV infection is associated with several malignancies, including EBV post-transplant lymphoproliferative disorders (LPD), Hodgkin and non-Hodgkin lymphomas, nasopharyngeal carcinoma and Burkitt lymphoma. The range of expression of latent EBV antigens varies in these tumors, which influences how susceptible the tumors are to immunotherapeutic approaches. Tumors expressing type III latency, such as in LPD, express the widest array of EBV antigens making them the most susceptible to immunotherapy. Treatment strategies for EBV-related tumors include restoring normal cellular immunity by adoptive immunotherapy with EBV-specific T cells and targeting the malignant B cells with monoclonal antibodies. We review the current immunotherapies and future studies aimed at targeting EBV antigen expression in these tumors.
doi:10.4084/MJHID.2009.010
PMCID: PMC3033176  PMID: 21416001
23.  The company malaria keeps: how co-infection with Epstein-Barr virus leads to endemic Burkitt lymphoma 
Purpose of review
Co-infection with Plasmodium falciparum (Pf-) malaria and Epstein-Barr virus (EBV) are implicated in the etiology of endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in equatorial Africa. Although the causal association between EBV and eBL has been established, Pf-malaria’s role is not as clearly defined. This review focuses on how malaria may disrupt EBV persistence and immunity.
Recent findings
Two mutually-compatible theories have been proposed. One suggests that Pf-malaria induces polyclonal B-cell expansion and lytic EBV reactivation, leading to the expansion of latently infected B-cells and the likelihood of c-myc translocation; a hallmark of BL tumors. The other advocates that EBV-specific T-cell immunity is impaired during Pf-malaria co-infection, either as a cause or consequence of enhanced EBV replication, leading to loss of viral control. Advancements in our ability to query the complexity of human responses to infectious diseases have stimulated interest in eBL pathogenesis.
Summary
EBV is necessary but not sufficient to cause eBL. A more dynamic model encompasses incremental contributions from both chronic and acute Pf-malaria leading to alterations in EBV persistence and EBV-specific immunity that culminate in eBL. A better understanding of how Pf-malaria modifies EBV infections in children may allow us to anticipate reductions in eBL incidence coinciding with malaria control programs.
doi:10.1097/QCO.0b013e328349ac4f
PMCID: PMC3265160  PMID: 21885920
Malaria; EBV; endemic Burkitt lymphoma; T-cell immunity; B-cell immunity
24.  Epstein-Barr Virus in Human Malignancy: A Special Reference to Epstein-Barr Virus associated Gastric Carcinoma 
Epstein-Bar virus (EBV), a human herpesvirus, establishes a life-long persistent infection in 90~95% of human adult population worldwide. EBV is the etiologic agent of infectious mononucleosis, and EBV is associated with a variety of human malignancy including lymphoma and gastric carcinoma. Recently, EBV has been classified as group 1 carcinogen by the WHO International Agency for Research on Cancer. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated malignancy. At present, the precise mechanisms by which EBV transforms B lymphocytes have been disclosed. Encouragingly, they have had enough success so far to keep them enthusiastic about novel therapeutic trial in the field of EBV-associated lymphoma. However, information on EBV-associated gastric carcinoma is still at dawn. This article reviews EBV biology, immunological response of EBV infection, unique oncogenic property of EBV, peculiarity of EBV-associated gastric carcinoma, and lastly, EBV-targeted therapy and vaccination.
doi:10.4143/crt.2005.37.5.257
PMCID: PMC2785932  PMID: 19956524
Human herpes virus 4; Epstein-Barr virus (EBV); Oncogenic virus; Stomach neoplasms; Lymphoma; EBV-targeted treatment
25.  Roles of the PI3K/Akt pathway in Epstein-Barr virus-induced cancers and therapeutic implications 
World Journal of Virology  2012;1(6):154-161.
Viruses have been shown to be responsible for 10%-15% of cancer cases. Epstein-Barr virus (EBV) is the first virus to be associated with human malignancies. EBV can cause many cancers, including Burkett’s lymphoma, Hodgkin’s lymphoma, post-transplant lymphoproliferative disorders, nasopharyngeal carcinoma and gastric cancer. Evidence shows that phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) plays a key role in EBV-induced malignancies. The main EBV oncoproteins latent membrane proteins (LMP) 1 and LMP2A can activate the PI3K/Akt pathway, which, in turn, affects cell survival, apoptosis, proliferation and genomic instability via its downstream target proteins to cause cancer. It has also been demonstrated that the activation of the PI3K/Akt pathway can result in drug resistance to chemotherapy. Thus, the inhibition of this pathway can increase the therapeutic efficacy of EBV-associated cancers. For example, PI3K inhibitor Ly294002 has been shown to increase the effect of 5-fluorouracil in an EBV-associated gastric cancer cell line. At present, dual inhibitors of PI3K and its downstream target mammalian target of rapamycin have been used in clinical trials and may be included in treatment regimens for EBV-associated cancers.
doi:10.5501/wjv.v1.i6.154
PMCID: PMC3782276  PMID: 24175221
Epstein-Barr virus; Latent membrane proteins 1; Latent membrane proteins 2A; Phosphoinositide 3-kinase/protein kinase B; Carcinogenesis; Drug resistance

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