The Epigenetic Life Cycle of Epstein–Barr Virus

2015 ◽  
pp. 103-117 ◽  
Author(s):  
Wolfgang Hammerschmidt
Keyword(s):  
Life Cycle ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Interpretation of EBV infection in pan-cancer genome considering viral life cycle: LiEB (Life cycle of Epstein-Barr virus)

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hyojin Song ◽  
Yoojoo Lim ◽  
Hogune Im ◽  
Jeong Mo Bae ◽  
Gyeong Hoon Kang ◽  
...  
Keyword(s):  
Life Cycle ◽  
Epstein Barr Virus ◽  
Viral Life Cycle ◽  
Cancer Genome ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Pan Cancer

scholarly journals Microtubule depolymerization activates the Epstein–Barr virus lytic cycle through protein kinase C pathways in nasopharyngeal carcinoma cells

2013 ◽  
Vol 94 (12) ◽  
pp. 2750-2758 ◽  
Author(s):  
Yi-Ru Liu ◽  
Sheng-Yen Huang ◽  
Jen-Yang Chen ◽  
Lily Hui-Ching Wang
Keyword(s):  
Protein Kinase C ◽  
Life Cycle ◽  
Protein Kinase ◽  
Nasopharyngeal Carcinoma ◽  
Epstein Barr Virus ◽  
Lytic Cycle ◽  
Barr Virus ◽  
Kinase C ◽  
Epstein Barr ◽  
In Cells

Elevated levels of antibodies against Epstein–Barr virus (EBV) and the presence of viral DNA in plasma are reliable biomarkers for the diagnosis of nasopharyngeal carcinoma (NPC) in high-prevalence areas, such as South-East Asia. The presence of these viral markers in the circulation suggests that a minimal level of virus reactivation may have occurred in an infected individual, although the underlying mechanism of reactivation remains to be elucidated. Here, we showed that treatment with nocodazole, which provokes the depolymerization of microtubules, induces the expression of two EBV lytic cycle proteins, Zta and EA-D, in EBV-positive NPC cells. This effect was independent of mitotic arrest, as viral reactivation was not abolished in cells synchronized at interphase. Notably, the induction of Zta by nocodazole was mediated by transcriptional upregulation via protein kinase C (PKC). Pre-treatment with inhibitors for PKC or its downstream signalling partners p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) abolished the nocodazole-mediated induction of Zta and EA-D. Interestingly, the effect of nocodazole, as well as colchicine and vinblastine, on lytic gene expression occurred only in NPC epithelial cells but not in cells derived from lymphocytes. These results establish a novel role of microtubule integrity in controlling the EBV life cycle through PKC and its downstream pathways, which represents a tissue-specific mechanism for controlling the life-cycle switch of EBV.

scholarly journals Interplay between the epigenetic enzyme lysine (K)-specific demethylase 2B and Epstein-Barr virus infection

2018 ◽  
Author(s):  
Romina C. Vargas-Ayala ◽  
Antonin Jay ◽  
Hector Hernandez-Vargas ◽  
Audrey Diederichs ◽  
Alexis Robitaille ◽  
...  
Keyword(s):  
Life Cycle ◽  
B Cells ◽  
Virus Infection ◽  
Burkitt Lymphoma ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Epstein Barr ◽  
Barr Virus Infection

AbstractHistone modifier lysine (K)-specific demethylase 2B(KDM2B) plays a role in hematopoietic cells differentiation and its expression appears to be deregulated in certain cancers of hematological and lymphoid origins. We have previously found that KDM2B gene is differentially methylated in cell lines derived from the Epstein-Barr virus (EBV) associated endemic Burkitt’s lymphomas (eBL) compared to EBV negative sporadic BL cells. However, whether KDM2B plays a role in eBL development has never been previously demonstrated. Oncogenic viruses have been shown to hijack the host cell epigenome to complete their life cycle and to promote the transformation process by perturbing cell chromatin organization. Here we investigated whether EBV would alter KDM2B levels to enable its life cycle and promote B-cells transformation. We show that infection of B-cells with EBV leads to down-regulation of KDM2B levels. We also show that LMP1, one of the main EBV transforming proteins, induces increased DNMT1 recruitment to KDM2B gene and augments its methylation. By altering KDM2B levels and performing chromatin immunoprecipitation in EBV infected B-cells, we were able to show that KDM2B is recruited to the EBV gene promoters and inhibits their expression. Furthermore, forced KDM2B expression in immortalized B-cells led to altered mRNA levels of some differentiation-related genes. Our data show that EBV deregulates KDM2B levels through an epigenetic mechanism and provide evidence for a role of KDM2B in regulating virus and host cell gene expression, warranting further investigations to assess the role of KDM2B in the process of EBV-mediated lymphomagenesis.IMPORTANCE. In Africa, Epstein-Barr virus infection is associated with endemic Burkitt lymphoma, a pediatric cancer. The molecular events leading to its development are poorly understood compared to the sporadic Burkitt lymphoma. In a previous study, by analyzing the DNA methylation changes in endemic compared to sporadic Burkitt lymphomas cell lines, we identified several differential methylated genomic positions in proximity of genes with a potential role in cancer, among them the KDM2B gene. KDM2B encodes a histone H3 demethylase already shown to be involved in some hematological disorders. However, whether KDM2B plays a role in the development of Epstein-Barr virus-mediated lymphoma has never been investigated before. In this study we show that Epstein-Barr virus deregulates KDM2B expression and describe the underlying mechanisms. We also reveal a role of the demethylase in controlling viral and B-cells genes expression, thus highlighting a novel interaction between the virus and the cellular epigenome.

Bortezomib Is a Novel Inducer of Latent Epstein Barr Virus (EBV) in EBV+ Lymphoma Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2511-2511 ◽  
Author(s):  
Vesna Kaluza ◽  
Helen Braun ◽  
Jeffrey Calimlim ◽  
Ren Sun ◽  
Jonathan Said ◽  
...  
Keyword(s):  
Life Cycle ◽  
Cell Line ◽  
Epstein Barr Virus ◽  
Histone Deacetylase Inhibitors ◽  
Barr Virus ◽  
Qrt Pcr ◽  
Chemical Agents ◽  
Xenograft Models ◽  
Epstein Barr

Abstract Epstein-Barr Virus (EBV)+ lymphomas are an important subgroup of aggressive malignant lymphomas which include lymphomas in the post-transplantation setting, Burkitt’s lymphomas (BL), AIDS-related lymphomas (ARL), and some forms of Hodgkin, T-cell, and natural killer (NK) cell lymphomas. EBV is a member of the herpes virus family, characterized by their ability to support two different life cycles: the productive “lytic” cycle leading to the production and release of new virions and the non-productive “latent” cycle. Most lymphoma cells are infected with latent EBV, and only few viral genes are expressed at low levels. Several groups of broad-acting chemical agents are able to reactivate EBV and induce herpes thymidine kinase (TK) expression in vitro and in vivo. NF-kB has been described to play a critical role in regulating the balance between latency and lytic replication of EBV. Therefore, we hypothesized that the proteasome inhibitor Bortezomib can be used to initiate EBV lytic antigen expression in EBV-related malignancies enabling the antiviral drug Ganciclovir to kill EBV+ lymphoma cells. The human cell line HR-1, derived from a Burkitt’s lymphoma and latently infected with EBV, was cultured in the presence of 50nM bortezomib for 24 hrs. The immediate early lytic phase EBV antigens ZEBRA and RTA were induced and expressed as measured by flow cytometry. The EBV-VCA and EBV-R antigens were not expressed in untreated controls but were induced as demonstrated by western blot analysis, indicating the switch to the lytic life-cycle of EBV. These results were successfully repeated using the EBV+ Akata cell line. Induction of viral thymidine kinase (vTK) was shown by QRT-PCR as well. Histone deacetylase inhibitors are a well known group of broad-acting chemical agents able to reactivate EBV. In combination experiments, we found that Bortezomib plus sodium butyrate or SAHA act at least additive in inducing the EBV lytic life cycle in HR-1 or RAJI cells. Bortezomib sensitizes the EBV+ Akata cell line 2A8-1 to growth inhibitory effects of ganciclovir as shown by MTT assays. The cells were treated with two different non-toxic drug concentrations which were chosen low enough not to induce apoptosis (bortezomib: 1nM and 2nM; ganciclovir:15 and 30μM). Bortezomib induces the lytic EBV life cycle in vivo. In murine xenograft models growing the Akata A.15 line subcutaneously bortezomib induces the immediate-early protein ZEBRA as shown by immunohistochemistry and vTK as shown by QRT-PCR. Experiments to induce lytic phase EBV in murine xenograft models using the Akata cell line and to combine EBV induction with the nucleoside analogue ganciclovir are in progress. Murine studies with EBV-transformed lymphoblastoid cell line (LCL) xenograft models, combination bortezomib plus ganciclovir, and molecular imaging with FHBG specific PET probes are in progress. Reactivating EBV with proteasome inhibitors alone or in combinations with low concentrations of histone deacetylase inhibitors may be a less toxic therapeutic strategy for EBV-associated lymphomas.

scholarly journals Extracellular Vesicles in Epstein-Barr Virus’ Life Cycle and Pathogenesis

2019 ◽  
Vol 7 (2) ◽  
pp. 48 ◽  
Author(s):  
Mengmeng Zhao ◽  
Asuka Nanbo ◽  
Lichun Sun ◽  
Zhen Lin
Keyword(s):  
Life Cycle ◽  
Extracellular Vesicles ◽  
Epstein Barr Virus ◽  
Current Knowledge ◽  
Cell Types ◽  
Eukaryotic Cell ◽  
Barr Virus ◽  
Cells Of Origin ◽  
Membrane Bound ◽  
Epstein Barr

Extracellular vesicles (EVs), including exosomes and microvesicles, are evolutionarily conserved phospholidpid membrane-bound entities secreted from most eukaryotic cell types. They carry bioactive cargos such as protein and nucleic acids derived from their cells of origin. Over the past 10 years, they have been attracting increased attention in many fields of life science, representing a new route for intercellular communication. In this review article, we will discuss the current knowledge of both normal and virally modified EVs in the regulation of Epstein-Barr virus (EBV)’s life cycle and its associated pathogenesis.

scholarly journals Epstein-Barr Virus Limits the Accumulation of IPO7, an Essential Gene Product

2021 ◽  
Vol 12 ◽  
Author(s):  
Ya-Chun Yang ◽  
Bill Sugden
Keyword(s):  
Life Cycle ◽  
Host Cell ◽  
Gene Product ◽  
Epstein Barr Virus ◽  
Essential Gene ◽  
Nucleocytoplasmic Transport ◽  
Barr Virus ◽  
Cellular Mrnas ◽  
Infected Cells ◽  
Epstein Barr

Epstein-Barr virus (EBV) encodes more than 40 miRNAs that target cellular mRNAs to aid its infection, replication, and maintenance in individual cells and in its human host. Importin-7 (IPO7), also termed Imp7 or RanBPM7, is a nucleocytoplasmic transport protein that has been frequently identified as a target for two of these viral miRNAs. How the viral life cycle might benefit from regulating IPO7 has been unclear, though. We demonstrate with CRISPR-Cas9 mutagenesis that IPO7 is essential in at least three cells lines and that increasing its levels of expression inhibits growth of infected cells. EBV thus regulates the level of IPO7 to limit its accumulation consistent with its being required for survival of its host cell.

scholarly journals Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
J. T. Guidry ◽  
J. E. Myers ◽  
M. Bienkowska-Haba ◽  
W. K. Songock ◽  
X. Ma ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Life Cycle ◽  
Epstein Barr Virus ◽  
Differentiation Markers ◽  
Barr Virus ◽  
Ebv Infection ◽  
Hpv E6 ◽  
Epstein Barr ◽  
E6 And E7 ◽  
Tonsillar Cells

ABSTRACTEpstein-Barr virus (EBV) is implicated in the pathogenesis of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OSCC). EBV-associated cancers harbor a latent EBV infection characterized by a lack of viral replication and the expression of viral oncogenes. Cellular changes promoted by HPV are comparable to those shown to facilitate EBV latency, though whether HPV-positive cells support a latent EBV infection has not been demonstrated. Using a model of direct EBV infection into HPV16-immortalized tonsillar cells grown in organotypic raft culture, we showed robust EBV replication in HPV-negative rafts but little to no replication in HPV-immortalized rafts. The reduced EBV replication was independent of immortalization, as human telomerase-immortalized normal oral keratinocytes supported robust EBV replication. Furthermore, we observed reduced EBV lytic gene expression and increased expression of EBER1, a noncoding RNA highly expressed in latently infected cells, in the presence of HPV. The use of human foreskin keratinocyte rafts expressing the HPV16 E6 and/or E7 oncogene(s) (HPV E6 and E7 rafts) showed that E7 was sufficient to reduce EBV replication. EBV replication is dependent upon epithelial differentiation and the differentiation-dependent expression of the transcription factors KLF4 and PRDM1. While KLF4 and PRDM1 levels were unaltered, the expression levels of KLF4 transcriptional targets, including late differentiation markers, were reduced in HPV E6 and E7 rafts compared to their levels in parental rafts. However, the HPV E7-mediated block in EBV replication correlated with delayed expression of early differentiation markers. Overall, this study reveals an HPV16-mediated block in EBV replication, through E7, that may facilitate EBV latency and long-term persistence in the tumor context.IMPORTANCEUsing a model examining the establishment of EBV infection in HPV-immortalized tissues, we showed an HPV-induced interruption of the normal EBV life cycle reminiscent of a latent EBV infection. Our data support the notion that a persistent EBV epithelial infection depends upon preexisting cellular alterations and suggest the ability of HPV to promote such changes. More importantly, these findings introduce a model for how EBV coinfection may influence HPV-positive (HPV-pos) OSCC pathogenesis. Latently EBV-infected epithelial cells, as well as other EBV-associated head-and-neck carcinomas, exhibit oncogenic phenotypes commonly seen in HPV-pos OSCC. Therefore, an HPV-induced shift in the EBV life cycle toward latency would not only facilitate EBV persistence but also provide additional viral oncogene expression, which can contribute to the rapid progression of HPV-pos OSCC. These findings provide a step toward defining a role for EBV as a cofactor in HPV-positive oropharyngeal tumors.

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