A-type and B-type Epstein-Barr virus differ in their ability to spontaneously enter the lytic cycle.
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In this study replication of A-type and B-type Epstein-Barr virus (EBV) strains has been assessed. A-type and B-type type lymphoblastoid cell lines (LCLs) were established by infecting B lymphocytes, isolated from five EBV-seropositive donors, with different A-type and B-type virus isolates. The presence of viral capsid antigens (VCA) in these LCLs was determined by immunofluoresence assay and by immunoblotting. All of the B-type EBV strains were capable of spontaneously generating virus regardless of the origin of the donor cells. In contrast the A-type strains, other than strain IARC-BL36, did not readily produce VCA in any of the different donor lymphocytes used. This study demonstrates another biological difference between the two virus types: their ability to spontaneously enter the lytic cycle.Keywords:
Lytic cycle
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Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus involved in the pathogenesis of a wide spectrum of malignant and non-malignant diseases. In healthy EBV carriers, the virus is believed to infect two major cellular targets - B lymphocytes and epithelial cells. While EBV latency is established predominantly, if not exclusively, in B-lymphocytes, virus replication can take place both in B cells and epithelial cells. Lytic replication ensures virus transmission to new carriers and replenishes the cellular reservoirs of virus persistence. The generally asymptomatic and harmless persistence of EBV relies on a tightly controlled immune response and distinct modes of virus/cell interactions observed at different stages of EBV life cycle. The aim of this thesis was to characterize the mutual influence of the host immune system and EBV at the replicative stage of virus infection. We showed that EBV enters monocytes and inhibits their differentiation into dendritic cells (DCs) without the need of viral gene expression. The sensitivity of the cells to virus-induced apoptosis progressively decreases along the process of DC maturation and is strongly dependent on the cell type in which the virus replicated before infecting DC precursors, since epithelial-cells derived viruses exhibited a significantly stronger pro-apoptotic activity than their B cell-derived counterparts. The capacity of the virus to suppress DC development might help in delaying the establishment of EBV specific immunity before the pool of infected B cells reaches the size sufficient for long-term virus persistence. During virus replication, both B cells and epithelial cells may escape recognition by cytotoxic CD8+ T cells through downregulation of MHC class I molecules. Our work demonstrated that MHC class I heavy-chain and beta2m mRNA and protein synthesis are inhibited during EBV replication. Several other characteristic changes observed in the MHC class I processing and presentation pathway during the lytic cycle were recapitulated by chemical inhibition of protein synthesis. These results were recently confirmed by others and the viral protein responsible for host-cell global protein synthesis shutdown was shown to be encoded by the BGLF5 open reading frame of the EBV genome. Triggering of receptors of the tumor necrosis factor (TNF) superfamily participates both in determining the fate of B-lymphocytes during the process of their differentiation and in immunologic clearance of virus infected targets. Initiation of EBV lytic cycle counteracted sensitization to death induced by TNF-related apoptosis-inducing ligand (TRAIL) that resulted from B-cell receptor (BCR) triggering in Burkitt s lymphoma cells. Differential modulation of death-transmitting and decoy TRAIL receptors was associated with sensitization to TRAIL in response to BCR-triggering or protection from TRAIL by EBV lytic cycle. Interference with TRAIL-mediated checkpoints in B-cell differentiation may account for the involvement of EBV in autoimmune diseases. Decreased sensitivity to TRAIL may also protect EBV infected cells from recognition by CTL and NK-cells. B-cell homeostasis is severely perturbed during malaria infection. We showed that the CIDR1a domain of P. falciparum erythrocyte membrane protein 1 (PfEMP1), a multiadhesive protein expressed during the erythrocytic phase of the parasite life cycle, binds to B cells and induces EBV replication. This might partly explain the increased EBV viral load during malaria infection and the increased risk of B cell immortalization in the ontogenesis of endemic Burkitt s lymphoma. Results presented in this thesis strengthen the notion that EBV replication actively modulates the functioning of the immune system at different levels through complex interactions of viral products with several types of cells and contributes to immune suppression, autoimmunity and tumorogenesis through a number of mechanisms whose details require further characterization. Research lines defined by this work may lead to new approaches towards management of EBV associated diseases.
Lytic cycle
Viral transformation
Antibody-dependent enhancement
Gammaherpesvirinae
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Immunofluorescence
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Epstein-Barr virus (EBV) is a widespread human herpes virus associated with lymphomas and epithelial cell cancers. It establishes two separate infection phases, latent and lytic, in the host. Upon infection of a new host cell, the virus activates several pathways, to induce the expression of lytic EBV antigens and the production of infectious virus particles. Although the carcinogenic role of latent EBV infection has been established, recent research suggests that lytic reactivation also plays a significant role in carcinogenesis. In this review, we summarize the mechanism of EBV reactivation and recent findings about the role of viral lytic antigens in tumor formation. In addition, we discuss the treatment of EBV-associated tumors with lytic activators and the targets that may be therapeutically effective in the future.
Lytic cycle
Virus latency
Oncovirus
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Proliferating B cell lesions developing in a series of immunosuppressed organ transplant recipients and patients with X-linked lymphoproliferative syndrome were examined for Epstein-Barr virus and cellular gene expression using immunocytochemistry and immunoblotting techniques. Results indicate that all the lesions examined from the patients in this series expressed Epstein-Barr virus gene products that were consistent with a latent, nonproductive type of infection. No lytic cycle antigens associated with productive viral infection were detected. This pattern is similar to the viral gene expression in normal B cells immortalized by Epstein-Barr virus in vitro. The demonstration in this study of Epstein-Barr virus viral gene expression in posttransplant and X-linked proliferative syndrome B cell disorders provides important new evidence for the primary role of Epstein-Barr virus in the development of these lesions. This is in contrast to the subsidiary role that the Epstein-Barr virus has in the etiology of Burkitt's lymphoma.
Lymphoproliferative Disorders
Lytic cycle
Gammaherpesvirinae
Epstein–Barr virus infection
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The Epstein-Barr virus (EBV) immediate early transactivator Zta plays a key role in regulating the transition from latency to the lytic replication stages of EBV infection. Regulation of Zta is known to be controlled through a number of transcriptional and posttranscriptional events. Here, we show that Zta is targeted for ubiquitin modification and that this can occur in EBV-negative and in EBV-infected cells. Genetic studies show critical roles for both an amino-terminal region of Zta and the basic DNA binding domain of Zta in regulating Zta ubiquitination. Pulse-chase experiments demonstrate that the bulk population of Zta is relatively stable but that at least a subset of ubiquitinated Zta molecules are targeted for degradation in the cell. Mutation of four out of a total of nine lysine residues in Zta largely abrogates its ubiquitination, indicating that these are primary ubiquitination target sites. A Zta mutant carrying mutations at these four lysine residues (lysine 12, lysine 188, lysine 207, and lysine 219) cannot induce latently infected cells to produce and/or release infectious virions. Nevertheless, this mutant can induce early gene expression, suggesting a possible defect at the level of viral replication or later in the lytic cascade. As far as we know, this is the first study that has investigated the targeting of Zta by ubiquitination or its role in Zta function.IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous human pathogen and associated with various human diseases. EBV undergoes latency and lytic replication stages in its life cycle. The transition into the lytic replication stage, at which virus is produced, is mainly regulated by the viral gene product, Zta. Therefore, the regulation of Zta function becomes a central issue regarding viral biology and pathogenesis. Known modifications of Zta include phosphorylation and sumoylation. Here, we report the role of ubiquitination in regulating Zta function. We found that Zta is subjected to ubiquitination in both EBV-infected and EBV-negative cells. The ubiquitin modification targets 4 lysine residues on Zta, leading to both mono- and polyubiquitination of Zta. Ubiquitination of Zta affects the protein's stability and likely contributes to the progression of viral lytic replication. The function and fate of Zta may be determined by the specific lysine residue being modified.
Lytic cycle
Gammaherpesvirinae
Viral protein
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The Epstein‐Barr Virus (EBV) is a member of the herpes virus family and causes infectious mononucleosis. Epstein‐Barr Virus was the first virus discovered to cause cancer in humans. After infection with EBV, the virus maintains a lifelong dormant infection within the host. The virus's life cycle consists of two phases, the latent and the lytic phase. The latent phase allows the virus to lie dormant within the host without presenting any symptoms, while during the lytic phase the virus reproduces and spreads among cells. The virus switches between the latent and lytic phases in response to environmental stimuli, including some pharmaceuticals. We investigated the response of the virus to atypical antipsychotic drugs. Antipsychotic drugs are used to treat conditions such as schizophrenia and bipolar disorder. Atypical antipsychotics, also known as second generation antipsychotics, have a different chemical structure and are generally more effective than the typical (first generation) antipsychotics. The effects of varying concentrations of the drugs on the reactivation of EBV into the lytic cycle were tested. The degree of viral reactivation was measured by expression of the viral BZLF1 gene, a regulatory gene expressed during reactivation into the Epstein‐Barr Virus lytic cycle. Quantitative polymerase chain reaction (qPCR) monitored BZLF1 gene expression. Expression of the BZLF1 gene and viral reactivation was found to be inhibited. Understanding the conditions and cellular pathways that inhibit the lytic phase of the virus will help to better understand the virus's life cycle in order to develop treatments for cancers caused by Epstein‐Barr Virus. Support or Funding Information This work was funded by the UWL College of Science and Health, UWL Faculty Research Grants to KLG, and Undergraduate Research and Creativity grants to AGA. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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In humans, Epstein–Barr virus (EBV) establishes a persistent latent infection in peripheral resting B lymphocytes. Virus reactivation is highly restricted. Whereas in healthy humans the infection usually is benign, immunocompromised patients show an increased risk for EBV-associated malignancies, accompanied by an increase in virus replication and in the number of virus-infected cells. To search for viral and host factors regulating virus reactivation, we used conditionally EBV-immortalized B cells. We found that CD40–CD40 ligand interaction and the viral mimic of activated CD40, EBV latent membrane protein 1, suppress virus reactivation. Both inhibit anti-IgM or phorbolester-induced transcription of the viral immediate early protein BZLF1, which controls entry into the viral lytic cycle. The finding that latent membrane protein 1 and CD40 contribute to the regulation of latency may have important implications for the balance between EBV and its host in normal as well as in immunocompromised individuals.
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Glycoprotein M (gM) is one of the very few nonessential glycoproteins conserved throughout the herpesvirus family. Despite this conservation little is known about its function in virus replication. To test for the importance of gM in vivo in a natural virus-host system, 6-week-old piglets were intranasally infected with a gM mutant of the alphaherpesvirus pseudorabies virus (PrV). Following infection virus excretion from the nasal mucosa was decreased ca. 100-fold compared to wild-type or revertant virus. Clinical signs were limited to transiently elevated temperature. In contrast, animals infected by wild-type or revertant virus exhibited high fever, severe respiratory symptoms and affliction of the central nervous system. Prior infection with gM PrV conferred protection against challenge infection and animals mounted an antibody response against gM after wild-type virus infection. Thus, gM is important for efficient virus replication in vivo and deletion of gM may contribute to development of live attenuated, genetically marked vaccines.
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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.
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Viral tegument
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