Perspective: Contribution of Epstein–Barr virus (EBV) Reactivation to the Carcinogenicity of Nasopharyngeal Cancer Cells

Background: Nasopharyngeal cancer is commonly associated with Epstein–Barr virus (EBV) infection, especially undifferentiated non-keratinized histology. EBV DNA quantification through nasopharyngeal brushing was previously reported to be not related to disease stage. This study aimed to reinvestigate the relationship of EBV viral load in tumor tissue with tumor extensiveness by more accurate EBV DNA quantification through microscopically confirmed tumor cells from nasopharyngeal biopsy. Method: The specimens for EBV DNA quantification were derived from histopathology slides which were pre-treated following the QIAsymphony® SP protocol for tissue DNA extraction. Then, the extracted DNA underwent real-time polymerase chain reaction (RT-PCR) using the artus® EBV RG PCR Kit for EBV DNA quantification. The tumor volume was determined by delineating the gross tumor based on 3D imaging of the patient’s nasopharynx. Result: Twenty-four subjects were included in this study. All subjects were stage III and above, with more males (75%) than females. EBV viral load in tumor cells was found to have no correlation to tumor volume both in local and nodal regions. The median local tumor volume was 81.3 cm3 ± 80 cm3. The median EBV viral load in tumor cells was 95,644.8 ± 224,758.4 copies/100 ng of DNA. The median nodal or regional tumor volume was 35.7 ± 73.63 cm3. Conclusion: EBV viral load from tumor cells from nasopharyngeal biopsy has no relationship with tumor extensiveness in nasopharyngeal cancer. The presence and amount of EBV in tumor cells did not translate into larger or smaller tumors. The EBV viral proteins and RNAs were perhaps more likely to confer some prognostic information due to the fact that those molecules were related to carcinogenesis.

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Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Promotes EBV Reactivation through Activation of the p38 Mitogen-Activated Protein Kinase

Journal of Virology ◽

10.1128/jvi.01410-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 1129-1138 ◽

Cited By ~ 28

Author(s):

XueQiao Liu ◽

Jeffrey I. Cohen

Keyword(s):

Protein Kinase ◽

Signaling Pathways ◽

Epstein Barr Virus ◽

Virus Production ◽

Mitogen Activated Protein Kinase ◽

Tegument Protein ◽

Barr Virus ◽

Ebv Reactivation ◽

Mitogen Activated Protein ◽

Epstein Barr

ABSTRACTEpstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus associated with both B cell and epithelial cell malignancies. EBV infection of B cells triggers activation of several signaling pathways that are critical for cell survival, virus latency, and growth transformation. To identify EBV proteins important for regulating cell signaling, we used a proteomic approach to screen viral proteins for AP-1 and NF-κB promoter activity in AP-1– and NF-κB–luciferase reporter assays. We found that EBV BGLF2 activated AP-1 but not NF-κB reporter activity. Expression of EBV BGLF2 in cells activated p38 and c-Jun N-terminal kinase (JNK), both of which are important for mitogen-activated protein kinase (MAPK) signaling. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of BGLF2 to activate JNK and p38. Expression of BGLF2 enhanced BZLF1 expression in latently EBV-infected lymphoblastoid cell lines, and knockdown of BGLF2 reduced EBV reactivation induced by IgG cross-linking. Expression of BGLF2 induced BZLF1 expression and virus production in EBV-infected gastric carcinoma cells. BGLF2 enhanced BZLF1 expression and EBV production by activating p38; chemical inhibition of p38 and MAPK/ERK kinases 1 and 2 (MEK1/2) reduced expression of BZLF1 and virus production induced by BGLF2. In summary, the EBV tegument protein BGLF2, which is delivered to the cell at the onset of virus infection, activates the AP-1 pathway and enhances EBV reactivation and virus production.IMPORTANCEEpstein-Barr virus (EBV) is associated with both B cell and epithelial cell malignancies, and the virus activates multiple signaling pathways important for its persistence in latently infected cells. We identified a viral tegument protein, BGLF2, which activates members of the mitogen-activated protein kinase signaling pathway. Expression of BGLF2 increased expression of EBV BZLF1, which activates a switch from latent to lytic virus infection, and increased production of EBV. Inhibition of BGFL2 expression or inhibition of p38/MAPK, which is activated by BGLF2, reduced virus reactivation from latency. These results indicate that a viral tegument protein which is delivered to cells upon infection activates signaling pathways to enhance virus production and facilitate virus reactivation from latency.

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Cytolytic Epstein-Barr Virus Reactivation Therapy for EBV-Associated Gastric Carcinoma

Clinical Oncology and Research ◽

10.31487/j.cor.2020.07.08 ◽

2020 ◽

pp. 1-10

Author(s):

Jaap M. Middeldorp ◽

Zlata Novalić ◽

Sandra A.W.M. Verkuijlen ◽

Astrid E. Greijer ◽

Jaap M. Middeldorp

Keyword(s):

Gastric Carcinoma ◽

Mouse Model ◽

Cell Lines ◽

Epstein Barr Virus ◽

Drug Combinations ◽

Model Systems ◽

Virus Reactivation ◽

Barr Virus ◽

Ebv Reactivation ◽

Epstein Barr

Background: Epstein-Barr virus associated gastric carcinoma (EBVaGC) is considered a distinct GC disease entity, with the virus persisting in a latent phase. Treatment with Epirubicin, Capecitabine and Cisplatin (ECC combination) showed survival benefit in patients with GC in clinical trials (MAGIC study and CRITICS study) when compared to chemotherapy with Capecitabine and Cisplatin (GCb/Cis). Current treatment protocols for GC do not consider virus involvement. Methods: In this study, we tested a CytoLytic Virus Activation (CLVA) strategy consisting of the ECC combination or GCb/Cis together with the HDAC inhibitor Valproic acid (VPA) to define whether EBV reactivation and subsequent antiviral treatment with Ganciclovir (GCV) could be used as virus-targeted therapy for EBVaGC. Drug combinations with VPA and GCV were evaluated in multiple cell lines and in an EBVaGC mouse model based on human naturally EBV-infected SNU-719 cells. Results: EBV reactivation was demonstrated by lytic mRNA transcripts and proteins in treated cells, and the virus-reactivating capacity of different CLVA drug combinations was compared in C666.1, AGS-BX1 and SNU-719 cell lines. In an EBVaGC mouse model, GCb/Cis with VPA and GCV strongly reduced tumor volume and showed the highest potential for EBV-reactivation. Upon a single round of CLVA treatment, EBV DNA levels in circulation decreased, and loss of EBV-positive cells in treated tumors was observed. In vivo EBV-reactivation was revealed by the presence of lytic gene transcripts and proteins in tumor tissues 6 days after treatment. Conclusion: In EBVaGC model systems, CLVA treatment showed a more potent virus reactivation and killing of tumor cells when compared to standard chemotherapy alone, suggesting that addition of VPA plus GCV to the ECC or GCb/Cis combination should be considered in future clinical studies.

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Clinical characteristics and outcomes of critically ill patients with acute COVID-19 with Epstein-Barr virus reactivation

BMC Infectious Diseases ◽

10.1186/s12879-021-06638-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yun Xie ◽

Song Cao ◽

Hui Dong ◽

Hui Lv ◽

Xiaolei Teng ◽

...

Keyword(s):

Epstein Barr Virus ◽

Mortality Rates ◽

Virus Reactivation ◽

Barr Virus ◽

Ebv Reactivation ◽

Imaging Characteristics ◽

Single Center Study ◽

Significant Difference ◽

Epstein Barr ◽

Epstein Barr Virus Reactivation

Abstract Background Our goal is to further elucidate the clinical condition and prognosis of patients with severe acute COVID-19 with EBV reactivation. Method This is a retrospective single-center study of COVID-19 patients admitted to the intensive care unit of Wuhan No. 3 Hospital (January 31 to March 27, 2020). According to whether Epstein-Barr virus reactivation was detected, the patients were divided into an EBV group and a Non-EBV group. Baseline data were collected including epidemiological, larithmics, clinical and imaging characteristics, and laboratory examination data. Results Of the 128 patients with COVID-19, 17 (13.3%) were infected with Epstein-Barr virus reactivation. In the symptoms,the rate of tachypnoea in the EBV group was apparently higher than that in the Non-EBV group. In lab tests, the lymphocyte and albumin of EBV group decreased more significantly than Non-EBV group, and the D-dimer and serum calcium of EBV group was higher than Non-EBV group. Regarding the infection index, CRP of EBV group was apparently above the Non-EBV group, and no significant difference was found in procalcitonin of the two groups. The incidence of respiratory failure, ARDS, and hypoproteinaemia of EBV group had more incidence than Non-EBV group. The 28-day and 14-day mortality rates of EBV group was significantly higher than that of Non-EBV group. Conclusions In the COVID-19 patients, patients with EBV reactivation had higher 28-day and 14-day mortality rates and received more immuno-supportive treatment than patients of Non-EBV group.

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Acyclovir Improves the Efficacy of Chemoradiation in Nasopharyngeal Cancer Containing the Epstein Barr Virus Genome

10.1101/2020.10.18.343236 ◽

2020 ◽

Author(s):

Aditya Thandoni ◽

Andrew Zloza ◽

Devora Schiff ◽

Malay Rao ◽

Kwok-wai Lo ◽

...

Keyword(s):

Epstein Barr Virus ◽

Treatment Options ◽

Immune Surveillance ◽

Nasopharyngeal Cancer ◽

Standard Of Care ◽

Virus Genome ◽

Barr Virus ◽

Standard Of Care Treatment ◽

Epstein Barr

AbstractNasopharyngeal carcinoma (NPC) is a malignancy endemic to East Asia and is caused by Epstein-Barr Virus (EBV)-mediated cancerous transformation of epithelial cells. The standard of care treatment for NPC involves radiation and chemotherapy. While treatment outcomes continue to improve, up to 50% of patients can be expected to recur by five years, and additional innovative treatment options are needed. We posit that a potential way to do this is by targeting the underlying cause of malignant transformation, namely EBV. One method by which EBV escapes immune surveillance is by undergoing latent phase replication, during which EBV expression of immunogenic proteins is reduced. However, chemoradiation is known to drive conversion of EBV from a latent to a lytic phase. This creates an opportunity for the targeting of EBV-infected cells utilizing anti-viral drugs. Indeed, we found that combining acyclovir with cisplatin and radiation significantly decreases the viability of the EBV-infected C666-1 cell line. Western blot quantification revealed a resultant increase of thymidine kinase (TK) and apoptosis-inducing mediators, cleaved PARP (cPARP) and phosphorylated ERK (pERK). These studies suggest that the addition of anti-viral drugs to frontline chemoradiation may improve outcomes in patients treated for EBV-related NPC and future in vivo and clinical studies are needed.

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Conserved Peptide with Therapeutic Potential to Overcome Nasopharyngeal Carcinoma

IIUM Medical Journal Malaysia ◽

10.31436/imjm.v13i1.490 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Muhaimin R ◽

Widyarti S ◽

Widodo N

Keyword(s):

B Cells ◽

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Therapeutic Potential ◽

Nasopharyngeal Cancer ◽

Passive Immunization ◽

Spleen Cells ◽

Specific Antibodies ◽

Barr Virus ◽

Epstein Barr

Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma that arises in the upper lining epithelium of the nasopharynx. In this study, conserved peptide (Ulin-1) of Epstein-Barr virus constructed by Biomodelling and Biocomputation was tested for its ability to stimulate B cells to produce specific antibodies. Spleen cells were isolated and cultured with anti-CD3 and lipopolysaccharide (LPS), and treated or not treated with Ulin-1. Cell culture was harvested six days after incubation and analyzed by flow cytometry. Here, we demonstrated the ability of Ulin-1 to stimulate B cells to produce specific antibodies. The results of this study illustrate the importance of Ulin-1 engineered by Biomodelling and Biocomputation as both active and passive immunization agents against nasopharyngeal cancer.

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