scholarly journals Epstein–Barr Virus: How Its Lytic Phase Contributes to Oncogenesis

2020 ◽  
Vol 8 (11) ◽  
pp. 1824
Author(s):  
Quincy Rosemarie ◽  
Bill Sugden
Keyword(s):  
Epstein Barr Virus ◽  
Tumor Formation ◽  
Gene Products ◽  
Lytic Gene ◽  
Barr Virus ◽  
Oncogenic Pathways ◽  
Epstein Barr ◽  
Latent Phase

Epstein–Barr Virus (EBV) contributes to the development of lymphoid and epithelial malignancies. While EBV’s latent phase is more commonly associated with EBV-associated malignancies, there is increasing evidence that EBV’s lytic phase plays a role in EBV-mediated oncogenesis. The lytic phase contributes to oncogenesis primarily in two ways: (1) the production of infectious particles to infect more cells, and (2) the regulation of cellular oncogenic pathways, both cell autonomously and non-cell autonomously. The production of infectious particles requires the completion of the lytic phase. However, the regulation of cellular oncogenic pathways can be mediated by an incomplete (abortive) lytic phase, in which early lytic gene products contribute substantially, whereas late lytic products are largely dispensable. In this review, we discuss the evidence of EBV’s lytic phase contributing to oncogenesis and the role it plays in tumor formation and progression, as well as summarize known mechanisms by which EBV lytic products regulate oncogenic pathways. Understanding the contribution of EBV’s lytic phase to oncogenesis will help design ways to target it to treat EBV-associated malignancies.

scholarly journals Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection

2020 ◽  
Author(s):  
Tomoki Inagaki ◽  
Yoshitaka Sato ◽  
Jumpei Ito ◽  
Mitsuaki Takaki ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Viral Infection ◽  
Epstein Barr Virus ◽  
Lytic Infection ◽  
Lytic Gene ◽  
Barr Virus ◽  
Ebv Infection ◽  
Infected Cells ◽  
Epstein Barr ◽  
Viral Responses ◽  
Latent Phase

AbstractViral infection induces dynamic changes in transcriptional profiles. Virus-induced and anti-viral responses are intertwined during the infection. Epstein-Barr virus (EBV) is a human gammaherpesvirus that provides a model of herpesvirus latency. To measure the transcriptome changes during the establishment of EBV latency, EBV-negative Akata cells were infected with EBV-EGFP and observed by transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 10, and 14 days after infection. We found transient downregulation of mitotic division-related genes, reflecting reprograming of cell growth by EBV. Moreover, a burst of viral lytic gene expression was detected in the early phase of infection. Experimental and mathematical investigations demonstrated that infectious virions were not produced in the pre-latent phase, suggesting the presence of an abortive lytic infection. Finally, we conducted fate mapping using recombinant EBV, enabling the noninvasive, continuous observation of infected cells during EBV infection. Our tracking analysis provided direct evidence that the abortive lytic infection in the pre-latent phase converges to latent infection during EBV infection of B-cells, shedding light on novel roles of viral lytic gene(s) in establishing latency.Author summaryViral infection is a complex process that activates both virus-triggered and host anti-viral responses. This process has classically been studied by snapshot analysis such as microarray and RNA-seq at discrete time points as population averages. Snapshot data lead to invaluable findings in host-pathogen interactions. However, these “snapshot” omics, even from a single cell, lack temporal resolution. Because the behavior of infected cells is highly dynamic and heterogenous, continuous analysis is required for deciphering the fate of infected cells during viral infection. Here, we exploited fate mapping techniques with recombinant Epstein-Barr virus (EBV) to track the infected cells and recorded a log of lytic gene expression during EBV infection. Our continuous observation of infected cells revealed that EBV established latency in B-cells via an abortive lytic infection in the pre-latent phase.

scholarly journals Direct Evidence of Abortive Lytic Infection-Mediated Establishment of Epstein-Barr Virus Latency During B-Cell Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Tomoki Inagaki ◽  
Yoshitaka Sato ◽  
Jumpei Ito ◽  
Mitsuaki Takaki ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Direct Evidence ◽  
Lytic Infection ◽  
Viral Gene ◽  
Cell Infection ◽  
Gene Expressions ◽  
Lytic Gene ◽  
Barr Virus ◽  
Epstein Barr ◽  
Latent Phase

Viral infection induces dynamic changes in transcriptional profiles. Virus-induced and antiviral responses are intertwined during the infection. Epstein-Barr virus (EBV) is a human gammaherpesvirus that provides a model of herpesvirus latency. To measure the transcriptome changes during the establishment of EBV latency, we infected EBV-negative Akata cells with EBV-EGFP and performed transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 10, and 14 days after infection. We found transient downregulation of mitotic division-related genes, reflecting reprogramming of cell growth by EBV, and a burst of viral lytic gene expression in the early phase of infection. Experimental and mathematical investigations demonstrate that infectious virions were not produced in the pre-latent phase, suggesting the presence of an abortive lytic infection. Fate mapping using recombinant EBV provided direct evidence that the abortive lytic infection in the pre-latent phase converges to latent infection during EBV infection of B-cells, shedding light on novel roles of viral lytic gene(s) in establishing latency. Furthermore, we find that the BZLF1 protein, which is a key regulator of reactivation, was dispensable for abortive lytic infection in the pre-latent phase, suggesting the divergent regulation of viral gene expressions from a productive lytic infection.

scholarly journals Role of BamHI-A Rightward Frame 1 in Epstein–Barr Virus-Associated Epithelial Malignancies

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 461
Author(s):  
Rancés Blanco ◽  
Francisco Aguayo
Keyword(s):  
Epstein Barr Virus ◽  
Immune Escape ◽  
Tumor Formation ◽  
Host Proteins ◽  
Barr Virus ◽  
Functional Aspects ◽  
Infected Cells ◽  
Epstein Barr ◽  
Apoptotic Effects

Epstein–Barr virus (EBV) infection is associated with a subset of both lymphoid and epithelial malignancies. During the EBV latency program, some viral products involved in the malignant transformation of infected cells are expressed. Among them, the BamHI-A rightward frame 1 (BARF1) is consistently detected in nasopharyngeal carcinomas (NPC) and EBV-associated gastric carcinomas (EBVaGCs) but is practically undetectable in B-cells and lymphomas. Although BARF1 is an early lytic gene, it is expressed during epithelial EBV latency, mainly as a secreted protein (sBARF1). The capacity of sBARF1 to disrupt both innate and adaptive host antiviral immune responses contributes to the immune escape of infected cells. Additionally, BARF1 increases cell proliferation, shows anti-apoptotic effects, and promotes an increased hTERT activity and tumor formation in nude mice cooperating with other host proteins such as c-Myc and H-ras. These facts allow for the consideration of BARF1 as a key protein for promoting EBV-associated epithelial tumors. In this review, we focus on structural and functional aspects of BARF1, such as mechanisms involved in epithelial carcinogenesis and its capacity to modulate the host immune response.

scholarly journals Malignant Transformation of Epstein-Barr Virus-Negative Akata Cells by Introduction of the BARF1 Gene Carried by Epstein-Barr Virus

2003 ◽  
Vol 77 (6) ◽  
pp. 3859-3865 ◽  
Author(s):  
Wang Sheng ◽  
Gisèle Decaussin ◽  
Audrey Ligout ◽  
Kenzo Takada ◽  
Tadamasa Ooka
Keyword(s):  
Cell Line ◽  
Tumor Cells ◽  
Malignant Transformation ◽  
Epstein Barr Virus ◽  
Dna Binding Protein ◽  
Tumor Formation ◽  
Scid Mice ◽  
Barr Virus ◽  
Epstein Barr ◽  
Human B Cell

ABSTRACT Spontaneous loss of the Epstein-Barr virus (EBV) genome in the BL cell line Akata led to loss of tumorigenicity in SCID mice, suggesting an important oncogenic activity of EBV in B cells. We previously showed that introduction of the BARF1 gene into the human B-cell line Louckes induced a malignant transformation in newborn rats (M. X. Wei, J. C. Moulin, G. Decaussin, F. Berger, and T. Ooka, Cancer Res. 54:1843-1848, 1994). Since 1 to 2% of Akata cells expressed lytic antigens and expressed the BARF1 gene, we investigated whether introduction of the BARF1 gene into EBV-negative Akata cells can induce malignant transformation. Here we show that BARF1-transfected, EBV-negative Akata cells activated Bcl2 expression and induced tumor formation when they were injected into SCID mice. In addition, when EBV-positive Akata cells expressing a low level of BARF1 protein were injected into SCID mice, the expression of BARF1, as well as several lytic proteins, such as EA-D, ZEBRA, and a 135-kDa DNA binding protein, increased in tumor cells while no latent LMP1 and late gp220-320 expression was observed in tumor cells. These observations suggest that the BARF1 gene may be involved in the conferral of tumorigenicity by EBV.

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