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Viruses
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Epstein-Barr Virus Replication and Pathogenesis
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Epstein-Barr Virus Replication and Pathogenesis

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (10 December 2023) | Viewed by 24756

Special Issue Editors

Dr. Zhi-Ming Zheng

E-Mail Website
Guest Editor
Tumor Virus RNA Biology Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
Interests: HPV; KSHV; tumor viruses; RNA splicing; RNA-protein interactions; noncoding RNA; RNA processing
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Erle S. Robertson

E-Mail Website
Guest Editor
Department of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: DNA viruses; oncogenic viruses; microbiome and cancer; infection-related autoimmunity; cancer biology; infectious diseases; pandemics; inflammation and cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is being developed to bring new insights into major EBV-associated pathologies into focus and to provide insights into the role of EBV, the first human oncogenic virus identified, in driving these pathologies. The issue provides a more clinical and translational component to the discussion of EBV as an oncovirus. We will provide the history and a general overview of the pathologies associated with EBV, the genome annotation that is so critical given updated information from next-generation sequencing that has contributed to a more comprehensive identification of ORFs and small non-coding RNAs, gene expression, reactivation, as well as the infection of epithelial cells and latent infection in nasopharyngeal carcinomas. We will also provide a review of the characteristics of the latent antigens and what is currently known about EBV-induced infectious mononucleosis, gastric cancers, lymphomas, and the more recently described association with multiple sclerosis. Additionally, we will provide insights into the role of EBV in oral cancer that is co-infected with other oncogenic viruses and how it may impact the pathogenesis. These reviews are intended to promote new avenues for research and provide a platform for new thoughts concerning the role of this ubiquitous human virus in a range of different pathologies that has a global impact on the world’s population.

Dr. Zhi-Ming Zheng
Prof. Dr. Erle S. Robertson
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

Jump to: Review

18 pages, 3043 KiB  
Article
Development of a Rapid Epstein–Barr Virus Detection System Based on Recombinase Polymerase Amplification and a Lateral Flow Assay
by Yidan Sun, Danni Tang, Nan Li, Yudong Wang, Meimei Yang and Chao Shen
Viruses 2024, 16(1), 106; https://doi.org/10.3390/v16010106 - 11 Jan 2024
Viewed by 846
Abstract
The quality of cellular products used in biological research can directly impact the ability to obtain accurate results. Epstein–Barr virus (EBV) is a latent virus that spreads extensively worldwide, and cell lines used in experiments may carry EBV and pose an infection risk. [...] Read more.
The quality of cellular products used in biological research can directly impact the ability to obtain accurate results. Epstein–Barr virus (EBV) is a latent virus that spreads extensively worldwide, and cell lines used in experiments may carry EBV and pose an infection risk. The presence of EBV in a single cell line can contaminate other cell lines used in the same laboratory, affecting experimental results. We developed three EBV detection systems: (1) a polymerase chain reaction (PCR)-based detection system, (2) a recombinase polymerase amplification (RPA)-based detection system, and (3) a combined RPA-lateral flow assay (LFA) detection system. The minimum EBV detection limits were 1 × 103 copy numbers for the RPA-based and RPA-LFA systems and 1 × 104 copy numbers for the PCR-based system. Both the PCR and RPA detection systems were applied to 192 cell lines, and the results were consistent with those obtained by the EBV assay methods specified in the pharmaceutical industry standards of the People’s Republic of China. A total of 10 EBV-positive cell lines were identified. The combined RPA-LFA system is simple to operate, allowing for rapid result visualization. This system can be implemented in laboratories and cell banks as part of a daily quality control strategy to ensure cell quality and experimental safety and may represent a potential new technique for the rapid detection of EBV in clinical samples. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Replication and Pathogenesis)
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16 pages, 2851 KiB  
Article
The Impact of Deleting Stem-Loop 1 of Epstein–Barr Virus-Encoded RNA 1 on Cell Proliferation
by Zubaida Hassan, Pretty S. Philip and Gulfaraz Khan
Viruses 2022, 14(11), 2538; https://doi.org/10.3390/v14112538 - 16 Nov 2022
Viewed by 1611
Abstract
Epstein–Barr virus-encoded RNAs (EBERs) are two small, noncoding, structurally conserved transcripts, constitutively expressed at >106 copies per EBV-infected cell. They have been shown to drive cell growth. However, the mechanism(s) involved in EBER-induced proliferation is not clear. In this study, we investigated [...] Read more.
Epstein–Barr virus-encoded RNAs (EBERs) are two small, noncoding, structurally conserved transcripts, constitutively expressed at >106 copies per EBV-infected cell. They have been shown to drive cell growth. However, the mechanism(s) involved in EBER-induced proliferation is not clear. In this study, we investigated the molecular mechanisms and structural impact of EBER1. Sequences of EBER1 stem-loops (SL) 1, 3, and 4 were deleted, creating three mutants: ∆SL1, ∆SL3, and ∆SL4. These mutants were cloned into pHebo plasmids and expressed in Jurkat cell lines. Cells transfected with wildtype EBER1 and pHebo were used as controls. Cell proliferation was monitored by microscopy and flow cytometry. Microarray, qPCR, and Western blotting were used to investigate the cell cycle markers. We found significantly higher cell proliferation in wildtype EBER1 cells compared to pHebo, ∆SL1, and ∆SL3, but not ∆SL4 mutants. There was also significant upregulation of S-phase and G2/M phase markers in wildtype EBER1 and ∆SL4 mutant. Furthermore, CDT1, a factor for DNA replication, was upregulated in wildtype EBER1 and ∆SL4 mutant. However, in ∆SL1 mutant, CDT1 was significantly downregulated and translocated to the cytoplasm. These data indicate that the structure of EBER1 is important in cell proliferation. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Replication and Pathogenesis)
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17 pages, 1619 KiB  
Article
Spatial Dispersal of Epstein–Barr Virus in South America Reveals an African American Variant in Brazilian Lymphomas
by Paula Alves, Marcella Larrate, Aruanã Garcia-Costa, Paulo Rohan, Bianca Ervatti Gama, Eliana Abdelhay, Edson Delatorre and Rocio Hassan
Viruses 2022, 14(8), 1762; https://doi.org/10.3390/v14081762 - 12 Aug 2022
Cited by 7 | Viewed by 1463
Abstract
Epstein–Barr virus (EBV) is a saliva-borne ɣ-herpesvirus associated with benign and malignant lymphoproliferation. EBV-mediated tumorigenic mechanisms are not fully understood and may be related to viral genetic variations. In this work, we characterize the genetic diversity of EBV from Brazil, assessing 82 samples [...] Read more.
Epstein–Barr virus (EBV) is a saliva-borne ɣ-herpesvirus associated with benign and malignant lymphoproliferation. EBV-mediated tumorigenic mechanisms are not fully understood and may be related to viral genetic variations. In this work, we characterize the genetic diversity of EBV from Brazil, assessing 82 samples derived from saliva from asymptomatic carriers (n = 45), biopsies of benign reactive hyperplasia (n = 4), and lymphomas (n = 33). Phylogenetic and phylogeographic analysis of the entire coding region of the LMP-1 was performed. Additionally, type 1/type 2 distinction by the EBNA3C gene and Zp variants were evaluated. Our results revealed a high diversity of EBV in Brazil, with the co-circulation of four main clades, described here as: Mediterranean (40.2%, n = 33), Raji/Argentine (39%, n = 32), B95-8 (6.1%, n = 5), and Asian II (1.2%, n = 1). The Raji/Argentine and Mediterranean clades were the most prevalent in South America (45% and 28%, respectively). The Raji/Argentine clade was associated with polymorphisms I124V/I152L, del30 bp, and ins15 bp (p < 0.0001, to all clades) and with a high haplotype diversity related to EBV type and Zp variants. We found that a Raji/Argentine subclade spread primarily from Brazil and later to other South American countries. Although no LMP1 variant has been directly associated with disease, the Raji/Argentine clade was predominantly clustered with lymphomas (61%) and the Mediterranean clade with non-malignant cases (59%) (p = 0.1). These data highlight the high genetic diversity of EBV circulating in Brazil, calling attention to a Raji-related variant with great recombination potential in Brazilian lymphomas. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Replication and Pathogenesis)
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Review

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13 pages, 680 KiB  
Review
Epstein–Barr Virus B Cell Growth Transformation: The Nuclear Events
by Bo Zhao
Viruses 2023, 15(4), 832; https://doi.org/10.3390/v15040832 - 24 Mar 2023
Cited by 3 | Viewed by 2279
Abstract
Epstein–Barr virus (EBV) is the first human DNA tumor virus identified from African Burkitt’s lymphoma cells. EBV causes ~200,000 various cancers world-wide each year. EBV-associated cancers express latent EBV proteins, EBV nuclear antigens (EBNAs), and latent membrane proteins (LMPs). EBNA1 tethers EBV episomes [...] Read more.
Epstein–Barr virus (EBV) is the first human DNA tumor virus identified from African Burkitt’s lymphoma cells. EBV causes ~200,000 various cancers world-wide each year. EBV-associated cancers express latent EBV proteins, EBV nuclear antigens (EBNAs), and latent membrane proteins (LMPs). EBNA1 tethers EBV episomes to the chromosome during mitosis to ensure episomes are divided evenly between daughter cells. EBNA2 is the major EBV latency transcription activator. It activates the expression of other EBNAs and LMPs. It also activates MYC through enhancers 400–500 kb upstream to provide proliferation signals. EBNALP co-activates with EBNA2. EBNA3A/C represses CDKN2A to prevent senescence. LMP1 activates NF-κB to prevent apoptosis. The coordinated activity of EBV proteins in the nucleus allows efficient transformation of primary resting B lymphocytes into immortalized lymphoblastoid cell lines in vitro. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Replication and Pathogenesis)
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19 pages, 2573 KiB  
Review
Epstein–Barr Virus History and Pathogenesis
by Hui Yu and Erle S. Robertson
Viruses 2023, 15(3), 714; https://doi.org/10.3390/v15030714 - 09 Mar 2023
Cited by 11 | Viewed by 7062
Abstract
Epstein–Barr virus (EBV) is the first identified human oncogenic virus that can establish asymptomatic life-long persistence. It is associated with a large spectrum of diseases, including benign diseases, a number of lymphoid malignancies, and epithelial cancers. EBV can also transform quiescent B lymphocytes [...] Read more.
Epstein–Barr virus (EBV) is the first identified human oncogenic virus that can establish asymptomatic life-long persistence. It is associated with a large spectrum of diseases, including benign diseases, a number of lymphoid malignancies, and epithelial cancers. EBV can also transform quiescent B lymphocytes into lymphoblastoid cell lines (LCLs) in vitro. Although EBV molecular biology and EBV-related diseases have been continuously investigated for nearly 60 years, the mechanism of viral-mediated transformation, as well as the precise role of EBV in promoting these diseases, remain a major challenge yet to be completely explored. This review will highlight the history of EBV and current advances in EBV-associated diseases, focusing on how this virus provides a paradigm for exploiting the many insights identified through interplay between EBV and its host during oncogenesis, and other related non-malignant disorders. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Replication and Pathogenesis)
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24 pages, 1127 KiB  
Review
EBV Association with Lymphomas and Carcinomas in the Oral Compartment
by B. J. H. Ward, Danielle L. Schaal, Ebubechukwu H. Nkadi and Rona S. Scott
Viruses 2022, 14(12), 2700; https://doi.org/10.3390/v14122700 - 01 Dec 2022
Cited by 1 | Viewed by 4403
Abstract
Epstein–Barr virus (EBV) is an oncogenic human herpesvirus infecting approximately 90% of the world’s population. The oral cavity serves a central role in the life cycle, transmission, and pathogenesis of EBV. Transmitted to a new host via saliva, EBV circulates between cellular compartments [...] Read more.
Epstein–Barr virus (EBV) is an oncogenic human herpesvirus infecting approximately 90% of the world’s population. The oral cavity serves a central role in the life cycle, transmission, and pathogenesis of EBV. Transmitted to a new host via saliva, EBV circulates between cellular compartments within oral lymphoid tissues. Epithelial cells primarily support productive viral replication, while B lymphocytes support viral latency and reactivation. EBV infections are typically asymptomatic and benign; however, the latent virus is associated with multiple lymphomas and carcinomas arising in the oral cavity. EBV association with cancer is complex as histologically similar cancers often test negative for the virus. However, the presence of EBV is associated with distinct features in certain cancers. The intrinsic ability of EBV to immortalize B-lymphocytes, via manipulation of survival and growth signaling, further implicates the virus as an oncogenic cofactor. A distinct mutational profile and burden have been observed in EBV-positive compared to EBV-negative tumors, suggesting that viral infection can drive alternative pathways that converge on oncogenesis. Taken together, EBV is also an important prognostic biomarker that can direct alternative therapeutic approaches. Here, we discuss the prevalence of EBV in oral malignancies and the EBV-dependent mechanisms associated with tumorigenesis. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Replication and Pathogenesis)
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17 pages, 1378 KiB  
Review
How EBV Infects: The Tropism and Underlying Molecular Mechanism for Viral Infection
by Guo-Long Bu, Chu Xie, Yin-Feng Kang, Mu-Sheng Zeng and Cong Sun
Viruses 2022, 14(11), 2372; https://doi.org/10.3390/v14112372 - 27 Oct 2022
Cited by 17 | Viewed by 6209
Abstract
The Epstein–Barr virus (EBV) is associated with a variety of human malignancies, including Burkitt’s lymphoma, Hodgkin’s disease, nasopharyngeal carcinoma and gastric cancers. EBV infection is crucial for the oncogenesis of its host cells. The prerequisite for the establishment of infection is the virus [...] Read more.
The Epstein–Barr virus (EBV) is associated with a variety of human malignancies, including Burkitt’s lymphoma, Hodgkin’s disease, nasopharyngeal carcinoma and gastric cancers. EBV infection is crucial for the oncogenesis of its host cells. The prerequisite for the establishment of infection is the virus entry. Interactions of viral membrane glycoproteins and host membrane receptors play important roles in the process of virus entry into host cells. Current studies have shown that the main tropism for EBV are B cells and epithelial cells and that EBV is also found in the tumor cells derived from NK/T cells and leiomyosarcoma. However, the process of EBV infecting B cells and epithelial cells significantly differs, relying on heterogenous glycoprotein–receptor interactions. This review focuses on the tropism and molecular mechanism of EBV infection. We systematically summarize the key molecular events that mediate EBV cell tropism and its entry into target cells and provide a comprehensive overview. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Replication and Pathogenesis)
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