Epstein–Barr Virus Strain Variation

Farrell, Paul J.

doi:10.1007/978-3-319-22822-8_4

Cited by 39 publications

(47 citation statements)

References 156 publications

(162 reference statements)

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“…The high incidence of some EBV-associated cancers in Asian populations, particularly NPC in Cantonese people, suggest a geographic variant that is in some way more oncogenic. The largest contributor to PC2 (2) was LMP1, and variation in LMP1 has been discussed extensively in relation to NPC and tumorigenicity in animal model systems (reviewed in reference 3). The high expression level of BART miRNAs in NPC and demonstration that BART miRNAs can mediate the tumorigenicity of EBV in an animal carcinoma model system (15) is also of interest, because part of PC2 was accounted for by variation in the BART miRNA cluster 2 region (2), which is part of the long pri-miRNA (primary miRNA) transcript from which BART miRNAs are processed.…”

Section: Resultsmentioning

confidence: 99%

“…Type 2 EBV is known to be relatively more frequent in people in sub-Saharan Africa and New Guinea than other parts of the world (3). Several studies have reported type 2 EBV infection in European or U.S. populations but studied either HIV-infected people (4) or healthy subjects and did not define the ethnicity of the EBV-infected people (5).…”

Section: Introductionmentioning

confidence: 99%

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Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA

Correia

Palser

Karstegl

et al. 2017

J Virol

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112

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Viral gene sequences from an enlarged set of about 200 Epstein-Barr virus (EBV) strains, including many primary isolates, have been used to investigate variation in key viral genetic regions, particularly LMP1, Zp, gp350, EBNA1, and the BART microRNA (miRNA) cluster 2. Determination of type 1 and type 2 EBV in saliva samples from people from a wide range of geographic and ethnic backgrounds demonstrates a small percentage of healthy white Caucasian British people carrying predominantly type 2 EBV. Linkage of Zp and gp350 variants to type 2 EBV is likely to be due to their genes being adjacent to the EBNA3 locus, which is one of the major determinants of the type 1/type 2 distinction. A novel classification of EBNA1 DNA binding domains, named QCIGP, results from phylogeny analysis of their protein sequences but is not linked to the type 1/type 2 classification. The BART cluster 2 miRNA region is classified into three major variants through single-nucleotide polymorphisms (SNPs) in the primary miRNA outside the mature miRNA sequences. These SNPs can result in altered levels of expression of some miRNAs from the BART variant frequently present in Chinese and Indonesian nasopharyngeal carcinoma (NPC) samples. The EBV genetic variants identified here provide a basis for future, more directed analysis of association of specific EBV variations with EBV biology and EBV-associated diseases.IMPORTANCE Incidence of diseases associated with EBV varies greatly in different parts of the world. Thus, relationships between EBV genome sequence variation and health, disease, geography, and ethnicity of the host may be important for understanding the role of EBV in diseases and for development of an effective EBV vaccine. This paper provides the most comprehensive analysis so far of variation in specific EBV genes relevant to these diseases and proposed EBV vaccines. By focusing on variation in LMP1, Zp, gp350, EBNA1, and the BART miRNA cluster 2, new relationships with the known type 1/type 2 strains are demonstrated, and a novel classification of EBNA1 and the BART miRNAs is proposed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA

Correia

Palser

Karstegl

et al. 2017

J Virol

Self Cite

112

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“…It is now clear that there are a large number of viral gene polymorphisms among EBV strains and that many of these are found in viral latent genes (4,5). The possibility that EBV variant strains exist that are relevant to EBV-associated diseases has started to attract interest (7,28,33). Clearly, it will be important to sequence more diseaseassociated viral genomes and to reconstitute and experimentally test such viruses in order to determine whether they behave differently from nonpathogenic strains.…”

Section: Discussionmentioning

confidence: 99%

Highly Efficient CRISPR/Cas9-Mediated Cloning and Functional Characterization of Gastric Cancer-Derived Epstein-Barr Virus Strains

Kanda

Furuse

Oshitani

et al. 2016

J Virol

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The Epstein-Barr virus (EBV) is etiologically linked to approximately 10% of gastric cancers, in which viral genomes are maintained as multicopy episomes. EBV-positive gastric cancer cells are incompetent for progeny virus production, making viral DNA cloning extremely difficult. Here we describe a highly efficient strategy for obtaining bacterial artificial chromosome (BAC) clones of EBV episomes by utilizing a CRISPR/Cas9-mediated strand break of the viral genome and subsequent homology-directed repair. EBV strains maintained in two gastric cancer cell lines (SNU719 and YCCEL1) were cloned, and their complete viral genome sequences were determined. Infectious viruses of gastric cancer cell-derived EBVs were reconstituted, and the viruses established stable latent infections in immortalized keratinocytes. While Ras oncoprotein overexpression caused massive vacuolar degeneration and cell death in control keratinocytes, EBV-infected keratinocytes survived in the presence of Ras expression. These results implicate EBV infection in predisposing epithelial cells to malignant transformation by inducing resistance to oncogene-induced cell death. IMPORTANCERecent progress in DNA-sequencing technology has accelerated EBV whole-genome sequencing, and the repertoire of sequenced EBV genomes is increasing progressively. Accordingly, the presence of EBV variant strains that may be relevant to EBV-associated diseases has begun to attract interest. Clearly, the determination of additional disease-associated viral genome sequences will facilitate the identification of any disease-specific EBV variants. We found that CRISPR/Cas9-mediated cleavage of EBV episomal DNA enabled the cloning of disease-associated viral strains with unprecedented efficiency. As a proof of concept, two gastric cancer cell-derived EBV strains were cloned, and the infection of epithelial cells with reconstituted viruses provided important clues about the mechanism of EBV-mediated epithelial carcinogenesis. This experimental system should contribute to establishing the relationship between viral genome variation and EBV-associated diseases. E pstein-Barr virus (EBV) is one of the most widespread human pathogens. EBV infection is usually asymptomatic, but it sometimes causes severe disorders, such as EBV-related lymphoproliferative disease, B-cell lymphomas, and NK/T-cell lymphomas (1). In addition, causal relationships between EBV infection and epithelial cell-derived cancers, such as nasopharyngeal carcinomas (NPCs) and gastric cancers, have been investigated extensively (2, 3). However, the precise mechanisms underlying EBV-mediated epithelial carcinogenesis remain largely unknown.Recent deep-sequencing studies demonstrated unexpected levels of heterogeneity in EBV genomes derived from various EBV-positive cell lines, including Burkitt's lymphoma-derived cell lines (4), spontaneously established lymphoblastoid cell lines (LCLs), Hodgkin's lymphoma cell lines, NPC-derived cell lines, a gastric cancer-derived cell line (5), and NPC biopsy samples ...

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“…Next-generation sequencing has revealed large numbers of polymorphisms in the latency-associated genes of EBV (Palser et al, 2015). Notably, a single amino acid polymorphism in EBNA2 confers more efficient immortalization of primary B-lymphocytes (Farrell, 2015), variants in LMP1 are enriched in nasopharyngeal carcinoma (NPC) (Edwards et al, 2004), deletions of EBNA2 are found in Burkitt’s lymphoma (BL) (Kelly et al, 2009), mutations in EBNA3B in Diffuse Large B cell Lymphoma (DLBCL) (White et al, 2012), and mutations in RPMS1 protein correlate with increase NPC risk (Feng et al, 2015). Viruses derived from NPC were also found to have mutations that increased spontaneous lytic reactivity and epithelial cell tropism (Tsai et al, 2013).…”

Section: Genetic Diversity: Strains and Polymorphismsmentioning

confidence: 99%

Epigenetics and Genetics of Viral Latency

Lieberman

2016

Cell Host & Microbe

122

118

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Viral latency can be considered a metastable, nonproductive infection state that is capable of subsequent reactivation to repeat the infection cycle. Viral latent infections have numerous associated pathologies, including cancer, birth defects, neuropathy, cardiovascular disease, chronic inflammation, and immunological dysfunctions. The mechanisms controlling the establishment, maintenance, and reactivation from latency are complex and diversified among virus families, species, and strains. Yet, as examined in this review, common properties of latent viral infections can be defined. Eradicating latent virus has become an important but elusive challenge and will require a more complete understanding of the mechanisms controlling these processes.

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Epstein–Barr Virus Strain Variation

Cited by 39 publications

References 156 publications

Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA

Natural Variation of Epstein-Barr Virus Genes, Proteins, and Primary MicroRNA

Highly Efficient CRISPR/Cas9-Mediated Cloning and Functional Characterization of Gastric Cancer-Derived Epstein-Barr Virus Strains

Epigenetics and Genetics of Viral Latency

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