Spontaneous lymphoblastoid cell lines from patients with Epstein-Barr virus infection show highly variable proliferation characteristics that correlate with the expression levels of viral microRNAs

Delecluse, Susanne; Yu, Jiyang; Bernhardt, Katharina; Haar, Janina; Poirey, Rémy; Tsai, Ming Han; Kiblawi, Rama; Kopp‐Schneider, Annette; Schnitzler, Paul; Zeier, Martin; Dreger, Peter; Wuchter, Patrick; Bulut, Olcay Cem; Behrends, Uta; Delecluse, Henri Jacques

doi:10.1371/journal.pone.0222847

Cited by 6 publications

(5 citation statements)

References 37 publications

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“…Notable differences in the levels of the different BART and BHRF1 miRNA are observed in different EBV-positive tumors, even of the same type [59][60][61]. It has been suggested that this could be because of strain variations [62,63]; in one study, variations in transformation potential between different virus isolates were associated with different levels of BHRF1 miRNA [64]. There could also be technical reasons for the differences observed between studies.…”

Section: Classical Hodgkin's Lymphomamentioning

confidence: 97%

MicroRNA and Other Non-Coding RNAs in Epstein–Barr Virus-Associated Cancers

Notarte

Senanayake

Macaranas

et al. 2021

Cancers

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EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.

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Section: Classical Hodgkin's Lymphomamentioning

confidence: 97%

MicroRNA and Other Non-Coding RNAs in Epstein–Barr Virus-Associated Cancers

Notarte

Senanayake

Macaranas

et al. 2021

Cancers

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“…2C). We have previously reported a correlation between the growing characteristics of our sLCL panel and their miRNA expression profile (10). This gave us an opportunity to assess the relation between miRNA expression and lytic replication.…”

Section: Introductionmentioning

confidence: 80%

Identification and Cloning of a New Western Epstein-Barr Virus Strain That Efficiently Replicates in Primary B Cells

Delecluse

Poirey

Zeier

et al. 2020

J Virol

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The Epstein-Barr virus (EBV) causes human cancers, and epidemiological studies have shown that lytic replication is a risk factor for some of these tumors. This fits with the observation that EBV M81, which was isolated from a Chinese patient with nasopharyngeal carcinoma, induces potent virus production and increases the risk of genetic instability in infected B cells. To find out whether this property extends to viruses found in other parts of the world, we investigated 22 viruses isolated from Western patients. While one-third of the viruses hardly replicated, the remaining viruses showed variable levels of replication, with three isolates replicating at levels close to that of M81 in B cells. We cloned one strongly replicating virus into a bacterial artificial chromosome (BAC); the resulting recombinant virus (MSHJ) retained the properties of its nonrecombinant counterpart and showed similarities to M81, undergoing lytic replication in vitro and in vivo after 3 weeks of latency. In contrast, B cells infected with the nonreplicating Western B95-8 virus showed early but abortive replication accompanied by cytoplasmic BZLF1 expression. Sequencing confirmed that rMSHJ is a Western virus, being genetically much closer to B95-8 than to M81. Spontaneous replication in rM81- and rMSHJ-infected B cells was dependent on phosphorylated Btk and was inhibited by exposure to ibrutinib, opening the way to clinical intervention in patients with abnormal EBV replication. As rMSHJ contains the complete EBV genome and induces lytic replication in infected B cells, it is ideal to perform genetic analyses of all viral functions in Western strains and their associated diseases. IMPORTANCE The Epstein-Barr virus (EBV) infects the majority of the world population but causes different diseases in different countries. Evidence that lytic replication, the process that leads to new virus progeny, is linked to cancer development is accumulating. Indeed, viruses such as M81 that were isolated from Far Eastern nasopharyngeal carcinomas replicate strongly in B cells. We show here that some viruses isolated from Western patients, including the MSHJ strain, share this property. Moreover, replication of both M81 and of MSHJ was sensitive to ibrutinib, a commonly used drug, thereby opening an opportunity for therapeutic intervention. Sequencing of MSHJ showed that this virus is quite distant from M81 and is much closer to nonreplicating Western viruses. We conclude that Western EBV strains are heterogeneous, with some viruses being able to replicate more strongly and therefore being potentially more pathogenic than others, and that the virus sequence information alone cannot predict this property.

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“…It was additionally shown that EBV-specific T cells can comprise up to 20% of all T cells within the tonsils (36). This T cell accumulation might be driven by EBV-induced B cell proliferation during IM-like primary infection (70, 71). EBV-infected B cells within the NALT seem to expand similarly during infection, which likely leads to enhanced T cell recruitment and stimulation in the NALT.…”

Section: Discussionmentioning

confidence: 99%

Epstein Barr virus infection induces tissue-resident memory T cells in mucosal lymphoid tissues

Kirchmeier,

Deng,

Rieble

et al. 2023

Preprint

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Epstein Barr virus (EBV) contributes to around 2% of all tumors worldwide. Simultaneously, more than 90% of healthy human adults persistently carry EBV without clinical symptoms. In most EBV carriers it is thought that virus-induced tumorigenesis is prevented by cell-mediated immunity. Specifically, memory CD8+T cells recognize EBV-infected cells during latent and lytic infection.Using a symptomatic primary infection model, similar to infectious mononucleosis (IM), we found EBV induced CD8+tissue resident memory T cells (TRMs) in mice with a humanized immune system. These human TRMs were preferentially established after intranasal EBV infection in nasal-associated lymphoid tissues (NALT), equivalent to tonsils, the primary site of EBV infection in humans. They expressed canonical TRM markers, including CD69, CD103 and BLIMP-1, as well as Granzyme B, CD107a and CCL5, while demonstrating reduced CD27 expression and proliferation by Ki-67 expression. Despite cytotoxic activity and cytokine productionex vivo, these TRMs failed to control EBV viral loads in the NALT during infection although effector memory T cells (TEMs) controlled viral titers in spleen and blood.Overall, TRMs in mucosal lymphoid tissues are established by EBV infection, but primarily systemic CD8+T cell expansion seems to attenuate viral loads in the context of IM-like infection.

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Spontaneous lymphoblastoid cell lines from patients with Epstein-Barr virus infection show highly variable proliferation characteristics that correlate with the expression levels of viral microRNAs

Cited by 6 publications

References 37 publications

MicroRNA and Other Non-Coding RNAs in Epstein–Barr Virus-Associated Cancers

MicroRNA and Other Non-Coding RNAs in Epstein–Barr Virus-Associated Cancers

Identification and Cloning of a New Western Epstein-Barr Virus Strain That Efficiently Replicates in Primary B Cells

Epstein Barr virus infection induces tissue-resident memory T cells in mucosal lymphoid tissues

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