Identification and cloning of a new western Epstein-Barr virus strain that replicates efficiently in primary B cells.
Fiche publication
Date publication
février 2020
Journal
Journal of virology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DELECLUSE Henri-Jacques
Tous les auteurs :
Delecluse S, Poirey R, Zeier M, Schnitzler P, Behrends U, Tsai MH, Delecluse HJ
Lien Pubmed
Résumé
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 that was isolated in 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 ones showed variable levels of replication with three isolates replicating at levels close to M81 in B-cells. We cloned one strongly replicating virus into a bacterial artificial chromosome; the resulting recombinant virus (MSHJ) retained the properties of its non-recombinant counterpart and showed similarities with M81, undergoing lytic replication and after three weeks of latency. In contrast, B-cells infected with the non-replicating western B95-8 virus showed an 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.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 East nasopharyngeal carcinomas replicate strongly in B-cells. We now show 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 much closer to non-replicating western viruses. We conclude that western EBV strains are heterogeneous, some viruses being able to replicate stronger and therefore being potentially more pathogenic than others, and that the virus sequence information alone cannot predict this property.
Référence
J. Virol.. 2020 Feb 26;: