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Abstract

The Epstein-Barr virus (EBV) infects the majority of the population. The EBV M81 strain isolated from a nasopharyngeal carcinoma (NPC) efficiently infects and transforms primary B cells, but it also induces potent virus lytic replication in a minority of these cells. We used recombinant viruses to reveal the function of the EBER RNAs. We found that the number of cells in which lytic replication takes place is increased both in vitro and in vivo by the non-coding RNA EBER2, but not by its homolog in the genome of the B95-8 strain. M81 and B95-8 EBER2 homologs displayed a limited number of polymorphisms, some of which influence their half-life and expression levels. M81 EBER2 modified the expression of a large number of cellular genes including CXCL8. This chemokine was able to compensate the absence of EBER2, suggesting that it represents the main target of this non-coding RNA. We found that the exosomal fraction of B cells infected with wild type M81 carries the EBER molecules, are able to increase CXCL8 and BZLF1 production. The effect of EBER2 on EBV lytic replication required a functional TLR7, a sensor of viral single- stranded RNA (ssRNA). Therefore, we propose a model in which EBERs are vehicled into the exosomal fraction of infected B cells to initiate lytic replication in a paracrine manner through CXCL8 secretion induced by TLR7 stimulation. These results indicate that EBERs NPC-derived virus variant contribute to lytic replication in B cells and activate production of a chemokine involved in carcinogenesis.