Hyperediting by ADAR1 of a new herpesvirus lncRNA during the lytic phase of the oncogenic Marek’s disease virus

Marek’s disease virus, or Gallid herpesvirus 2 (GaHV-2), is an avian alphaherpesvirus that induces T-cell lymphoma in chickens. During transcriptomic studies of the RL region of the genome, we characterized the 7.5 kbp gene of the ERL lncRNA (edited repeat-long, long noncoding RNA), which may act as a natural antisense transcript (NAT) of the major GaHV-2 oncogene meq and of two of the three miRNA clusters. During infections in vivo and in vitro, we detected hyperediting of the ERL lncRNA that appeared to be directly correlated with ADAR1 expression levels. The ERL lncRNA was expressed equally during the lytic and latent phases of infection and during viral reactivation, but its hyperediting increased only during the lytic infection of chicken embryo fibroblasts. We also showed that chicken ADAR1 expression was controlled by the JAK/STAT IFN-response pathway, through an inducible promoter containing IFNstimulated response elements that were functional during stimulation with IFN-α or poly(I:C). Like the human and murine miR-155-5p, the chicken gga-miR-155-5p and the GaHV-2 analogue mdv1-miR-M4-5p deregulated this pathway by targeting and repressing expression of suppressor of cytokine signalling 1, leading to the upregulation of ADAR1. Finally, we hypothesized that the natural antisense transcript role of the ERL lncRNA could be disrupted by its hyperediting, particularly during viral lytic replication, and that the observed deregulation of the innate immune system by mdv1-miR-M4-5p might contribute to the viral cycle.