LAUSR

Members of the Birnaviridae family, including infectious bursal disease virus (IBDV), exhibit a dual behavior, causing acute infections that are often followed by the establishment of lifelong persistent asymptomatic infections. Indeed, persistently infected specimens might act as efficient virus reservoirs, potentially contributing to virus dissemination. ABSTRACT Infectious bursal disease virus (IBDV), the best-characterized member of the Birnaviridae family, is a highly relevant avian pathogen causing both acute and persistent infections in different avian hosts. Here, we describe the establishment of clonal, long-term, productive persistent IBDV infections in DF-1 chicken embryonic fibroblasts. Although virus yields in persistently infected cells are exceedingly lower than those detected in acutely infected cells, the replication fitness of viruses isolated from persistently infected cells is higher than that of the parental virus. Persistently infected DF-1 and IBDV-cured cell lines derived from them do not respond to type I interferon (IFN). High-throughput genome sequencing revealed that this defect is due to mutations affecting the IFN-α/β receptor subunit 2 (IFNAR2) gene, resulting in the expression of IFNAR2 polypeptides harboring large C-terminal deletions that abolish the signaling capacity of IFN-α/β receptor complex. Ectopic expression of a recombinant chicken IFNAR2 gene efficiently rescues IFN-α responsiveness. IBDV-cured cell lines derived from persistently infected cells exhibit a drastically enhanced susceptibility to establishing new persistent IBDV infections. Additionally, experiments carried out with human HeLa cells lacking the IFNAR2 gene fully recapitulate results obtained with DF-1 cells, exhibiting a highly enhanced capacity to both survive the acute IBDV infection phase and to support the establishment of persistent IBDV infections. Results presented here show that the inactivation of the JAK-STAT signaling pathway significantly reduces the apoptotic response induced by the infection, facilitating the establishment and maintenance of IBDV persistent infections. IMPORTANCE Members of the Birnaviridae family, including infectious bursal disease virus (IBDV), exhibit a dual behavior, causing acute infections that are often followed by the establishment of lifelong persistent asymptomatic infections. Indeed, persistently infected specimens might act as efficient virus reservoirs, potentially contributing to virus dissemination. Despite the key importance of this biological trait, information about mechanisms triggering IBDV persistency is negligible. Our report evidences the capacity of IBDV, a highly relevant avian pathogen, to establish long-term, productive, persistent infections in both avian and human cell lines. Data presented here provide novel and direct evidence about the crucial role of type I IFNs on the fate of IBDV-infected cells and their contribution to controlling the establishment of IBDV persistent infections. The use of cell lines unable to respond to type I IFNs opens a promising venue to unveiling additional factors contributing to IBDV persistency.