Murine Gamma-Herpesvirus 68 Hijacks MAVS and IKKβ to Initiate Lytic Replication

Upon viral infection, the mitochondrial antiviral signaling (MAVS)-IKK beta pathway is activated to restrict viral replication. Manipulation of immune signaling events by pathogens has been an outstanding theme of host-pathogen interaction. Here we report that the loss of MAVS or IKK beta impaired the lytic replication of gamma-herpesvirus 68 (gamma HV68), a model herpesvirus for human Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus. gamma HV68 infection activated IKK beta in a MAVS-dependent manner; however, IKK beta phosphorylated and promoted the transcriptional activation of the gamma HV68 replication and transcription activator (RTA). Mutational analyses identified IKK beta phosphorylation sites, through which RTA-mediated transcription was increased by IKK beta, within the transactivation domain of RTA. Moreover, the lytic replication of recombinant gamma HV68 carrying mutations within the IKK beta phosphorylation sites was greatly impaired. These findings support the conclusion that gamma HV68 hijacks the antiviral MAVS-IKK beta pathway to promote viral transcription and lytic infection, representing an example whereby viral replication is coupled to host immune activation.