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

Abstract

Upon viral infection, the mitochondrial antiviral signaling (MAVS)-IKKβ 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 IKKβ impaired the lytic replication of gamma-herpesvirus 68 (γHV68), a model herpesvirus for human Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus. γHV68 infection activated IKKβ in a MAVS-dependent manner; however, IKKβ phosphorylated and promoted the transcriptional activation of the γHV68 replication and transcription activator (RTA). Mutational analyses identified IKKβ phosphorylation sites, through which RTA-mediated transcription was increased by IKKβ, within the transactivation domain of RTA. Moreover, the lytic replication of recombinant γHV68 carrying mutations within the IKKβ phosphorylation sites was greatly impaired. These findings support the conclusion that γHV68 hijacks the antiviral MAVS-IKKβ pathway to promote viral transcription and lytic infection, representing an example whereby viral replication is coupled to host immune activation. Innate immunity represents the first line of defense against pathogen infection. Recent studies uncovered an array of sensors that detect pathogen-associated molecular patterns and induce antiviral cytokine production via two closely related kinase complexes, i.e., the IKKα/β/γ and TBK-1/IKKε. To counteract host immune defense, herpesviruses have evolved diverse strategies to evade, manipulate, and exploit host immune responses. Here we report that infection by murine gamma-herpesvirus 68 (γHV68), a model gamma-herpesvirus for human Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, activated the IKKβ kinase and IKKβ was usurped to promote viral transcriptional activation. As such, uncoupling IKKβ from transcriptional activation by biochemical and genetic approaches impaired γHV68 lytic replication. Our study represents an example whereby viral lytic replication is coupled to host innate immune activation and sheds light on herpesvirus exploitation of immune responses.