Rhesus Macaque Rhadinovirus Encodes a Viral Interferon Regulatory Factor To Disrupt Promyelocytic Leukemia Nuclear Bodies and Antagonize Type I Interferon Signaling

Abstract

Interferon (IFN) production and the subsequent induction of IFNstimulated genes (ISGs) are highly effective innate strategies utilized by cells to protect against invading pathogens, including viruses. Critical components involved in this innate process are promyelocytic leukemia nuclear bodies (PML-NBs), which are subnuclear structures required for the development of a robust IFN response. As such, PML-NBs serve as an important hurdle for viruses to overcome to successfully establish an infection. Both Kaposi's sarcoma-associated herpesvirus (KSHV) and the closely related rhesus macaque rhadinovirus (RRV) are unique for encoding viral homologs of IFN regulatory factors (termed vIRFs) that can manipulate the host immune response by multiple mechanisms. All four KSHV vIRFs inhibit the induction of IFN, while vIRF1 and vIRF2 can inhibit ISG induction downstream of the IFN receptor. Less is known about the RRV vIRFs. RRV vIRF R6 can inhibit the induction of IFN by IRF3; however, it is not known whether any RRV vIRFs inhibit ISG induction following IFN receptor signaling. In our present study, we demonstrate that the RRV vIRF R12 aids viral replication in the presence of the type I IFN response. This is achieved in part through the disruption of PML-NBs and the inhibition of robust ISG transcription. IMPORTANCE KSHV and RRV encode a unique set of homologs of cellular IFN regulatory factors, termed vIRFs, which are hypothesized to help these viruses evade the innate immune response and establish infections in their respective hosts. Our work elucidates the role of one RRV vIRF, R12, and demonstrates that RRV can dampen the type I IFN response downstream of IFN signaling, which would be important for establishing a successful infection in vivo.

Beyond Viral Interferon Regulatory Factors: Immune Evasion Strategies

“…The present knowledge also clearly suggested that vIRFs have ample impacts on both the KSHV and host gene expression, which conjointly contribute to KSHV life cycle as well as KSHV-associated pathogenesis. In fact, rhesus macaque rhadinovirus (RRV), which is closely related to the γ-herpesvirus KSHV and also encodes eight vIRFs, highlighted the importance of vIRFs in viral pathogenesis, as infection of vIRFs-knockout (KO) RRV in rhesus macaques showed reduced viral loads and significantly decreased B-cell hyperplasia [54,55]. Thus, future studies on the vIRFs will be necessary to confirm their roles during the viral life cycle and pathogenesis in a genetic context similar with RRV.…”