Gammaherpesviruses are ubiquitous pathogens that establish lifelong
infections and are associated with several
malignancies, including
B cell lymphomas. Uniquely, these viruses manipulate B cell differentiation to establish long-term latency in memory B cells. This study focuses on the interaction between gammaherpesviruses and
interferon regulatory factor 3 (IRF-3), a ubiquitously expressed
transcription factor with multiple direct target genes, including
beta interferon (IFN-β), a type I IFN. IRF-3 attenuates acute replication of a plethora of viruses, including gammaherpesvirus. Furthermore, IRF-3-driven IFN-β expression is antagonized by the conserved gammaherpesvirus
protein kinase during lytic virus replication in vitro In this study, we have uncovered an unexpected proviral role of IRF-3 during chronic gammaherpesvirus
infection. In contrast to the
antiviral activity of IRF-3 during acute
infection, IRF-3 facilitated establishment of latent gammaherpesvirus
infection in B cells, particularly, germinal center and activated B cells, the cell types critical for both natural
infection and viral lymphomagenesis. This proviral role of IRF-3 was further modified by the route of
infection and viral dose. Furthermore, using a combination of viral and host genetics, we show that IRF-3 deficiency does not rescue attenuated
chronic infection of a
protein kinase null gammaherpesvirus mutant, highlighting the multifunctional nature of the conserved gammaherpesvirus
protein kinases in vivo In summary, this study unveils an unexpected proviral nature of the classical innate
immune factor, IRF-3, during chronic
virus infection.IMPORTANCE
Interferon regulatory factor 3 (IRF-3) is a critical component of the innate immune response, in part due to its transactivation of
beta interferon (IFN-β) expression. Similar to that observed in all acute
virus infections examined to date, IRF-3 suppresses lytic viral replication during acute gammaherpesvirus
infection. Because gammaherpesviruses establish lifelong
infection, this study aimed to define the
antiviral activity of IRF-3 during
chronic infection. Surprisingly, we found that, in contrast to acute
infection, IRF-3 supported the establishment of gammaherpesvirus latency in splenic B cells, revealing an unexpected proviral nature of this classical innate immune host factor.