Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are associated with a variety of malignancies, including lymphomas. Interferon regulatory factor 7 (IRF-7) is an innate immune transcription factor that restricts acute replication of diverse viruses, including murine gammaherpesvirus 68 (MHV68). Importantly, very little is known about the role of IRF-7 during chronic virus infections. In this study, we demonstrate that IRF-7 attenuates chronic infection by restricting establishment of gammaherpesvirus latency in the peritoneal cavity and, to a lesser extent, viral reactivation in the spleen. Despite the classical role of IRF-7 as a stimulator of type I interferon (IFN) transcription, there were no global effects on the expression of IFN-induced genes (ISGs) in the absence of IRF-7, with only a few ISGs showing attenuated expression in IRF-7-deficient peritoneal cells. Further, IRF-7 expression was dispensable for the induction of a virus-specific CD8 T cell response. In contrast, IRF-7 expression restricted latent gammaherpesvirus infection in the peritoneal cavity under conditions where the viral latent reservoir is predominantly hosted by peritoneal B cells. This report is the first demonstration of the antiviral role of IRF-7 during the chronic stage of gammaherpesvirus infection.

IMPORTANCE The innate immune system of the host is critical for the restriction of acute viral infections. In contrast, the role of the innate immune network during chronic herpesvirus infection remains poorly defined. Interferon regulatory factor 7 (IRF-7) is a transcription factor with many target genes, including type I interferons (IFNs). In this study, we show that the antiviral role of IRF-7 continues into the chronic phase of gammaherpesvirus infection, wherein IRF-7 restricts the establishment of viral latency and viral reactivation. This study is, to our knowledge, the first to define the role of IRF-7 in chronic virus infection.