Interferon Regulatory Factor 7 Attenuates Chronic Gammaherpesvirus Infection

Abstract

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 mouse 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 virus-specific CD8 T cell response. In contrast, IRF-7 expression restricted latent gammaherpesvirus infection in the peritoneal cavity under conditions when 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.

IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis

“…CNOT knock-outs suppressed HIV replication, by upregulating and type 1 interferon signaling pathways, a phenotype that was rescued by deletion of IRF7 [ 62 ]. Further evidence that IRF7 restricts the establishment of viral latency and viral reactivation was recently confirmed in a study that compared chronic gammaherpesvirus infections in IRF7-deficient mice and wild-type mice [ 42 ]. This study also showed higher IFN-γ levels in IRF7-deficient mice, the data from our study point in the same direction as we found higher IFN-γ levels in the supernatant of PBMC of subjects with rs7113204-A variant after stimulation with imiquimod.…”

“…S8). There is evidence that IRF7 also plays a role in interferon-gamma (IFN-γ) production [ 42 , 43 ]. In PBMCs stimulated with Imiquimod (TLR7 agonist), we observed a significant difference in IFN-γ production between rs7113204-A ( n = 16) and rs7113204-G ( n = 122) bearers after 7 days (108.56 pg/ml [141.92] vs 51.11 pg/mL [82.59], p = 0.011; Fig.…”

IRF7 and UNC93B1 variants in an infant with recurrent herpes simplex virus infection

“…IRF7 is a transcription factor that serves as a crucial regulator of the type I IFN immune response to viral infections, including HSV ( 22 , 30 ). In mouse models, experiments show that IRF7 –/– mice are unable to generate a type I IFN response, and in adult humans, reports of single-gene variants in IRF7 have been associated with severe presentation of common viral infections ( 31 – 34 ). However, to the best of our knowledge, the association between an IRF7 mutation and HSV susceptibility in humans has not been described.…”

B cell-intrinsic STAT3-mediated support of latency and interferon suppression during murine gammaherpesvirus 68 infection revealed through anin vivocompetition model

“…Type I and II interferon responses restrict MHV68 latency through the induction of interferon stimulated genes (ISGs) which promote an antiviral state (4,77,(92)(93)(94). Host factors that restrict MHV68 infection include those that promote IFN production like IRF3 and IRF7, and those that respond to IFN to directly induce ISG transcription like IRF1, STAT1, and STAT2 (66,69,(95)(96)(97)(98). Mice lacking STAT1, IFN-αβ receptor, or combination IFN-αβ and IFN-γ receptors succumb to infection with MHV68 (99), stressing the importance of the IFN response in combating the virus.…”