A Gammaherpesvirus Cooperates with Interferon-alpha/beta-Induced IRF2 to Halt Viral Replication, Control Reactivation, and Minimize Host Lethality

The gammaherpesviruses, including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), establish latency in memory B lymphocytes and promote lymphoproliferative disease in immunocompromised individuals. The precise immune mechanisms that prevent gammaherpesvirus reactivation and tumorigenesis are poorly defined. Murine gammaherpesvirus 68 (MHV68) is closely related to EBV and KSHV, and type I (alpha/beta) interferons (IFNαβ) regulate MHV68 reactivation from both B cells and macrophages by unknown mechanisms. Here we demonstrate that IFNβ is highly upregulated during latent infection, in the absence of detectable MHV68 replication. We identify an interferon-stimulated response element (ISRE) in the MHV68 M2 gene promoter that is bound by the IFNαβ-induced transcriptional repressor IRF2 during latency in vivo. The M2 protein regulates B cell signaling to promote establishment of latency and reactivation. Virus lacking the M2 ISRE (ISREΔ) overexpresses M2 mRNA and displays uncontrolled acute replication in vivo, higher latent viral load, and aberrantly high reactivation from latency. These phenotypes of the ISREΔ mutant are B-cell-specific, require IRF2, and correlate with a significant increase in virulence in a model of acute viral pneumonia. We therefore identify a mechanism by which a gammaherpesvirus subverts host IFNαβ signaling in a surprisingly cooperative manner, to directly repress viral replication and reactivation and enforce latency, thereby minimizing acute host disease. Since we find ISREs 5′ to the major lymphocyte latency genes of multiple rodent, primate, and human gammaherpesviruses, we propose that cooperative subversion of IFNαβ-induced IRFs to promote latent infection is an ancient strategy that ensures a stable, minimally-pathogenic virus-host relationship

Interferon regulatory factors interact with viral M2 gene during murine gammaherpesvirus 68 infection

Gammaherpesviruses are enveloped viruses with a large genomic size. Gammaherpesviruses infect most individuals worldwide and this subfamily is represented by human viruses Epstein Barr virus (EBV) and Kaposi sarcoma associated herpesvirus (KSHV). Studies of gammaherpesviruses have been limited due to the species specificity of EBV and KSHV. Murine gammaherpesvirus 68 (MHV68) has been used as a tractable small animal model to better understand virus-host interactions, antiviral immunity, and pathogenesis. MHV68 is a natural pathogen of wild rodents and upon sequencing has been shown to be closely related to EBV and KSHV. MHV68, like all herpesviruses, has a triphasic life span which includes lytic infection, latent infection, and reactivation. Acute lytic infection is cleared by the innate and adaptive immune response, followed by a lifelong latent infection, and eventual periodic reactivation of lytic viral replication under immunosuppression. What remains unclear is the regulation of latent virus gene expression and reactivation. Interferon alpha/beta (IFNαβ) is part of the innate immune system and has antiviral and immune-stimulating properties. IFNαβ has been shown to have a critical role in the regulation of MHV68 infection. The objective of this work is to further understand the interactions between the host innate immune system and lifelong latent infection. This work has elucidated one of the biochemical mechanisms by which the host cell and virus interact to regulate reactivation