gammaherpesvirus
Pathogenesis and ImmunityDeletion of Murine Gammaherpesvirus Gene M2 in Activation-Induced Cytidine Deaminase-Expressing B Cells Impairs Host Colonization and Viral ReactivationGammaherpesviruses establish lifelong chronic infections in cells of the immune system that can lead to lymphomas and other diseases. To facilitate colonization of a host, gammaherpesviruses encode gene products that manipulate processes involved in cellular proliferation and differentiation. Whether and how these viral gene products function in specific cells of the immune system is poorly defined. We report here the use of a viral...
Pathogenesis and ImmunityInterferon Regulatory Factor 7 Attenuates Chronic Gammaherpesvirus InfectionThe 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...
Pathogenesis and ImmunityB Cell-Intrinsic Expression of Interferon Regulatory Factor 1 Supports Chronic Murine Gammaherpesvirus 68 InfectionGammaherpesviruses establish lifelong infection in over 95% of all adults and are associated with B cell lymphomas. The virus’s manipulation of the germinal center response and B cell differentiation to establish lifelong infection is thought to also precipitate malignant transformation, through a mechanism that remains poorly understood. The host transcription factor IRF-1, a well-established tumor suppressor, selectively attenuates...
Pathogenesis and ImmunityA CD4+ T Cell-NK Cell Axis of Gammaherpesvirus ControlGammaherpesviruses are widespread and cause cancers. CD4+ T cells are a key defense. We found that they defend indirectly, engaging uninfected presenting cells and recruiting innate immune cells to attack infected targets. This segregation of CD4+ T cells from immediate contact with infection helps the immune system to cope with viral evasion. Priming this defense by vaccination offers a way to protect against...
Genome Replication and Regulation of Viral Gene ExpressionConserved CxnC Motifs in Kaposi’s Sarcoma-Associated Herpesvirus ORF66 Are Required for Viral Late Gene Expression and Are Essential for Its Interaction with ORF34Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is an oncogenic gammaherpesvirus that is the causative agent of multiple human cancers. The release of infectious virions requires the production of capsid proteins and other late genes, whose production is transcriptionally controlled by a complex of six virally encoded proteins that hijack the host transcription machinery. It is poorly understood how this complex...
Pathogenesis and ImmunityB Cell-Intrinsic SHP1 Expression Promotes the Gammaherpesvirus-Driven Germinal Center Response and the Establishment of Chronic InfectionGammaherpesviruses establish lifelong infection in a majority of adults worldwide and are associated with a number of malignancies, including B cell lymphomas. These viruses infect naive B cells and manipulate B cell differentiation to achieve a lifelong infection of memory B cells. The germinal center stage of B cell differentiation is important as both an amplifier of the viral latent reservoir and the target of malignant...
Pathogenesis and ImmunityConserved Gammaherpesvirus Protein Kinase Selectively Promotes Irrelevant B Cell ResponsesGammaherpesviruses are ubiquitous cancer-associated pathogens that usurp the B cell differentiation process to establish life-long latent infection in memory B cells. A unique feature of early gammaherpesvirus infection is the robust increase in differentiation of B cells that are not specific for viral antigens and instead encode antibodies that react with self-antigens and antigens of other species. Viral mechanisms that are involved...
Virus-Cell InteractionsRhesus Macaque Rhadinovirus Encodes a Viral Interferon Regulatory Factor To Disrupt Promyelocytic Leukemia Nuclear Bodies and Antagonize Type I Interferon SignalingKSHV 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...
Pathogenesis and ImmunityLXR Alpha Restricts Gammaherpesvirus Reactivation from Latently Infected Peritoneal CellsLiver X receptors (LXRs) are nuclear receptors that mediate cholesterol and fatty acid homeostasis. Importantly, as ligand-activated transcription factors, LXRs represent potential targets for the treatment of hypercholesterolemia and atherosclerosis. Here, we demonstrate that LXRα, one of the two LXR isoforms, restricts reactivation of latent gammaherpesvirus from peritoneal cells. As gammaherpesviruses are ubiquitous oncogenic agents...
Pathogenesis and Immunity | SpotlightA Human Gain-of-Function STING Mutation Causes Immunodeficiency and Gammaherpesvirus-Induced Pulmonary Fibrosis in MiceA variety of human rheumatologic disease-causing mutations have recently been identified. Some of these mutations are found in viral nucleic acid-sensing proteins, but whether viruses can influence the onset or progression of these human diseases is less well understood. One such autoinflammatory disease, called STING-associated vasculopathy with onset in infancy (SAVI), affects children and leads to severe lung disease. We generated...