Gammaherpesviruses establish life-long infection in most adults and are associated with the development of B cell lymphomas. While the interaction between gammaherpesviruses and splenic B cells has been explored, very little is known about gammaherpesvirus infection of B-1 B cells, innate-like B cells that primarily reside in body cavities. This study demonstrates that B-1 B cells harbor the highest frequency of latently infected cells in the peritoneum throughout chronic infection, highlighting a previously unappreciated feature of gammaherpesvirus biology.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in Ͼ95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection.IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I interferon (IFN) signaling and interferon regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.KEYWORDS IRF-1, acute infection, gammaherpesvirus, interferon, viral replication G ammaherpesviruses are ubiquitous pathogens that establish lifelong infection in a majority of the adult population and are associated with cancer (1-3). Similar to replication of other viruses, replication of both human (Epstein-Barr virus [EBV] and Kaposi's sarcoma-associated herpesvirus [KSHV]) and murine (mouse gammaherpesvirus 68[MHV68]) gammaherpesviruses is suppressed by type I and type II interferons (IFNs), two partially overlapping yet distinct host networks that are critical for the control of gammaherpesvirus infection (4-10). In the case of MHV68, both acute and chronic MHV68 infection is attenuated by type I and type II IFNs (4,6,11,12). While the antiviral role of IFNs in the context of gammaherpesvirus infection, including in vivo, is firmly established, the mechanism by which this restriction is imposed and the molecular players involved in this response are still being defined.Interferon regulatory factor 1 (IRF-1) is a broadly antiviral transcription factor that restricts replication of diverse RNA and DNA viruses in cell culture via a poorly understood mechanism (13, 14). While initially IRF-1 was thought to induce type I interferon (IFN) expression (15)

The cholesterol synthesis pathway is a ubiquitous cellular biosynthetic pathway that is attenuated therapeutically by statins. Importantly, type I interferon (IFN), a major antiviral mediator, also depresses the cholesterol synthesis pathway. Here we demonstrate that attenuation of cholesterol synthesis decreases gammaherpesvirus replication in primary macrophages in vitro and reactivation from peritoneal exudate cells in vivo. Specifically, the reduced availability of the intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route-of-infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN. Our studies suggest that type I IFN signaling counteracts the antiviral nature of the subdued cholesterol synthesis pathway and offer a novel insight into the utility of statins as antiviral agents. IMPORTANCEStatins are cholesterol synthesis inhibitors that are therapeutically administered to 12.5% of the U.S. population. Statins attenuate the replication of diverse viruses in culture; however, this attenuation is not always obvious in an intact animal model. Further, it is not clear whether statins alter parameters of highly prevalent chronic herpesvirus infections. We show that statin treatment attenuated gammaherpesvirus replication in primary immune cells and during chronic infection of an intact host. Further, we demonstrate that type I interferon signaling counteracts the antiviral effects of statins. Considering the fact that type I interferon decreases the activity of the cholesterol synthesis pathway, it is intriguing to speculate that gammaherpesviruses have evolved to usurp the type I interferon pathway to compensate for the decreased cholesterol synthesis activity. I ntracellular cholesterol is acquired via two major mechanisms: internalization of exogenous cholesterol via the low-density lipoprotein receptor (LDLR) and endogenous cholesterol synthesis. The latter mechanism (Fig. 1A) operates in all cell types and is positively regulated by sterol regulatory element-binding protein 2 (Srebp2). Srebp2, a transcription factor synthesized as an inactive membrane-associated precursor, is cleaved by Golgi apparatus-specific proteases under conditions of low cholesterol to release an active product (1). This active cleaved product induces expression of most enzymes involved in cholesterol synthesis, including the rate-limiting enzyme hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) (2). Active Srebp2 also increases the expression of LDLR to promote the acquisition of exogenous cholesterol. Due to the critical role of cholesterol for cell viability, genetic disruption of Srebp2 leads to early embryonic lethality (3).Elevated plasma cholesterol levels are a potent risk factor for atherosclerosis, and the targeting of the cholesterol synth...

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