SummaryRecent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway.

Low public awareness of cytomegalovirus (CMV) results from the only mild and transient symptoms that it causes in the healthy immunocompetent host, so that primary infection usually goes unnoticed. The virus is not cleared, however, but stays for the lifetime of the host in a non-infectious, replicatively dormant state known as 'viral latency'. Medical interest in CMV results from the fact that latent virus can reactivate to cytopathogenic, tissue-destructive infection causing life-threatening end-organ disease in immunocompromised recipients of solid organ transplantation (SOT) or hematopoietic cell transplantation (HCT). It is becoming increasingly clear that CMV latency is not a static state in which the viral genome is silenced at all its genetic loci making the latent virus immunologically invisible, but rather is a dynamic state characterized by stochastic episodes of transient viral gene desilencing. This gene expression can lead to the presentation of antigenic peptides encoded by 'antigenicity-determining transcripts expressed in latency (ADTELs)' sensed by tissue-patrolling effector-memory CD8 T cells for immune surveillance of latency [In Reddehase et al., Murine model of cytomegalovirus latency and reactivation, Current Topics in Microbiology and Immunology, vol 325. Springer, Berlin, pp 315-331, 2008]. A hallmark of the CD8 T cell response to CMV is the observation that with increasing time during latency, CD8 T cells specific for certain viral epitopes increase in numbers, a phenomenon that has gained much attention in recent years and is known under the catchphrase 'memory inflation.' Here, we provide a unifying hypothesis linking stochastic viral gene desilencing during latency to 'memory inflation.'

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Chemokines are chemotactic cytokines whose main function is to direct cell migration. The chemokine network is highly complex and its deregulation is linked to several diseases including immunopathology, cancer and chronic pain. Chemokines also play essential roles in the antiviral immune response. Viruses have therefore developed several counter strategies to modulate chemokine activity. One of these is the expression of type I transmembrane or secreted proteins with the ability to bind chemokines and modulate their activity. These proteins, termed viral chemokine binding proteins (vCKBP), do not share sequence homology with host proteins and are immunomodulatory in vivo. In this review we describe the discovery and characterization of vCKBP, explain their role in the context of infection in vivo and discuss relevant novel findings.

Activated macrophages play a central role in controlling inflammatory responses to infection and are tightly regulated to rapidly mount responses to infectious challenge. Type I interferon (alpha/beta interferon [IFN-␣/␤]) and type II interferon (IFN-␥Murine cytomegalovirus (MCMV) infection in mice is a well-established model system for the study of acute, persistent, and latent infections of betaherpesviruses and their control by the host immune system (32,35,58,60). Both human CMV (HCMV) and MCMV infect a broad range of tissues in their respective hosts, including fibroblasts, endothelial and epithelial cells, and, significantly, immune cells of the myeloid lineage (13,57,69,70). Differentiated macrophages of this lineage residing in infected tissues play a key role in eliciting the host immune response but are also permissive for CMV infection and serve as disseminators of the virus throughout the host (reviewed in reference 29).In immunocompetent hosts, primary CMV infections are generally asymptomatic, with immune cells either killing virusinfected cells or restricting viral cell-to-cell spread and replication. The latter effect occurs via induction of an antiviral state in noninfected cells or the activation of immune cells by soluble mediators such as type I interferon (alpha/beta interferon [IFN-␣/␤]) and type II interferon (IFN-␥) (8,10,41,50,60,73). Several hundred genes stimulated in response to both type I and type II IFNs have been identified by microarrays in various cell types over the years (18,19,37,38,66). In contrast, the recently discovered type III IFNs are not well characterized but may have comparable functions to the type I IFNs, mediated by shared downstream signaling and IFN-stimulated genes (ISGs) (3, 33, 42, 63, 72, 78, 84). Type III IFNs are