During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature and lymphoid tissue destruction correlate with disease progression. Here, we demonstrate that blockade of type 1 interferon (IFN-I) signaling using a type 1 interferon receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus (LCMV). IFN-I blockade both prior to and following establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T-cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization and virus persistence. Our results suggest therapies that target IFN-I may help control persistent virus infections.

Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11-E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150 −/− but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150 −/− cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150 −/− cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses. M easles virus (MV), a member of the family Paramyxoviridae, infects more than 10 million persons worldwide each year, resulting in several hundred thousand deaths (1, 2). A serious complication is the persistent infection of the CNS known as subacute sclerosing panencephalitis (SSPE) that occurs at a frequency of 4-11 cases per 100,000 cases of MV infection. SSPE is a progressive fatal neurodegenerative disease with characteristic features of replication of MV in neurons in the presence of high titers of MV antibodies, modest infiltration of T and B cells into the CNS, and replication of defective MV in the CNS with biased mutation of U-to-C and A-to-G in the viral genome (3-5). These hypermutations occur primarily in the matrix (M) gene but are also observed to a lesser extent in the fusion (F) and hemagglutinin (H) genes (3, 4). A transgenic mouse model that expresses the human MV receptor CD46 recapitulates all the features of SSPE on infection with MV, with biased hypermutations of U-to-C and A-to-G accounting for more than 95% of point mutations in the M gene (3,4,6). Interestingly, these biased hypermutations play a direct role in the pathogenesis of SSPE by facilitating a significant prolongation of MV persistence within the CNS, as opposed to mere accumulation as a result of persistent infection (7). In support of a direct role of M gene hypermutations in the establishment of SSPE, MV generated by reverse genetics and containing a hypermutated M...

We explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinfl ammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3infl ammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Effi cacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the signifi cant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infi ltration into T cell-poor tumors and rescued anti-PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein-Barr virus-specifi c T-cell transfer. SIGNIFICANCE :Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP-P2X7-infl ammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the effi cacy of adoptive T-cell transfer.

Summary Although type I interferon (IFN-I) is thought to be beneficial against microbial infections, persistent viral infections are characterized by high interferon signatures suggesting that IFN-I signaling may promote disease pathogenesis. During persistent lymphocytic choriomeningitis virus (LCMV) infection, IFNα and IFNβ are highly induced early after infection and blocking IFN-I receptor (IFNAR) signaling promotes virus clearance. We assessed the specific roles of IFNβ versus IFNα in controlling LCMV infection. While blockade of IFNβ alone does not alter early viral dissemination, it is important in determining lymphoid structure, lymphocyte migration, and anti-viral T cell responses that lead to accelerated virus clearance, approximating what occurs during attenuation of IFNAR signaling. Comparatively, blockade of IFNα was not associated with improved viral control but with early dissemination of virus. Thus, despite their use of the same receptor, IFNβ and IFNα have unique and distinguishable biologic functions, with IFNβ being mainly responsible for promoting viral persistence.

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The impacts of ocean acidification will depend on the ability of marine organisms to tolerate, acclimate and eventually adapt to changes in ocean chemistry. Here, we use a unique transgenerational experiment to determine the molecular response of a coral reef fish to short-term, developmental and transgenerational exposure to elevated CO, and to test how these responses are influenced by variations in tolerance to elevated CO exhibited by the parents. Within-generation responses in gene expression to end-of-century predicted CO levels indicate that a self-amplifying cycle in GABAergic neurotransmission is triggered, explaining previously reported neurological and behavioural impairments. Furthermore, epigenetic regulator genes exhibited a within-generation specific response, but with some divergence due to parental phenotype. Importantly, we find that altered gene expression for the majority of within-generation responses returns to baseline levels following parental exposure to elevated CO conditions. Our results show that both parental variation in tolerance and cross-generation exposure to elevated CO are crucial factors in determining the response of reef fish to changing ocean chemistry.

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Arenaviruses are a major cause of hemorrhagic fevers endemic to Sub-Saharan Africa and South America, and thus a major public health and medical concern. The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) is widely used as a model system for studying persistent and acute infections, as well as for gaining an understanding of mammalian immune function. When originally characterized three decades ago, the LCMV isolate, Armstrong, which causes an acute infection in adult mice, was found to differ from the LCMV Clone 13 strain that causes a persistent infection by two amino acid changes, one within the virus surface glycoprotein (GP1: F260L) and the other within the virus L polymerase (K1076Q). Mutation F260L was considered solely responsible for the exceptionally strong binding affinity of Clone 13 (L at GP1 260) to its cellular receptor, α-dystroglycan, which among cells of the immune system is preferentially expressed on dendritic cells, and consequently, alters dendritic cell function leading to viral persistence. Recently, we noted a previously overlooked nucleotide difference between these two strains that results in an additional amino acid change in GP1, N176D. To investigate the potential contribution of this newly identified mutation to the Clone 13 phenotype, we used reverse-genetics approaches to generate recombinant LCM viruses with each of these individual mutations. Phenotypic characterization of these rLCMV showed that mutation F260L, but not N176D, in the GP1 of LCMV is essential for mediating the long-term persistence of Clone 13 infections. This work emphasizes the importance of subtle differences in viral strains that determine disease outcomes.