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ine that can broaden immune responses against known pathogenic Ebola viruses. Selleckchem Tofacitinib This approach provides a new method to broaden and potentially extend protective immune responses against Ebola viruses. Copyright © 2020 American Society for Microbiology.Recognition of Influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activates innate immune cells, and regulates adaptive immunity. However, excessive innate immune activation can exaggerate disease. The pathways promoting excessive activation are incompletely understood, with limited experimental models to investigate mechanisms driving influenza-induced inflammation in humans. Interferon regulatory factor (IRF5) is a transcription factor that plays important roles in induction of cytokines after viral sensing. In an in vivo model of IAV infection, IRF5 deficiency reduced IAV-driven immune pathology and associated inflammatory cytokine production, specifically reducing cytokine-producing myeloid cell populations in Irf5 -/- mice, but not impacting type 1 IFN production or virus replication. Using cytometry by time-of-flight (CyTOF), we identified that human lung IRF5 expression was highest in cells of the myeloid lineage. To investigate the role of IRF5 in meys are incompletely understood. We show that interferon regulatory factor 5 (IRF5) mediates IAV-induced inflammation and, in mice, drives pathology. This was independent of antiviral type 1 IFN and virus replication, implying that IRF5 could be specifically targeted to treat influenza-induced inflammation. We show for the first time that human iPSC technology can be exploited in genetic studies of virus-induced immune responses. Using this technology, we deleted IRF5 in human myeloid cells. These IRF5-deficient cells exhibited impaired influenza-induced cytokine production and revealed that IRF5 acts downstream of Toll-like receptor 7 and possibly retinoic acid-inducible gene-I. Our data demonstrate the importance of IRF5 in influenza-induced inflammation, suggesting genetic variation in the IRF5 gene may influence host susceptibility to viral diseases. Copyright © 2020 Forbester et al.Dendritic cells (DC) are one of the earliest targets of HIV-1 infection acting as a ‘Trojan Horse’, concealing the virus from the innate immune system and delivering it to T-cells via virological synapses (VS). To explicate how the virus is trafficked through the cell to the VS and evades degradation, a high-throughput siRNA screen targeting membrane trafficking proteins was performed in monocyte-derived dendritic cells (MDDC). We identified several proteins including BIN-1 and RAB7L1 that share common roles in transport from endosomal compartments. Depletion of target proteins resulted in an accumulation of virus in intracellular compartments and significantly reduced viral trans-infection via the VS. By targeting endocytic trafficking and retromer recycling to the plasma membrane, we were able to reduce the virus’s ability to accumulate at budding microdomains and the VS. Thus, we identify key genes involved in a pathway within DC that is exploited by HIV-1 to traffic to the VS.IMPORTANCEThe lentivirus Human Immunodeficiency Virus (HIV) targets and destroys CD4+ T-cells, leaving the host vulnerable to life-threatening opportunistic infections associated with Acquired Immunodeficiency Syndrome (AIDS). Dendritic cells form a Virological synapse (VS) with CD4+ T-cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ARF1, BIN1, RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore infection of CD4+ T-cells. We found these cellular factors to be essential for endosomal protein trafficking and formation of the VS, depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4+ T-cells has the potential for development of targeted therapy to reduce trans-infection of HIV-1 in vivo. Copyright © 2020 Bayliss et al.Infants of HIV positive mothers can acquire HIV infection by various routes, but even in the absence of antiviral treatment, the majority of these infants do not become infected. There is evidence that maternal antibodies may provide some protection from infection, but gestational maternal antibodies have not yet been characterized in detail. One of the most studied vertically-infected infants is BG505, as the virus from this infant yielded an Envelope protein that was successfully developed as a stable trimer. Here, we isolated and characterized 39 HIV-specific neutralizing monoclonal antibodies (nAbs) from MG505, the mother of BG505, at a time point just prior to vertical transmission. These nAbs belonged to 21 clonal families, employed a variety of VH genes, many were specific for the HIV-1 Env V3 loop, and this V3 specificity correlated with measurable antibody-dependent cellular cytotoxicity (ADCC) activity. The isolated nAbs did not recapitulate the full breadth of heterologous nor autologous virus neute potential of HIV-specific immune responses to provide protection against HIV is a central goal of HIV vaccine design, understanding the nature of maternal antibodies may provide insights into immune mechanisms of protection. In this study, we isolated and characterized HIV-specific antibodies from the mother of an infant whose transmitted virus has been well studied. Copyright © 2020 American Society for Microbiology.Human enteroviruses (EVs), including coxsackieviruses, the numbered enteroviruses and echoviruses, cause a wide range of diseases, such as hand, foot and mouth disease (HFMD), encephalitis, myocarditis, acute flaccid myelitis (AFM), pneumonia, and bronchiolitis. Therefore, broad-spectrum anti-EV drugs are urgently needed to treat EV infection. Here, we demonstrate that FNC, a small nucleoside analog inhibitor that has been demonstrated to be a potent inhibitor of HIV and entered into a clinical phase II trial in China, potently inhibits the viral replication of a multitude of EVs, including enterovirus 71 (EV71), coxsackievirus A16 (CA16), CA6, EVD68, and CVB3, at the nanomolar level. The antiviral mechanism of FNC involves mainly positive- and negative-strand RNA synthesis inhibition by targeting and competitively inhibiting the activity of EV71 viral RNA-dependent RNA polymerase (3Dpol), as demonstrated through RT-qPCR, in vitro 3Dpol activity and isothermal titration calorimetry (ITC) experiments. We further demonstrated that FNC treatment every two days with 1 mg/kg in EV71 and CA16 infection neonatal mouse models successfully protected mice from lethal challenge with EV71 and CA16 viruses and reduced the viral load in various tissues.