RIG-I and MDA5 independently signal downstream to an adaptor molecule named mitochondrial antiviral signaling. MAVS subsequently activates transcription factors including NF-kB, IRF3, and IRF7, which translocate to the nucleus and upregulate expression of type I interferons and interferon-stimulated genes . Additional evidence has also suggested participation of recently characterized cytosolic dsDNA sensors, including RNA polymerase III, interferon inducible protein 16 , and DNA-dependent activator of interferon regulatory factor in induction of type I IFNs after viral infection. Type I IFNs and hundreds of ISGs function synergistically to establish an active antiviral state in host cells. Herpes simplex virus type 1 is a dsDNA virus that belongs to the herpes virus family Herpesviridae. HSV-1 features high infectivity of macrophages and is recognized by multiple innate defense pathways including TLR- and RIG-I/MDA5dependent pathways. The broad defense pathways Bortezomib triggered by HSV-1 as well as its high infectivity of macrophages make it well suited as a model virus to study antiviral pathways. Here we report an image-based high-throughput genetic screen to identify uncharacterized genes controlling cellular antiviral immunity and characterize roles for IL-27 and Tagap in antiviral defense. Further investigation holds the promise of finding strategies that enhance the antiviral activity of these genes and developing novel effective antiviral drugs that work to combat complex diseases as well. To directly assess the antiviral activity of IL-27 against HSV infection, RAW 264.7 cells were treated with recombinant IL-27 either alone or in combination with IFN-c. 24 hours later, the cells were then infected with HSV-GFP, fixed, and imaged as described above. IL-27 treatment alone did not result in an inhibitory effect on viral infectivity and priming with IFN-c decreased the viral infectivity by 46%. Interestingly, the combination of IFN-c and IL-27 had an additive effect and resulted in the greatest antiviral activity. Upon viral infection, host cells sense viral components through PRRs and activate antiviral signaling cascades, including the NFkB pathway and IFN-responsive pathways. IRF3 plays an essential role in this process. Upon activation, IRF3, along with its binding partner IRF7, translocates into the nucleus and binds target DNA through its DNA-binding domain to activate transcription of genes including IFNa and IFNb. A number of studies have suggested a connection between genetic susceptibility to complex disease and viral infection. However, there are only a handful of reports on specific virusgene interactions and it remains unclear how many of the genes within T1D susceptibility loci are associated with antiviral immunity. Placing T1D genes into the viral defense pathway could help identify therapeutic entry points for T1D treatment as well as a more complete understanding of the environmental factors altering disease susceptibility. From the screen, we identified 14 candidate genes, the differential expression of which influences the antiviral activity of HSV-1-infected macrophage cells.