In an effort to identify novel host restriction factors against HSV-1 infection by IFNs and HSV-1. While this strategy was successful at identifying host restriction factors, a number of identified genes collaborate with IFN-induced genes to construct the antiviral network in host cells. Among the 14 candidates identified from the screen, only 5 were upregulated by IFN-c and/or HSV-1. This result suggests that a number of antiviral host defense genes are constitutively expressed and their activity is only enhanced in the presence of antiviral cytokines such as IFN-c. While our screening strategy takes an unbiased approach, due to the use of IFN-c in the screen, the genes that function in late stage of viral suppression may be undervalued because the loss of these genes may be rescued or compensated by the activity of IFN-c and its effector molecules. Regardless, our screen preserved the integrity of IFN pathways and thus examined the role of each candidate in the context of an intact antiviral response which creates a physiologically relevant system. In HIV infection, IL-27 mediates viral suppression in human macrophages in a mechanism similar to IFN-a, which induces the expression of downstream antiviral molecules such as the family of APOBEC cytidine deaminases. In our experimental system, IL-27 alone is not sufficient to induce antiviral immunity, suggesting that host restriction factors induced by IFN-c cooperate with IL-27 to boost antiviral immunity to HSV-1 infection. Recently, IFN-l1, a type III IFN, was shown to be co-induced with IL-27 by HBV infection and to cooperate with IL-27 to limit HBV replication in HepG2 cells. Unfortunately, the IFN-l1 gene is a pseudogene in mice and examination of the other two members of the type III IFN family, IFN-l2 and -l3, suggested that the coordinated regulation of IL-27 and IFN-l does not seem to operate in murine macrophage cells upon HSV-1 infection. Taken together, these data suggest that IL-27 can work in concert with a variety of IFNs to mediate host defense against a plethora of viruses. Single nucleotide polymorphisms within the Tagap locus have been identified as a shared risk factor for Crohn’s disease and celiac disease, while other SNPs within this locus have been associated with protection from rheumatoid arthritis and T1D. Tagap is highly expressed in immune cells, including B cells, T cells, dendritic cells, natural killer cells, and monocytes; however, little is known about the function of Tagap in host defense. Our data suggest that Tagap plays a role in regulating key antiviral cytokines. However, future studies will be important to define the mechanism of action of Tagap given its broad association with Nilotinib moa complex diseases. In summary, our unbiased loss-of-function genetic screen identified genes within T1D susceptibility loci that work in concert with IFN signaling pathways to protect host cells from detrimental viral infection, thus preventing improper immune responses leading to inflammation and autoimmunity. Better understanding of the mechanisms of the gene-plus-virus interaction will provide new approaches to design therapies to treat complex diseases.