GADD45γ activated early in the course of HSV-1 infection suppresses the activation of a network of innate immunity genes.

The stress response genes encoding GADD45 gamma, and to a lesser extent GADD45 beta, are activated early in infection with herpes simplex virus 1 (HSV-1). Cells that had been depleted of GADD45 gamma by transfection of short hairpin RNA (shRNA) or in which the gene had been knocked out (Delta GADD45 gamma) yielded significantly less virus than untreated infected cells. Consistent with lower virus yields, the Delta GADD45 gamma cells (either uninfected or infected with HSV-1) exhibited significantly higher levels of transcripts of a cluster of innate immunity genes, including those encoding IFI16, IFIT1, MDA5, and RIG-I. Members of this cluster of genes were reported by this laboratory to be activated concurrently with significantly reduced virus yields in cells depleted of LGP2 or HDAC4. We conclude that innate immunity to HSV-1 is normally repressed in unstressed cells and repression appears to be determined by two mechanisms. The first, illustrated here, is through activation by HSV-1 infection of the gene encoding GADD45 gamma. The second mechanism requires constitutively active expression of LGP2 and HDAC4. IMPORTANCE Previous studies from our laboratory reported that knockout of some innate immunity genes was associated with increases in the expression of overlapping networks of genes and significant loss of the ability to support the replication of HSV-1; knockout of other genes was associated with decreases in the expression of overlapping networks of genes and had no effect on virus replication. In this report, we document that depletion of GADD45 gamma reduced virus yields concurrently with significant upregulation of the expression of a cluster of innate immunity genes comprising IFI16, IFIT1, MDA5, and RIG-I. This report differs from the preceding study in an important respect; i.e., the preceding study found no evidence to support the hypothesis that HSV-1 maintained adequate levels of LGP2 or HDAC4 to block upregulation of the cluster of innate immunity genes. We show that HSV-1 causes upregulation of the GADD45 gamma gene to prevent the upregulation of innate immunity genes.