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The stress response genes encoding GADD45γ and to a lesser extent GADD45β are activated early in infection with HSV-1. Cells depleted of GADD45γ by transfection of shRNA or in which the gene had been knocked out (ΔGADD45γ yield significantly less virus than untreated infected cells. Consistent with lower virus yields the ΔGADD45γ cells, both uninfected or infected with HSV-1 exhibit significantly higher levels of transcripts encoding a cluster of a network of innate immunity genes that include those encoding IFI16, IFIT1, MDA5 and RIG-I. Members of this cluster of genes have been reported by this laboratory to be activated concurrent with significantly reduced virus yields in cell depleted of LGP2 or HDAC4. We conclude the following: (i) Innate immunity to HSV-1 is normally repressed in unstressed cells. The repression appears to be determined by two mechanisms. The first, illustrated here is by activation by HSV-1 infection of the gene encoding GADD45γ. The second mechanism requires constitutively active expression of LGP2 and HDAC4. [ABSTRACT FROM AUTHOR]