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Acute herpes simplex virus (HSV) infection causes apoptosis in the adrenal cortex and myenteric plexus of the gut, ovary, pituitary gland, and liver of mice. Apoptosis of infected cells is increased in immunosuppressed regions of the adrenal cortex and liver of macrophage-depleted mice. HSV carries the US3 gene which interferes with host cell apoptosis. When the livers of macrophage-depleted mice are infected with a US3-null virus, apoptosis occurs in the narrow areas of inflammatory cell infiltration, restricting viral replication and spread. Thus, these data suggest that apoptosis may function as a primitive immune response to HSV infection in mice.