THE PATHOGENICITY OF A US-3-PROTEIN KINASE-DEFICIENT MUTANT OF HERPES-SIMPLEX VIRUS TYPE-2 IN MICE

We have investigated the pathogenicity of a US 3 protein kinase-defici ent mutant (L1 BR1) of herpes simplex virus type 2 (HSV-2) for 4-week- old ICR mice to define the role of the viral protein kinase in virus-h ost interaction. When mice were intraperitoneally infected with 10(5) PFU of L1 BR1, the virus disappeared from the peritoneal cavity by 2 d ays postinfection and failed to induce any significant histopathologic al changes in the liver and spleen although viral antigens were occasi onally detected in the epithelial cells of small bile ducts and small vascular wall. The parental virus (HSV-2 186) and a revertant of the m utant (L1 B- 11) both caused severe hepatitis, and viral antigens were clearly detected in the hepatocytes and Kupffer cells in the focal ne crotic areas. Both of the virulent viruses, unlike L1 BR1, could produ ce infectious progeny and cytopathic effects in freshly harvested peri toneal macrophages. The growth of L1 BR1 in peritoneal macrophages was restricted at a stage of or prior to viral DNA synthesis but after th e induction of viral DNA polymerase. In addition, the production and/o r the spread of the mutant in mouse embryo fibroblasts (MEF) was found to be much more effectively suppressed by cocultivation of peritoneal macrophages than that of 186. An almost complete inhibition of L1 BR1 -plaque formation was observed at a macrophage-to-MEF ratio of 4:1. Th ese results suggest that the attenuation of L1 BR1 following intraperi toneal infection is primarily due to its high sensitivity to intrinsic and extrinsic inhibition of peritoneal macrophages and that the US 3 protein kinase may play a role in viral DNA replication in peritoneal macrophages.