Herpes simplex virus type 1 blocks the apoptotic host cell defense mechanisms that target Bcl-2 and manipulates activation of p38 mitogen-activated protein kinase to improve viral replication

Wild-type (wt) herpes simplex virus type 1 (HSV-1) suppresses cell death. W e investigated the apoptotic pathways triggered during infection with mutan t viruses fsk and 27lacZ which lack functional ICP4 and ICP27 viral protein s, respectively) and examined the mechanisms used by wt HSV-1 to protect ag ainst programmed cell death induced by the DNA-damaging compound cisplatin. In our studies, we used BHK and HeLa cells, with similar results. We sugge st that a decrease in the levels of Bcl-2 protein is a key event during apo ptosis induced by the mutant viruses and that Bcl-2 levels are targeted by (i) a decrease of bcl-2 RNA, (ii) caspase-related proteolysis, and (iii) p3 8 mitogen-activated protein kinase (p38MAPK)-dependent destabilization of B cl-2 protein. We show that wt HSV-1, but not the mutant viruses, maintains bcl-2 RNA and protein levels during infection and protects from the cisplat in-induced decrease in bcl-2 RNA; our data suggest that both ICP27 and ICP4 are required for this function. Additionally, wt HSV-1 evades but does not actively block activation of caspases. Although wt HSV-1 induces p38MAPK a ctivation during infection, it prevents p38MAPK-dependent destabilization o f Bcl-2 and exploits p38MAPK stimulation to enhance transcription of specif ic viral gene promoters to increase viral yields.