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. We investigated the apoptotic pathways triggered during infection with mutant viruses tsk and 27lacZ (which lack functional ICP4 and ICP27 viral proteins, respectively) and examined the mechanisms used by wt HSV-1 to protect against programmed cell death induced by the DNA-damaging compound cisplatin. In our studies, we used BHK and HeLa cells, with similar results. We suggest that a decrease in the levels of Bcl-2 protein is a key event during apoptosis 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) p38 mitogen-activated protein kinase (p38MAPK)-dependent destabilization of Bcl-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 cisplatin-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 activation during infection, it prevents p38MAPK-dependent destabilization of Bcl-2 and exploits p38MAPK stimulation to enhance transcription of specific viral gene promoters to increase viral yields.
Institute of Virology, University of Glasgow, Glasgow G11 5JR, United Kingdom.
G
G
Zachos
M
M
Koffa
C M
CM
Preston
J B
JB
Clements
J
J
Conner
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D006224:Cricetinae; D003574:Cytochrome c Group / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D006367:HeLa Cells; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014162:Transfection; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases
D003574:Cytochrome c Group; D004279:DNA, Viral; C057120:ICP27 protein, human herpesvirus 1; D017874:Immediate-Early Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C048925:herpes simplex virus, type 1 protein ICP4; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D002945:Cisplatin