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Journal of Virology, March 2001, p. 2710-2728, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2710-2728.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

George Zachos,1,2,dagger Margy Koffa,1 Chris M. Preston,3 J. Barklie Clements,1 and Joe Conner2,*

Institute of Virology, University of Glasgow,1 and MRC Virology Unit, Institute of Virology,3 Glasgow G11 5JR, and School of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA,2 United Kingdom

Received 20 September 2000/Accepted 19 December 2000

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.

* Corresponding author. Mailing address: School of Biological and Biomedical Sciences, Glasgow Caledonian University, Cowcaddens Rd., Glasgow G4 0BA, United Kingdom. Phone: (44 141) 331 3219. Fax: (44 141) 331 3208. E-mail: J.Conner{at}gcal.ac.uk.

dagger Present address: CRC Beatson Institute for Cancer Research, Glasgow G61 1BD, United Kingdom.

Journal of Virology, March 2001, p. 2710-2728, Vol. 75, No. 6
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.6.2710-2728.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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