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Journal of Virology, July 2006, p. 6810-6821, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00334-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

ICP0 Gene Expression Is a Herpes Simplex Virus Type 1 Apoptotic Trigger

Christine M. Sanfilippo and John A. Blaho*

Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029

Received 15 February 2006/ Accepted 25 April 2006

Apoptosis is a highly regulated programmed cell death process which is activated during normal development and by various stimuli, such as viral infection, which disturb cellular metabolism and physiology. That herpes simplex virus type 1 (HSV-1) induces apoptosis but then prevents its killing of infected cells is well-established. However, little is known about the viral factor/event which triggers the apoptotic process. We previously reported that infections with either (i) a temperature-sensitive virus at its nonpermissive temperature which does not inject viral DNA into nuclei or (ii) various UV-inactivated wild-type viruses do not result in the induction of apoptosis (C. M. Sanfilippo, F. N. W. Chirimuuta, and J. A. Blaho, J. Virol. 78:224-239, 2004). This indicates that virus receptor binding/attachment to cells, membrane fusion, virion disassembly/tegument dispersal, virion RNAs, and capsid translocation to nuclei are not responsible for induction and implicates viral immediate-early (IE) gene expression in the process. Here, we systematically evaluated the contribution of each IE gene to the stimulation of apoptosis. Using a series of viruses individually deleted for {alpha}27, {alpha}4, and {alpha}22, we determined that these genes are not required for apoptosis induction but rather that their products play roles in its prevention, likely through regulatory effects. Sole expression of {alpha}0 acted as an "apoptoxin" that was necessary and sufficient to trigger the cell death cascade. Importantly, results using a recombinant virus which contains a stop codon in {alpha}0 showed that it was not the ICP0 protein which acted as the apoptotic inducer. Based on these findings, we propose that {alpha}0 gene expression acts as an initial inducer of apoptosis during HSV-1 infection. This represents the first description of apoptosis induction in infected cells triggered as a result of expression of a single viral gene. Expression of apoptotic viral genes is a unique mechanism through which human pathogens may modulate interactions with their host cells.

* Corresponding author. Mailing address: Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574. Phone: (212) 241-7319. Fax: (212) 534-1684. E-mail: john.blaho{at}mssm.edu.

Journal of Virology, July 2006, p. 6810-6821, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00334-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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