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Journal of Virology, March 2001, p. 2400-2410, Vol. 75, No. 5
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.5.2400-2410.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Activators of the Epstein-Barr Virus Lytic Program Concomitantly Induce Apoptosis, but Lytic Gene Expression Protects from Cell Death

Gareth J. Inman,dagger Ulrich K. Binné, Gillian A. Parker, Paul J. Farrell, and Martin J. Allday*

Section of Virology and Cell Biology and Ludwig Institute for Cancer Research, Imperial College of Science Technology and Medicine, London W2 1PG, United Kingdom

Received 11 September 2000/Accepted 27 November 2000

Expression of the lytic cycle genes of Epstain-Barr virus (EBV) is induced in type I Burkitt's lymphoma-derived cells by treatment with phorbol esters (e.g., phorbol myristate acetate [PMA]), anti-immunoglobulin, or the cytokine transforming growth factor beta  (TGF-beta ). Concomitantly, all these agents induce apoptosis as judged by a sub-G1 fluorescence-activated cell sorter (FACS) profile, proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. However, caspase activation is not required for induction of the lytic cycle since the latter is not blocked by the caspase inhibitor ZVAD. Furthermore, not all agents that induce apoptosis in these cultures (for example, cisplatin and ceramide) induce the EBV lytic programme. Although it is closely associated with the lytic cycle, apoptosis is neither necessary nor sufficient for its activation. Multiparameter FACS analysis of cultures treated with PMA, anti-Ig, or TGF-beta revealed BZLF1-expressing cells distributed in different phases of the cell cycle according to which inducer was used. However, BZLF1-positive cells did not appear to undergo apoptosis and accumulate with a sub-G1 DNA content, irrespective of the inducer used. This result, which suggests that lytic gene expression is protective, was confirmed and extended by immunofluorescence staining doubled with TUNEL analysis. BZLF1- and also gp350-expressing cells were almost always shown to be negative for TUNEL staining. Similar experiments using EBV-positive and -negative subclones of Akata BL cells carrying an episomal BZLF1 reporter plasmid confirmed that protection from apoptosis was associated with the presence of the EBV genome. Finally, treatment with phosphonoacetic acid or acyclovir prior to induction with PMA, anti-Ig, or TGF-beta blocked the protective effect in Mutu-I cells. These data suggest that a late gene product(s) may be particularly important for protection against caspase activity and cell death.

* Corresponding author. Mailing address: Section of Virology and Cell Biology and Ludwig Institute for Cancer Research, Imperial College of Science Technology and Medicine, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom. Phone: (44) 207 563 7724. Fax: (44) 207 724 8586 E-mail: m.allday{at}ic.ac.uk.

dagger Present address: Developmental Signalling Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.

Journal of Virology, March 2001, p. 2400-2410, Vol. 75, No. 5
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.5.2400-2410.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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