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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,
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
(TGF-
). 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-
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-
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.

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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