J Virol, April 1998, p. 3018-3028, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Department of Microbiology and Immunology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-77, Japan
Received 29 September 1997/Accepted 19 December 1997
Infection of erythroid-lineage cells by human parvovirus B19 is
characterized by a gradual cytocidal effect. Accumulating evidence now
implicates the nonstructural (NS1) protein of the virus in
cytotoxicity, but the mechanism underlying the NS1-induced cell death
is not known. Using a stringent regulatory system, we demonstrate
that NS1 cytotoxicity is closely related to apoptosis, as evidenced by
cell morphology, genomic DNA fragmentation, and cell cycle analysis
with the human erythroleukemia cell line K562 and the
erythropoietin-dependent megakaryocytic cell line UT-7/Epo. Apoptosis
was significantly inhibited by an interleukin-1
(IL-1
)-converting enzyme (ICE)/CED-3 family protease inhibitor,
Ac-DEVD-CHO (CPP32; caspase 3), whereas a similar
inhibitor of ICE (caspase 1), Ac-YVAD-CHO, had no effect. Furthermore,
stable expression of the human Bcl-2 proto-oncogene resulted in
near-total protection from cell death in response to NS1 induction.
Mutations engineered into the nucleoside triphosphate-binding domain of
NS1 significantly rescued cells from NS1-induced apoptosis without
having any effect on NS1-induced activation of the IL-6 gene expression
which is mediated by NF-
B. Furthermore, using pentoxifylline, an
inhibitor of NF-
B activation, we demonstrate that the
NF-
B-mediated IL-6 activation by NS1 is uncoupled from the apoptotic
pathway. This functional dissection indicates a complexity underlying
the biochemical function of human parvovirus NS1 in transcriptional
activation and induction of apoptosis. Our findings indicate that NS1
of parvovirus B19 induces cell death by apoptosis in at least
erythroid-lineage cells by a pathway that involves caspase 3, whose
activation may be a key event during NS1-induced cell death.
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