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Journal of Virology, December 1998, p. 9698-9705, Vol. 72, No. 12
Unité de Biologie des Rétrovirus,
Received 28 April 1998/Accepted 9 September 1998
This work aims at characterizing the interplay between human
immunodeficiency virus type 1 (HIV-1) and the antiapoptotic cellular protein Bcl-2 responsible for a persistent infection in lymphoblastoid T (J.Jhan) or monocytic (U937) cells. We report that the kinetics of
Bcl-2 protein level during the establishment of a chronic infection is
biphasic, characterized by a transient decrease followed by restoration
to the initial level. The extent and duration of this transient
decrease were inversely correlated with the basal level of Bcl-2 as
shown by kinetics of Bcl-2 levels in J.Jhan or U937 clones exhibiting
different levels of Bcl-2. Using these clones, we also showed that
Bcl-2 downregulates HIV-1 replication. Therefore, the cells
overexpressing Bcl-2 are characterized by a low viral burden which, in
turn, has little effect on the level of this protein. The observed
bipasic kinetics is the result of a dual regulation of Bcl-2 induced by
HIV-1 infection itself: an upregulation at the transcriptional level of
the bcl-2 gene concomitant with a downregulation at the
protein level. Convergent data suggest that this downregulation is
caused by the oxidative stress induced by the infection itself as shown
by the associated modulations of glutathione and thioredoxin levels and
by the prevention of these dysregulations by
N-acetylcysteine. Altogether, these data indicate that
infection first results in a decrease of Bcl-2, permitting an initial
boost of replication. Then, as the synthesis at the transcriptional
level proceeds, the replication is negatively controlled by Bcl-2 to
reach a balance characterized by low virus production and a level of
Bcl-2 compatible with cell survival. We suggest that the basal level of
Bcl-2, together with infection-inducible transcription factors able to
activate bcl-2 gene transcription, is a critical cellular
determinant in the tendency toward an acute or a persistent infection.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Human Immunodeficiency Virus Induces a Dual
Regulation of Bcl-2, Resulting in Persistent Infection of
CD4+ T- or Monocytic Cell Lines
*
Corresponding author. Mailing address: Unité de
Biologie des Rétrovirus, Institut Pasteur, 28 rue du Dr. Roux,
75724 Paris Cedex 15, France. Phone: 33 1 4568 8944/8733. Fax: 33 1 4568 8957. E-mail: nisrael{at}pasteur.fr.
Journal of Virology, December 1998, p. 9698-9705, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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