Human Immunodeficiency Virus Induces a Dual Regulation of Bcl-2, Resulting in Persistent Infection of CD4+ T- or Monocytic Cell Lines

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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.

Human Immunodeficiency Virus Induces a Dual Regulation of Bcl-2, Resulting in Persistent Infection of CD4⁺ T- or Monocytic Cell Lines

Fabienne Aillet,¹ Hiroshi Masutani,¹^,² Carole Elbim,³ Hervé Raoul,¹ Laurent Chêne,¹ Marie-Thérèse Nugeyre,¹ Carlos Paya,⁴ Françoise Barré-Sinoussi,¹ Marie-Anne Gougerot-Pocidalo,³ and Nicole Israël¹^,^*

Unité de Biologie des Rétrovirus, Institut Pasteur, 75724 Paris Cedex 15,¹ and Unité INSERM U479, Hopital Bichat, 75018 Paris,³ France; Institute for Virus Research, Kyoto University, Kawaharacho, Shogoin, Sakyo, Kyoto 606, Japan²; and Infectious Diseases and Immunology, Mayo Clinic, Rochester, Minnesota 55905⁴

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 cellularprotein Bcl-2 responsible for a persistent infection in lymphoblastoidT (J.Jhan) or monocytic (U937) cells. We report that the kineticsof Bcl-2 protein level during the establishment of a chronic infectionis biphasic, characterized by a transient decrease followed byrestoration to the initial level. The extent and duration of thistransient decrease were inversely correlated with the basal levelof Bcl-2 as shown by kinetics of Bcl-2 levels in J.Jhan or U937clones 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 viralburden which, in turn, has little effect on the level of thisprotein. The observed bipasic kinetics is the result of a dualregulation of Bcl-2 induced by HIV-1 infection itself: an upregulationat the transcriptional level of the bcl-2 gene concomitant witha downregulation at the protein level. Convergent data suggestthat this downregulation is caused by the oxidative stress inducedby the infection itself as shown by the associated modulationsof glutathione and thioredoxin levels and by the prevention ofthese dysregulations by N-acetylcysteine. Altogether, these dataindicate that infection first results in a decrease of Bcl-2,permitting an initial boost of replication. Then, as the synthesisat the transcriptional level proceeds, the replication is negativelycontrolled by Bcl-2 to reach a balance characterized by low virusproduction and a level of Bcl-2 compatible with cell survival.We suggest that the basal level of Bcl-2, together with infection-inducibletranscription factors able to activate bcl-2 gene transcription,is a critical cellular determinant in the tendency toward an acuteor a persistentinfection.

^* Corresponding author. Mailing address: Unité de Biologie des Rétrovirus, Institut Pasteur, 28 rue du Dr. Roux, 75724 ParisCedex 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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