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Originally published In Press as doi:10.1074/jbc.M209622200 on November 4, 2002
J. Biol. Chem., Vol. 278, Issue 4, 2219-2227, January 24, 2003
Exogenous Nef Protein Activates NF- B, AP-1, and c-Jun
N-Terminal Kinase and Stimulates HIV Transcription in Promonocytic
Cells
ROLE IN AIDS PATHOGENESIS*
Audrey
Varin ,
Sunil K.
Manna§,
Vincent
Quivy¶ ,
Anne-Zélie
Decrion ,
Carine
Van
Lint¶**,
Georges
Herbein , and
Bharat B.
Aggarwal§
From the Department of Virology and Institut d'Etude
et de Transfert de Gènes, Franche-Comté University, F-25030
Besançon, France, the ¶ Université Libre de Bruxelles,
Institut de Biologie et de Médecine Moléculaires (IBMM),
Chimie Biologique, 6041 Gosselies, Belgium, and the
§ Cytokine Research Section, Department of Bioimmunotherapy,
Cytokine Research Section, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas 77030
The human immunodeficiency virus (HIV) Nef
protein plays a critical role in AIDS pathogenesis by enhancing
replication and survival of the virus within infected cells and by
facilitating its spread in vivo. Most of the data obtained
so far have been in experiments with endogenous Nef protein, so far
overlooking the effects of exogenous soluble Nef protein. We used
recombinant exogenous Nef proteins to activate nuclear transcription
factors NF- B and AP-1 in the promonocytic cell line U937. Exogenous
SIV and HIV-1 Nef proteins activated NF- B and AP-1 in a dose- and time-dependent manner. Activation of NF- B by exogenous
Nef was concomitant to the degradation of the inhibitor of NF- B,
I B . In agreement with increased AP-1 activation, a time- and
dose-dependent increase in JNK activation was observed
following treatment of U937 cells with exogenous Nef. Since exogenous
Nef activates the transcription factors NF- B and AP-1, which bind to
the HIV-1 long terminal repeat (LTR), we investigated the effect of
exogenous Nef on HIV-1 replication. We observed that exogenous Nef
stimulated HIV-1 LTR via NF- B activation in U937 cells and enhanced
viral replication in the chronically infected promonocytic cells U1. Therefore, our results suggest that exogenous Nef could fuel the progression of the disease via stimulation of HIV-1 provirus present in
such cellular reservoirs as mononuclear phagocytes in HIV-infected patients.
*
This research was funded by The Clayton Foundation for
Research (to B. B. A.), by grants from the Franche-Comté
University, France (to G. H.), and from the Fonds National de la
Recherche Scientifique (FNRS, Belgium), the
Télévie-Program, the Université Libre de Bruxelles
(ULB), the Internationale Brachet Stiftung, the CGRI-INSERM
cooperation, the Région Wallonne-Commission Européenne FEDER, the Agence Nationale de Recherches sur le SIDA (ANRS, France), the Theyskens-Mineur Foundation (to C. V. L.), the Biotechnology and
Biological Sciences Research Council (Grant 24/C12902), and the
European Union Fifth Framework (Grant QLK2-CT-2000-01630).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Aspirant of the FNRS.
**
Maître de Recherches of the FNRS.

To whom correspondence should be addressed: Cytokine Research
Section; Dept. of Bioimmunotherapy, The University of Texas, M. D.
Anderson Cancer Center; Houston, TX 77030. Tel.: 713-794-1817; Fax:
713-794-1613; E-mail: aggarwal@mdanderson.org.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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