The Journal of Experimental Medicine
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Published 1 March 2004. doi:10.1084/jem.20031216
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 5, 629-640
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NF-{kappa}B and p53 Are the Dominant Apoptosis-inducing Transcription Factors Elicited by the HIV-1 Envelope

Jean-Luc Perfettini1, Thomas Roumier1, Maria Castedo1, Nathanael Larochette1, Patricia Boya1, Brigitte Raynal1, Vladimir Lazar2, Fabiola Ciccosanti3, Roberta Nardacci3, Josef Penninger4, Mauro Piacentini3, and Guido Kroemer1

1 Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, F-94805 Villejuif, France
2 Unité de Génomique Fonctionnelle, Institut Gustave Roussy, F-94805 Villejuif, France
3 National Institute for Infectious Diseases IRCCS "L. Spallanzani, " Rome, Italy
4 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria

Address correspondence to Guido Kroemer, Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42-11-60-46; Fax: 33-1-42-11-60-47; email: kroemer{at}igr.fr

The coculture of cells expressing the HIV-1 envelope glycoprotein complex (Env) with cells expressing CD4 results into cell fusion, deregulated mitosis, and subsequent cell death. Here, we show that NF-{kappa}B, p53, and AP1 are activated in Env-elicited apoptosis. The nuclear factor {kappa}B (NF-{kappa}B) super repressor had an antimitotic and antiapoptotic effect and prevented the Env-elicited phosphorylation of p53 on serine 15 and 46, as well as the activation of AP1. Transfection with dominant-negative p53 abolished apoptosis and AP1 activation. Signs of NF-{kappa}B and p53 activation were also detected in lymph node biopsies from HIV-1–infected individuals. Microarrays revealed that most (85%) of the transcriptional effects of HIV-1 Env were blocked by the p53 inhibitor pifithrin-{alpha}. Macroarrays led to the identification of several Env-elicited, p53-dependent proapoptotic transcripts, in particular Puma, a proapoptotic "BH3-only" protein from the Bcl-2 family known to activate Bax/Bak. Down modulation of Puma by antisense oligonucleotides, as well as RNA interference of Bax and Bak, prevented Env-induced apoptosis. HIV-1–infected primary lymphoblasts up-regulated Puma in vitro. Moreover, circulating CD4+ lymphocytes from untreated, HIV-1–infected donors contained enhanced amounts of Puma protein, and these elevated Puma levels dropped upon antiretroviral therapy. Altogether, these data indicate that NF-{kappa}B and p53 cooperate as the dominant proapoptotic transcription factors participating in HIV-1 infection.

Key Words: Bax • mitochondria • NF-{kappa}B • Puma • Bak

The online version of this article includes supplemental material.

Abbreviations used in this paper: Cdk1, cyclin B1–dependent kinase 1; DN, dominant-negative; Env, envelope glycoprotein complex; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; HAART, highly active antiretroviral therapy; IKSR, I{kappa}B super-repressor; mTOR, mammalian target of rapamycin; NF-{kappa}B, nuclear factor {kappa}B.


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