NF-κB and p53 Are the Dominant Apoptosis-inducing Transcription Factors Elicited by the HIV-1 Envelope

Jean Luc Perfettini, Thomas Roumier, Maria Castedo, Nathanael Larochette, Patricia Boya, Brigitte Raynal, Vladimir Lazar, Fabiola Ciccosanti, Roberta Nardacci, Josef Penninger, Mauro Piacentini, Guido Kroemer

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Abstract

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-κB, p53, and AP1 are activated in Env-elicited apoptosis. The nuclear factor κB (NF-κB) 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-κB 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-α. 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-κB and p53 cooperate as the dominant proapoptotic transcription factors participating in HIV-1 infection.

Original languageEnglish
Pages (from-to)629-640
Number of pages12
JournalJournal of Experimental Medicine
Volume199
Issue number5
DOIs
Publication statusPublished - Mar 1 2004

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Keywords

  • Bak
  • Bax
  • Mitochondria
  • NF-κB
  • Puma

ASJC Scopus subject areas

  • Immunology

Cite this

Perfettini, J. L., Roumier, T., Castedo, M., Larochette, N., Boya, P., Raynal, B., Lazar, V., Ciccosanti, F., Nardacci, R., Penninger, J., Piacentini, M., & Kroemer, G. (2004). NF-κB and p53 Are the Dominant Apoptosis-inducing Transcription Factors Elicited by the HIV-1 Envelope. Journal of Experimental Medicine, 199(5), 629-640. https://doi.org/10.1084/jem.20031216