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

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    110 Citations (Scopus)

    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)629-640
    Nombre de pages12
    journalJournal of Experimental Medicine
    Volume199
    Numéro de publication5
    Les DOIs
    étatPublié - 1 mars 2004

    Contient cette citation