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

• Published in: The Journal of experimental medicine Vol. 199; no. 5; pp. 629 - 640
• Main Authors: Perfettini, Jean-Luc, Roumier, Thomas, Castedo, Maria, Larochette, Nathanael, Boya, Patricia, Raynal, Brigitte, Lazar, Vladimir, Ciccosanti, Fabiola, Nardacci, Roberta, Penninger, Josef, Piacentini, Mauro, Kroemer, Guido
• Format: Journal Article
• Language: English
• Published: The Rockefeller University Press 01-03-2004
• Subjects: Human immunodeficiency virus 1
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20031216

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.