title: Human immunodeficiency virus-1 Tat activates NF-κB via physical interaction with IκB-α and p65.
abstract: Nuclear factor (NF)-κB is a master regulator of pro-inflammatory genes and is upregulated in human immunodeficiency virus 1 (HIV-1) infection. Mechanisms underlying the NF-κB deregulation by HIV-1 are relevant for immune dysfunction in AIDS. We report that in single round HIV-1 infection, or single-pulse PMA stimulation, the HIV-1 Tat transactivator activated NF-κB by hijacking the inhibitor IκB-α and by preventing the repressor binding to the NF-κB complex. Moreover, Tat associated with the p65 subunit of NF-κB and increased the p65 DNA-binding affinity and transcriptional activity. The arginine- and cysteine-rich domains of Tat were required for IκB-α and p65 association, respectively, and for sustaining the NF-κB activity. Among an array of NF-κB-responsive genes, Tat mostly activated the MIP-1α expression in a p65-dependent manner, and bound to the MIP-1α NF-κB enhancer thus promoting the recruitment of p65 with displacement of IκB-α; similar findings were obtained for the NF-κB-responsive genes CSF3, LTA, NFKBIA and TLR2. Our results support a novel mechanism of NF-κB activation via physical interaction of Tat with IκB-α and p65, and may contribute to further insights into the deregulation of the inflammatory response by HIV-1.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Catanzaro Magna Graecia, Viale Europa-Germaneto, 88100 Catanzaro, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiume
authors.forename: Eleonora
authors.initials: E
authors.lastname: Vecchio
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Laurentiis
authors.forename: Francesca
authors.initials: F
authors.lastname: Trimboli
authors.forename: Camillo
authors.initials: C
authors.lastname: Palmieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisano
authors.forename: Cristina
authors.initials: C
authors.lastname: Falcone
authors.forename: Marilena
authors.initials: M
authors.lastname: Pontoriero
authors.forename: Annalisa
authors.initials: A
authors.lastname: Rossi
authors.forename: Annarita
authors.initials: A
authors.lastname: Scialdone
authors.forename: Francesca
authors.initials: F
authors.lastname: Fasanella Masci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scala
authors.forename: Ileana
authors.initials: I
authors.lastname: Quinto
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054405:Chemokine CCL3; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA