Human immunodeficiency virus-1 Tat activates NF-kappa B via physical interaction with I kappa B-alpha and p65

摘要

Nuclear factor (NF)-kappa B is a master regulator of pro-inflammatory genes and is upregulated in human immunodeficiency virus 1 (HIV-1) infection. Mechanisms underlying the NF-kappa B 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-kappa B by hijacking the inhibitor I kappa B-alpha and by preventing the repressor binding to the NF-kappa B complex. Moreover, Tat associated with the p65 subunit of NF-kappa B and increased the p65 DNA-binding affinity and transcriptional activity. The arginine- and cysteine-rich domains of Tat were required for I kappa B-alpha and p65 association, respectively, and for sustaining the NF-kappa B activity. Among an array of NF-kappa B-responsive genes, Tat mostly activated the MIP-1 alpha expression in a p65-dependent manner, and bound to the MIP-1 alpha NF-kappa B enhancer thus promoting the recruitment of p65 with displacement of I kappa B-alpha; similar findings were obtained for the NF-kappa B-responsive genes CSF3, LTA, NFKBIA and TLR2. Our results support a novel mechanism of NF-kappa B activation via physical interaction of Tat with I kappa B-alpha and p65, and may contribute to further insights into the deregulation of the inflammatory response by HIV-1.