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

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

SUBMITTER: Fiume G 

PROVIDER: S-EPMC3333881 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other