I kappa kappa mediates NF-kappa B activation in human immunodeficiency virus-infected cells

Human monocytes and macrophages are persistent reservoirs of human immunode ficiency virus (HIV) type-1. Persistent HN infection of these cells results in increased levels of NF-kappa B in the nucleus secondary to increased I kappa B alpha, I kappa B beta, and I kappa B epsilon degradation, a mechani sm postulated to regulate viral persistence. To characterize the molecular mechanisms regulating HIV-mediated degradation of I kappa B, we have sought to identify the regulatory domains of I kappa B alpha targeted by HIV infe ction. Using monocytic cells stably expressing different transdominant mole cules of I kappa B alpha, we determined that persistent HIV infection of th ese cells targets the NH2 but not the COOH terminus of I kappa B alpha. Fur ther analysis demonstrated that phosphorylation at S-32 and S-36 is necessa ry for HIV-dependent I kappa B alpha degradation and NF-kappa B activation. Of the putative N-terminal I kappa B alpha kinases, we demonstrated that t he I kappa kappa complex, but not p90(rsk), is activated by HIV infection a nd mediates HIV-dependent NF-kappa B activation, Analysis of viral replicat ion in cells that constitutively express I kappa B alpha negative transdomi nant molecules demonstrated a lack of correlation between virus-induced NF- kappa B (p65/p50) nuclear translocation and degree of viral persistence in human monocytes.