PROTEIN-KINASE C-ZETA MEDIATES NF-KAPPA-B ACTIVATION IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED MONOCYTES

The molecular mechanisms regulating human immunodeficiency virus (HIV) persistence in a major cell reservoir such as the macrophage remain u nknown. NF-kappa B is a transcription factor involved in the regulatio n of the HIV long terminal repeat and is selectively activated followi ng HIV infection of human macrophages. Although little information as to what signal transduction pathways mediate NF-kappa B activation in monocytes-macrophages is available, our previous work indicated that c lassical protein kinase C (PKC) isoenzymes were not involved in the HI V-mediated NF-kappa B activation. In this study, we have focused on at ypical PKC isoenzymes. PKC-zeta belongs to this family and is known to be an important step in NF-kappa B activation in other cell systems. Immunoblotting experiments with U937 cells demonstrate that PKC-zeta i s present in these cells, and its expression can be downmodulated by a ntisense oligonucleotides (AO). The HIV-mediated NF-kappa B activation is selectively reduced by AO to PKC-zeta. In addition, cotransfection of a negative dominant molecule of PI(C-S (PKC-zeta(mut))) with NF-ka ppa B dependent reporter genes selectively inhibits the HIV but not ph orbol myristate acetate- or lipopolysaccharide-mediated activation of NF-kappa B. That PKC-S is specific in regulating NF-kappa B is conclud ed from the inability of PKC-zeta(mut) to interfere with the basal or phorbol myristate acetate-inducible CREB- or AP1-dependent transcripti onal activity. Lastly, we demonstrate a selective inhibition of p24 pr oduction by HIV-infected human macrophages when treated with AO to PKC -zeta. Altogether, these results suggest that atypical PKC isoenzymes, including PKC-S, participate in the signal transduction pathways by w hich HIV infection results in the activation of NF-kappa B in human mo nocytic cells and macrophages.