NF-KAPPA-B-DEPENDENT INDUCTION OF THE NF-KAPPA-B P50-SUBUNIT GENE PROMOTER UNDERLIES SELF-PERPETUATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TRANSCRIPTION IN MONOCYTIC CELLS

The molecular mechanisms underlying the sustained nuclear translocation of NF-kappa-B observed in U937 monocytic cells chronically infected with human immunodeficiency virus (HIV) were studied. The activity of the promoter regulating the synthesis of the p105 precursor of the NF-kappa-B p50 subunit was enhanced in these cells. Deletions in this promoter indicated that this upregulation was mediated through the NF-kappa-B- but not the AP-1-binding motif, by bona fide p50/p65 heterodimers. Analysis of cytosolic extracts indicated that NF-kappa-B levels were increased in HIV-infected cells. In contrast to the transient NF-kappa-B activation induced by phorbol ester, the permanent NF-kappa-B translocation induced by HIV infection was not dependent on PKC isoenzymes alpha and beta as shown by the use of a specific inhibitor (GF 109203X). These observations indicate that during chronic HIV infection of U937 cells, continuous NF-kappa-B (p50/p65) translocation results in p105 promoter up-regulation with subsequent cytosolic NF-kappa-B accumulation, ready for further translocation. This HIV-mediated mechanism results in a self-perpetuating loop of NF-kappa-B production.