REGULATION OF I-KAPPA-B-ALPHA AND P105 IN MONOCYTES AND MACROPHAGES PERSISTENTLY INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS

The mechanisms regulating human immunodeficiency virus (HIV) persisten ce in human monocytes/macrophages are partially understood. Persistent HIV infection of U937 monocytic cells results in NF-kappa B activatio n. Whether virus-induced NF-KB activation is a mechanism that favors c ontinuous viral replication in macrophages remains unknown. To further delineate the molecular mechanisms involved in the activation of NF-k appa B in HIV-infected monocytes and macrophages, we have focused on t he regulation of the I kappa B molecules. First, we show that persiste nt HIV infection results in the activation of NF-kappa B not only in m onocytic cells but also in macrophages. In HIV-infected cells, I kappa B alpha protein levels are decreased secondary to enhanced protein de gradation. This parallels the increased I kappa B alpha synthesis seco ndary to increased I kappa B alpha gene transcription, i.e., increased RNA and transcriptional activity of its promoter-enhancer. Another pr otein with I kappa B function, p105, is also modified in HIV-infected cells: p105 and p50 steady-state protein levels are increased as a res ult of increased synthesis and proteolytic processing of p105. Transcr iptional activity of p105 is also increased in infected cells and is a lso mediated by NF-kappa B through a specific kappa B moth. These resu lts demonstrate the existence of a triple autoregulatory loop in monoc ytes and macrophages involving HIV, p105 and p50, and MAD3, with the e nd result of persistent NF-kappa B activation and viral persistence. F urthermore, persistent HIV infection of monocytes and macrophages prov ides a useful model with which to study concomitant modifications of d ifferent I kappa B molecules.