TRAF activation of C/EBPβ (NF-IL6) via p38 MAPK induces HIV-1 gene expression in monocytes/macrophages

C/EBPβ plays a pivotal role in activation of human immunodeficiency virus type 1 (HIV-1) in monocytes/macrophages. However, mechanisms for functional regulation of C/EBPβ remain uncharacterized. Previous studies indicated that NF-κB activation by tumor necrosis factor (TNF) receptor family, which activates TNF receptor associated factor (TRAF), induces HIV-1 expression. We found that TRAF signals activate HIV-1 LTR with mutations of NF-κB sites in promonocytic cell line U937, suggesting existence of an alternative HIV-1 activating pathway. In this study, we have characterized the signal transduction pathway of TRAF other than that leading to NF-κB, using U937 cell line, and its subline, U1, which is chronically infected by HIV-1. We show that signals downstream of TRAF2 and TRAF5 activate p38 MAPK, which directly phosphorylates C/EBPβ, and that activation of p38 MAPK potently activates C/EBPβ-mediated induction of HIV-1 gene expression. We also show TRAF2 and TRAF5 are expressed in monocytes/macrophages of spleen samples from HIV-1 infected patients. Identification of TRAF-p38 MAPK-CEBPβ pathway provides a new target for controlling reactivation of latent HIV-1 in monocytes/macrophages.