TREATMENT OF HIV-1 BY MODULATION OF VPR ACTIVATION OF THE M-CSF PROMOTER

摘要

Macrophage colony-stimulating factor (M-CSF) is important for human immunodeficiency virus-type 1 (HIV-1) infection, replication and survival of infected cells. The mechanism(s) by which HIV-1 infection increases M-CSF production are, however, poorly understood. Here, we report that HIV-1 Vpr enhances M-CSF promoter activity and production in primary human monocytes and macrophages. Vpr activates M-CSF transcription through four C/EBP beta binding sites present within the M-CSF promoter, possibly through increased phosphorylation of C/EBP beta. RU486 (mifepristone) blocked Vpr-mediated up-regulation of M-CSF, suggesting that Vpr activates M-CSF promoter activity via the glucocorticoid pathway. The invention provides new avenues for therapeutic interventions in HIV-1 infection and other diseases involving M-CSF dysregulation (including malignancy, osteoporosis, autoimmune disorders, arthritis, and obesity) using glucocorticoid antagonists and modulators of C/EBP beta activity.