CONTROL OF HIV1 REPLICATION BY C/EBP PROTEINS

Our long term goals are to understand how cellular transcription proteins regulate the growth of human immunodeficiency virus (HIV). In preliminary studies we have recently identified the CCAAT/enhancer binding protein (C/EBP) family of transcriptional regulators as an important family of inducible transcription proteins which regulate HIV expression. C/EBP proteins and NF-kappaB/rel proteins are the only cellular transcription proteins known to regulate HIV-1 that are induced when T cells or monocyte/macrophages are activated. The studies proposed here will: i) establish precisely the role of C/EBP proteins for HIV growth in T cells, and monocyte/macrophages ii) explore the molecular mechanisms involved in regulation of HIV expression by C/EBP proteins and iii) elucidate how C/EBP proteins are regulated upon cellular activation. We will create mutant viruses to determine the importance of C/EBP proteins for HIV growth in monocyte macrophages and T cells. We will study the molecular mechanisms by which the inducible C/EBP protein NF-IL6 activates HIV transcription by elucidating precisely how NF-IL6 participates in autoregulatory loops with cytokines and HIV-1 expression and by identifying proteins which associate with NF-IL6. Since NF-IL6 appears to play a key role in HIV expression in monocyte/macrophages, we will also study the mechanisms which regulate NF-IL6 activity in these cells. Finally, we will attempt to design strong dominant negative forms of NF-IL6 as a tool for studying the function of C/EBP proteins and to provide a basis for the design of therapeutic agents to block C/EBP activators.