Activation of macrophages and microglia cells after HIV-1 infection and their production of inflammatory mediators contribute to HIV-associated CNS diseases. The mechanisms that initiate and maintain inflammation after HIV-1 infection in the brain have not been well studied. Furthermore, it is not understood why in HIV-associated CNS disease, macrophages and microglia are biased toward inflammation rather than production of mediators that control inflammation. We have focused on the receptor tyrosine kinase RON, a critical negative regulator of macrophage function and inflammation, to determine whether this receptor regulates HIV-1 expression. Overexpressing RON in monocytes/macrophages demonstrates that RON inhibits HIV-1 proviral transcription in part by decreasing the binding activity of NF-κB to the HIV-1 long terminal repeat. Because macrophages and microglia cells are a critical reservoir for HIV-1 in the CNS, we examined brain tissues for RON expression and detected RON in astrocytes, cortical neurons, and monocytoid cells. RON was detected in all control patients who were HIV seronegative (n = 7), whereas six of nine brain samples obtained from AIDS patients exhibited reduced RON protein. These data suggest that RON initiates signaling pathways that negatively regulate HIV-1 transcription in monocytes/macrophages and that HIV-1 suppresses RON function by decreasing protein levels in the brain to assure efficient replication. Furthermore, HIV-1 infection would compromise the ability of RON to protect against inflammation and consequent CNS damage.

CCAAT/enhancer binding proteins (C/EBP) have been shown to be required for HIV-1 transcription and replication in macrophages. However, whether these transcription factors influence the ability of virus to establish infection by altering cytokine or receptor expression or primarily regulate HIV-1 transcription has not been determined. By inhibiting endogenous C/EBP activity with a dominant-negative protein, we demonstrate that functional C/EBPs are not required for HIV-1 infection and that these factors influence replication by a transcriptional mechanism. C/EBPbeta recruits coactivators to the HIV-1 long-terminal repeat (LTR) and physically interacts with histone acetyltransferase (HAT) complexes, suggesting that C/EBPs participate in remodeling the chromatin organization of the HIV-1 provirus. Furthermore, overexpression of a C/EBP dominant-negative inhibits displacement of nucleosomes located at the HIV-1 transcriptional start site. These results provide insight into the general mechanisms by which C/EBPs regulate macrophage-restricted HIV-1 transcription.

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