In vitro treatment of human monocyte-derived macrophages with HIV-1 protein Nef activates cellular signaling pathways leading to type I Interferon production

The viral protein Nef is a virulence factor that plays multiple roles during the HIV replication cycle. Nef expression regulates cell surface expression of critical proteins, inducing downregulation of CD4 and MHC-I, T cell receptor signaling and apoptosis, inducing pro-apoptotic effects in uninfected bystander cells and anti-apoptotic effects in infected cells [1]. The exogenous Nef treatment of cells in culture has several effects ranging from induction of apoptosis in uninfected T cells, maturation in dendritic cells and suppression of CD40- dependent immunoglobulin class switching in B cells. We have previously observed that Nef treatment of monocyte-derived macrophages (MDM) induces a pro-inflammatory state characterized by the activation of NF-?B pathway and the release of a set of chemo- and cytokines. Analyses performed on treated MDM showed that Nef is able to up-regulate the expression of IFN? mRNA. The induction of IFN? mRNA is correlated to the phosphorylation of IRF-3 and is followed by the synthesis and the release of this cytokine leading to the activation of STAT2 and the induction of IRF-7.