HIV-1 Nef activates STAT1 in human monocytes/macrophages through the release of soluble factors

Monocytes/macrophages play a predominant role in the immunologic network by secreting and reacting to a wide range of soluble factors. Human immunodef iciency virus (HIV) infection leads to deep immunologic dysfunctions, also as a consequence of alterations in the pattern of cytokine release. Recent studies on in vivo models demonstrated that the expression of HIV Nef alone mimics many pathogenetic effects of HIV infection. In particular, Nef expr ession in monocytes/ macrophages has been correlated with remarkable modifi cations in the pattern of secreted soluble factors, suggesting that the int eraction of Nef with monocytes/ macrophages plays a role in the pathogenesi s of acquired immunodeficiency syndrome (AIDS). This study sought to define possible alterations in intracellular signaling induced by Nef in monocyte s/macrophages. Results demonstrate that HIV-1 Nef specifically activates bo th alpha and beta isoforms of the signal transducer and activator of transc ription 1 (STAT1). This was observed both by infecting human monocyte-deriv ed macrophages (MDMs) with HIV-1 deletion mutants, and by exploiting the ab ility of MDMs to internalize soluble, recombinant Nef protein (rNef). STAT1 -alpha activation occurs on phosphorylation of both C-terminal Tyr701 and S er727 and leads to a strong binding activity. Nef-dependent STAT1 activatio n is followed by increased expression of both STAT1 and interferon regulato ry factor-1, a transcription factor transcriptionally regulated by STAT1 ac tivation. It was also established that Nef-induced STAT1-alpha/beta activat ion occurs through the secretion of soluble factors. Taken together, the re sults indicate that HIV-1 Nef could interfere with STAT1-governed Intracell ular signaling in human monocytes/macrophages.