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HIV-1 Nef Induces the Release of Inflammatory Factors from Human Monocyte/Macrophages: Involvement of Nef Endocytotic Signals and NF-B Activation ¹

Eleonora Olivetta^*, Zulema Percario, Gianna Fiorucci, Gianfranco Mattia^,¶, Ilaria Schiavoni^*, Caitriona Dennis^¶, Joachim Jäger^¶, Mark Harris^¶, Gianna Romeo, Elisabetta Affabris and Maurizio Federico^2,*

Laboratories of ^* Virology and Clinical Biochemistry, Istituto Superiore di Sanità, Department of Biology, University of Roma Tre, and Institute of Biomedical Technology, Consiglio Nazionale delle Ricerche, Rome, Italy; and ^¶ School of Biochemistry and Molecular Biology, University of Leeds, Leeds, United Kingdom

It has been recently reported that the endogenous expression of HIV-1 Nef in human monocyte/macrophages induces the release of chemokines and other as yet unidentified soluble factors leading to multiple effects of pathogenic significance, such as the recruitment and activation of quiescent lymphocytes. However, the description of underlying molecular mechanisms remained elusive. We recently demonstrated that human monocyte-derived macrophages (MDM) efficiently internalize soluble rNef, thereby inducing effects largely resembling those observed in cells endogenously expressing Nef. By exploiting the rNef/MDM model, we sought to gain more insights on the molecular mechanisms underlying the response of MDM to Nef. Array analysis for the detection of transcripts from a large number of monokines, chemokines, cytokines, and receptors thereof showed that MDM promptly responded to rNef treatment by increasing the transcription of genes for several inflammatory factors. Analysis of supernatants revealed that rNef treatment induced the release of macrophage inflammatory proteins 1 and 1, IL-1, IL-6, and TNF-. Conversely, rNefs mutated in domains critical for the interaction with the endocytotic machinery (i.e., EE155-156QQ, and DD174-175AA) were ineffective. Interestingly, we found that the Nef-dependent release of inflammatory factors correlated with the activation of the NF-B transcription factor, mainly in its p50/p50 homodimeric form, and in a de novo protein synthesis-independent manner. Our data add new hints supporting the idea that the presence of Nef is per se heavily detrimental for monocyte/macrophages and relative cross-talking cell types.

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