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Journal of Virology, March 2007, p. 2777-2791, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.01640-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro Treatment of Human Monocytes/Macrophages with Myristoylated Recombinant Nef of Human Immunodeficiency Virus Type 1 Leads to the Activation of Mitogen-Activated Protein Kinases, IB Kinases, and Interferon Regulatory Factor 3 and to the Release of Beta Interferon

Giorgio Mangino,¹ Zulema A. Percario,¹ Gianna Fiorucci,^2,3 Gabriele Vaccari,⁴ Santiago Manrique,⁵ Giovanna Romeo,^3,7 Maurizio Federico,⁵ Matthias Geyer,⁶ and Elisabetta Affabris^1*

Department of Biology, University Roma Tre,¹ Institute of Molecular Biology and Pathology, CNR, Rome, Italy,² Department of Infectious, Parasitic and Immune-Mediated Diseases,³ Department of Food Safety and Veterinary Public Health,⁴ National AIDS Center, Ist. Superiore di Sanità, Rome, Italy,⁵ Max-Planck-Institut für Molekulare Physiologie, Abteilung Physikalische Biochemie, Dortmund, Germany,⁶ Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy⁷

Received 1 August 2006/ Accepted 6 December 2006

The viral protein Nef is a virulence factor that plays multiple roles during the early and late phases of human immunodeficiency virus (HIV) replication. Nef regulates the cell surface expression of critical proteins (including down-regulation of CD4 and major histocompatibility complex class I), T-cell receptor signaling, and apoptosis, inducing proapoptotic effects in uninfected bystander cells and antiapoptotic effects in infected cells. It has been proposed that Nef intersects the CD40 ligand signaling pathway in macrophages, leading to modification in the pattern of secreted factors that appear able to recruit and activate T lymphocytes, rendering them susceptible to HIV infection. There is also increasing evidence that in vitro cell treatment with Nef induces signaling effects. Exogenous Nef treatment is able to induce apoptosis in uninfected T cells, maturation in dendritic cells, and suppression of CD40-dependent immunoglobulin class switching in B cells. Previously, we reported that Nef treatment of primary human monocyte-derived macrophages (MDMs) induces a cycloheximide-independent activation of NF-B and the synthesis and secretion of a set of chemokines/cytokines that activate STAT1 and STAT3. Here, we show that Nef treatment is capable of hijacking cellular signaling pathways, inducing a very rapid regulatory response in MDMs that is characterized by the rapid and transient phosphorylation of the and ß subunits of the IB kinase complex and of JNK, ERK1/2, and p38 mitogen-activated protein kinase family members. In addition, we have observed the activation of interferon regulatory factor 3, leading to the synthesis of beta interferon mRNA and protein, which in turn induces STAT2 phosphorylation. All of these effects require Nef myristoylation.

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* Corresponding author. Mailing address: Department of Biology—University Roma Tre, V.le G. Marconi 446-00146 Rome, Italy. Phone: 39 06 55176341. Fax: 39 06 55176321. E-mail: affabris{at}uniroma3.it.

Published ahead of print on 20 December 2006.

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Journal of Virology, March 2007, p. 2777-2791, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.01640-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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