This Article Full Text (PDF) Other Versions of this Article: JVI.01640-06v1 81/6/2777    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mangino, G. Articles by Affabris, E. Search for Related Content PubMed PubMed Citation Articles by Mangino, G. Articles by Affabris, E.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.01640-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

In vitro treatment of human monocyte/macrophages with myristoylated recombinant Nef of HIV-1 leads to the activation of MAPKs, IB kinases and Interferon Regulatory Factor 3 and to the release of Beta Interferon

Dept. of Biology, University Roma Tre, Inst. of Molecular Biology and Pathology, CNR, Rome, Italy; Dept. of Infectious, Parasitic and Immune-mediated Diseases, and, Dept. of Food Safety and Veterinary Public Health, Ist. Superiore di Sanità, Rome, Italy; Max-Planck-Institut für molekulare Physiologie, Abteilung Physikalische Biochemie, Dortmund, Germany; Dept. of Exp. Medicine and Pathology, University La Sapienza, Rome, Italy

^* To whom correspondence should be addressed. Email: affabris{at}uniroma3.it.

	Abstract

The viral protein Nef is a virulence factor that plays multiple roles during the early and late phase of HIV replication. Nef regulates cell surface expression of critical proteins (including down-regulation of CD4 and MHC-I), T cell receptor signalling and apoptosis, inducing pro-apoptotic effects in uninfected bystander cells and anti-apoptotic effects in infected cells. It has been proposed that Nef intersects the CD40 ligand signalling pathway in macrophages leading to the 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 signalling 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 described that Nef treatment of primary human MDMs induces a cycloheximide-independent activation of NF-B and the synthesis and secretion of a set of chemokine/cytokines that activates STAT1 and STAT3. Here we show that Nef treatment is capable of hijack cellular signalling pathways inducing a very rapid regulatory response in MDMs that is characterized by the rapid and transient phosphorylation of the - and - subunits of the I-B kinase complex and of JNK, ERK1/2 and p38 MAPK family members. In addition, we have observed the activation of IRF-3 leading to the synthesis of IFN mRNA and protein which in turn induces STAT2 phosphorylation. All those effects require Nef myristoylation.