| HIV-1 Nef triggers macrophage fusion in a p61Hck- and protease-dependent manner. | |
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MedLine Citation:
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PMID: 20488787 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Macrophages are a major target of HIV-1 infection. HIV-1-infected macrophages form multinucleated giant cells (MGCs) using poorly elucidated mechanisms. In this study, we show that MGC formation was reduced when human macrophages were infected with nef-deleted HIV-1. Moreover, expression of Nef, an HIV-1 protein required in several aspects of AIDS, was sufficient to trigger the formation of MGCs in RAW264.7 macrophages. Among Nef molecular determinants, myristoylation was dispensable, whereas the polyproline motif was instrumental for this phenomenon. Nef has been shown to activate hematopoietic cell kinase (Hck), a Src tyrosine kinase specifically expressed in phagocytes, through a well-described polyproline-SH3 interaction. Knockdown approaches showed that Hck is involved in Nef-induced MGC formation. Hck is expressed as two isoforms located in distinct subcellular compartments. Although both isoforms were activated by Nef, only p61Hck mediated the effect of Nef on macrophage fusion. This process was abolished in the presence of a p61Hck kinase-dead mutant or when p61Hck was redirected from the lysosome membrane to the cytosol. Finally, lysosomal proteins including vacuolar adenosine triphosphatase and proteases participated in Nef-induced giant macrophage formation. We conclude that Nef participates in HIV-1-induced MGC formation via a p61Hck- and lysosomal enzyme-dependent pathway. This work identifies for the first time actors of HIV-1-induced macrophage fusion, leading to the formation of MGCs commonly found in several organs of AIDS patients. |
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Authors:
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Christel V?rollet; Yan Mei Zhang; V?ronique Le Cabec; Julie Mazzolini; Guillaume Charri?re; Arnaud Labrousse; J?r?me Bouchet; Indira Medina; Erik Biessen; Florence Niedergang; Serge B?nichou; Isabelle Maridonneau-Parini |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-19 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 184 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-07 Completed Date: 2010-06-18 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 7030-9 Citation Subset: AIM; IM |
Affiliation:
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D?partement M?canismes Mol?culaires des Infections Mycobact?riennes, Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique Unit? Mixte de Recherche 5089, France. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Gene Products, nef / immunology, metabolism* Giant Cells / immunology, metabolism, virology* HIV Infections / immunology, metabolism* Humans Immunoblotting Isoenzymes Macrophages / immunology, metabolism, virology* Mice Microscopy, Fluorescence Proto-Oncogene Proteins c-hck / immunology, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Gene Products, nef; 0/Isoenzymes; EC 2.7.10.2/Proto-Oncogene Proteins c-hck |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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