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Blood. 2015 Mar 5;125(10):1611-22. doi: 10.1182/blood-2014-08-596775. Epub 2014 Dec 19.

HIV-1 reprograms the migration of macrophages.

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Centre National de la Recherche Scientifique Unité Mixte de Recherche 5089, Institut de Pharmacologie et de Biologie Structurale, Toulouse Cedex 04, France; Université de Toulouse-Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France;
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC, Canada; Division of Experimental Medicine, McGill University, Montreal, QC, Canada; Department of Microbiology and Immunology, University of Montreal, Montreal, QC, Canada;
Centre de Microscopie Électronique Appliquée à la Biologie, Faculté de Médecine de Rangueil, Toulouse Cedex, France;
Department of Infectious Diseases, Integrative Virology, Heidelberg, Germany;
INSERM U1016, Institut Cochin, Paris, France; and Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France.


Macrophages are motile leukocytes, targeted by HIV-1, thought to play a critical role in host dissemination of the virus. However, whether infection impacts their migration capacity remains unknown. We show that 2-dimensional migration and the 3-dimensional (3D) amoeboid migration mode of HIV-1-infected human monocyte-derived macrophages were inhibited, whereas the 3D mesenchymal migration was enhanced. The viral protein Nef was necessary and sufficient for all HIV-1-mediated effects on migration. In Nef transgenic mice, tissue infiltration of macrophages was increased in a tumor model and in several tissues at steady state, suggesting a dominant role for mesenchymal migration in vivo. The mesenchymal motility involves matrix proteolysis and podosomes, cell structures constitutive of monocyte-derived cells. Focusing on the mechanisms used by HIV-1 Nef to control the mesenchymal migration, we show that the stability, size, and proteolytic function of podosomes are increased via the phagocyte-specific kinase Hck and Wiskott-Aldrich syndrome protein (WASP), 2 major regulators of podosomes. In conclusion, HIV-1 reprograms macrophage migration, which likely explains macrophage accumulation in several patient tissues, which is a key step for virus spreading and pathogenesis. Moreover, Nef points out podosomes and the Hck/WASP signaling pathway as good candidates to control tissue infiltration of macrophages, a detrimental phenomenon in several diseases.

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