title: HIV-1 reprograms the migration of macrophages.
abstract: 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.
authors.affiliation: 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;
authors.forename: Christel
authors.initials: C
authors.lastname: Vérollet
authors.affiliation: 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;
authors.forename: Shanti
authors.initials: S
authors.lastname: Souriant
authors.affiliation: 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;
authors.forename: Emilie
authors.initials: E
authors.lastname: Bonnaud
authors.affiliation: 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;
authors.forename: Paul
authors.initials: P
authors.lastname: Jolicoeur
authors.affiliation: 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;
authors.forename: Brigitte
authors.initials: B
authors.lastname: Raynaud-Messina
authors.affiliation: 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;
authors.forename: Cassandre
authors.initials: C
authors.lastname: Kinnaer
authors.affiliation: Centre de Microscopie Électronique Appliquée à la Biologie, Faculté de Médecine de Rangueil, Toulouse Cedex, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fourquaux
authors.affiliation: Department of Infectious Diseases, Integrative Virology, Heidelberg, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Imle
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France; and Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Benichou
authors.affiliation: Department of Infectious Diseases, Integrative Virology, Heidelberg, Germany;
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
authors.affiliation: 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;
authors.forename: Renaud
authors.initials: R
authors.lastname: Poincloux
authors.affiliation: 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;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maridonneau-Parini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D021961:Cell Membrane Structures / Q000473:pathology / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology; D015658:HIV Infections / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000502:physiology* / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D051572:Proto-Oncogene Proteins c-hck / Q000502:physiology; D051316:Wiskott-Aldrich Syndrome Protein / Q000502:physiology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000502:physiology*
chemical_list: C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; C496631:HCK protein, human; D051572:Proto-Oncogene Proteins c-hck