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Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):E2556-E2565. doi: 10.1073/pnas.1713370115. Epub 2018 Feb 20.

Bone degradation machinery of osteoclasts: An HIV-1 target that contributes to bone loss.

Author information

1
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31400 Toulouse Cedex 4, France; raynaud@ipbs.fr maridono@ipbs.fr verollet@ipbs.fr.
2
International Associated Laboratory, CNRS "Immuno-Metabolism-Macrophages-Tuberculosis/HIV" (1167), 31000 Toulouse, France.
3
International Associated Laboratory, CNRS "Immuno-Metabolism-Macrophages-Tuberculosis/HIV" (1167), 1425 Buenos Aires, Argentina.
4
INSERM U1016, Institut Cochin, 75014 Paris, France.
5
CNRS UMR8104, Université Paris Descartes, 75006 Paris, France.
6
Institut Pasteur Shanghai, Chinese Academy of Sciences, 200000 Shanghai, China.
7
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31400 Toulouse Cedex 4, France.
8
Institute of Experimental Medicine-Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, National Academy of Medicine, 1425 Buenos Aires, Argentina.
9
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129.
10
Harvard Medical School, Boston, MA 02115.
11
Multiscale Electron Imaging Platform, 31062 Toulouse, France.
12
Laboratory for Analysis and Architecture of Systems, CNRS, 31400 Toulouse, France.
13
Institut National des Sciences Appliquées de Toulouse, Université de Toulouse, 31400 Toulouse, France.
14
INSERM, Université Paul Sabatier, École Nationale Vétérinaire de Toulouse, Centre Régional d'Exploration Fonctionnelle et de Ressources Expérimentales, Service d'Histopathologie, 31000 Toulouse Cedex 3, France.
15
Centre de Physiopathologie de Toulouse-Purpan, INSERM-CNRS UMR 1043, Université Paul Sabatier, 31062 Toulouse, France.
16
Institut Fédératif de Biologie, Centre Hospitalier Universitaire Toulouse, 31059 Toulouse, France.
17
Institut de Génomique Fonctionnelle de Lyon, CNRS UMR3444, Université de Lyon, Ecole Normale Supérieure de Lyon, 69007 Lyon, France.
18
Division of Experimental Medicine, McGill University, Montreal, QC H3G 1A4, Canada.
19
Department of Microbiology and Immunology, University of Montreal, Montreal, QC H3T IJ4, Canada.
20
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, QC H2W 1R7, Canada.

Abstract

Bone deficits are frequent in HIV-1-infected patients. We report here that osteoclasts, the cells specialized in bone resorption, are infected by HIV-1 in vivo in humanized mice and ex vivo in human joint biopsies. In vitro, infection of human osteoclasts occurs at different stages of osteoclastogenesis via cell-free viruses and, more efficiently, by transfer from infected T cells. HIV-1 infection markedly enhances adhesion and osteolytic activity of human osteoclasts by modifying the structure and function of the sealing zone, the osteoclast-specific bone degradation machinery. Indeed, the sealing zone is broader due to F-actin enrichment of its basal units (i.e., the podosomes). The viral protein Nef is involved in all HIV-1-induced effects partly through the activation of Src, a regulator of podosomes and of their assembly as a sealing zone. Supporting these results, Nef-transgenic mice exhibit an increased osteoclast density and bone defects, and osteoclasts derived from these animals display high osteolytic activity. Altogether, our study evidences osteoclasts as host cells for HIV-1 and their pathological contribution to bone disorders induced by this virus, in part via Nef.

KEYWORDS:

HIV-1 infection; Nef; bone loss; osteoclast; podosome

Comment in

PMID:
29463701
PMCID:
PMC5856515
DOI:
10.1073/pnas.1713370115
[Indexed for MEDLINE]
Free PMC Article

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