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Bones: the guilty osteoclasts were under HIV-1 influence

Bone deficits are frequent complications observed in HIV-1 infected patients. Researchers of the team “Phagocyte migration and differentiation” at the Institute of Pharmacology and Structural Biology (IPBS – CNRS/Université Toulouse III - Paul Sabatier) have demonstrated that HIV-1 infects osteoclasts, the bone degrading cells, and enhances their osteolytic activity. This study is published in the Proceedings of the National Academy of Sciences of the USA, on February 20th, 2018.

Poisson-cover.pngFigure: The osteoclast is a multinucleated (nuclei in blue) giant cell. The size of the sealing zone (in green), the bone degradation machinery, is enhanced in HIV-1 (in red) infected human osteoclasts. (© Shanti Souriant & Remi Mascarau, IPBS, CNRS/Université Toulouse III-Paul Sabatier)

 

There is a 6-fold increased risk of low bone mineral density in HIV-1-positive individuals compared to the general population. In addition to antiretroviral drugs associated with bone loss, HIV can alter bone homeostasis by itself, favoring bone resorption. In this study, the authors demonstrated that HIV-1 targets osteoclasts, in vivo in a humanized murine model and ex vivo in synovial explants. Human osteoclasts are infected by cell-free virus and more efficiently by transfer from infected CD4+ T lymphocytes. HIV-1 replicates within osteoclasts with no cytotoxic effects and accumulates in intracellular compartments. It stimulates the migration of osteoclasts precursors towards bones, their differentiation and their bone degradation activity. To do so, the virus modifies the structure and the activity of the sealing zone, the bone-resorption machinery. In HIV-infected osteoclasts, increased bone resorption correlates with enhanced activity of Src, an enzyme involved in the organization and stability (of podosomes, the structural elements of) the sealing zone.

The viral protein Nef, a known activator of Src, is responsible for all the observed effects of HIV-1 in osteoclasts. Supporting these data, Nef-transgenic mice exhibit an increased osteoclast density and bone defects.

Therefore, Raynaud-Messina et al. provide evidence that osteoclasts constitute a target of HIV-1, contributing to bone deficits in vivo and may serve as putative viral reservoirs.

This work was performed in collaboration with Dr. S. Benichou (Institut Cochin, Paris, France), Dr. I. Gennero, JL. Davignon and T. Al Saati (CPTP, Toulouse, France), Dr. T.R. Mempel (Harvard Medical School, Boston, USA), Dr. P. Jolicoeur (University of Montreal, Montreal, Quebec, Canada), and Dr. P. Jurdic (Lyon).

This work was funded by ANR, ANRS, FRM and Sidaction.

 

Reference

Brigitte Raynaud-Messina, Lucie Bracq, Maeva Dupont, Shanti Souriant, Shariq M. Usmani, Amsha Proag, Karine Pingris, Vanessa Soldan, Christophe Thibault, Florence Capilla, Talal Al Saati, Isabelle Gennero, Pierre Jurdic, Paul Jolicoeur, Jean-Luc Davignon, Thorsten R. Mempel, Serge Benichou, Isabelle Maridonneau-Parini & Christel Vérollet. The bone degradation machinery of osteoclasts: a novel HIV-1 target that contributes to bone loss. Proc Natl Acad Sci USA doi.org/10.1073/pnas.1713370115

 

CONTACTS

Research: Brigitte Raynaud-MessinaIsabelle Maridonneau-Parini and Christel Verollet.

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