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Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses

Nature Medicine volume 16, pages 8389 (2010) | Download Citation

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Abstract

Human T cell leukemia virus type 1 (HTLV-1) is a lymphotropic retrovirus whose cell-to-cell transmission requires cell contacts. HTLV-1–infected T lymphocytes form 'virological synapses', but the mechanism of HTLV-1 transmission remains poorly understood. We show here that HTLV-1–infected T lymphocytes transiently store viral particles as carbohydrate-rich extracellular assemblies that are held together and attached to the cell surface by virally-induced extracellular matrix components, including collagen and agrin, and cellular linker proteins, such as tetherin and galectin-3. Extracellular viral assemblies rapidly adhere to other cells upon cell contact, allowing virus spread and infection of target cells. Their removal strongly reduces the ability of HTLV-1–producing cells to infect target cells. Our findings unveil a novel virus transmission mechanism based on the generation of extracellular viral particle assemblies whose structure, composition and function resemble those of bacterial biofilms. HTLV-1 biofilm-like structures represent a major route for virus transmission from cell to cell.

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Acknowledgements

This work has been funded by La Ligue Contre le Cancer, l'Association pour la Recherche Contre le Cancer, l'Agence National de Recherche, l'Institut Pasteur PTR-214, and the CNRS. A.-M.P.-C. is supported by Fundação para a Ciência e a Tecnologia, Portugal, V.R. by the European Union Marie Curie Actions Early Stage Training Program Intrapath and R.L. by a Bourse Roux, Institut Pasteur and l'Agence National de Recherche. We thank the US National Institutes of Health AIDS Research and Reference Reagent Program for providing MT2 cells and Env-specific 0.5α antibodies. We thank M. Rüegg (University of Basel) for agrin-specific antibodies, C. Pique (Institut Cochin, Institut National de la Santé et de la Recherche Médicale (INSERM)) for Env gp46–specific antibody and S. Charrin and E. Rubinstein (Institut A. Lwoff, INSERM) for tetraspanin-specific antibodies. We thank S. Ozden and P.-E. Ceccaldi for the C91/PL cell line and expertise, F. Delebecque (Novartis) for the gift of pCS-HTLV-1, and A. Cartaud, J. Cartaud and U. Hazan for sharing expertise. We thank C. Cuche for technical assistance and S. Bassot for technical help with human samples. We thank ICAReB (plateforme d'investigation clinique et d'accès aux ressources biologiques) and the Centre d'Immunologie Humaine, Institut Pasteur for support in biomedical research. We thank, E. Perret, P. Roux, C. Machu A. Danckaert and M.C. Prevost for sharing expertise in microscopy, J.M. Ghigo and S. Wain-Hobson for helpful discussions and R. Mahieux (Ecole Normale Supérieure de Lyon, INSERM) for pLTR-Luc plasmid and for suggestions and critical reading of the manuscript.

Author information

Affiliations

  1. Institut Pasteur, Unité de Biologie Cellulaire des Lymphocytes, Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Associée (URA) 1961, Paris, France.

    • Ana-Monica Pais-Correia
    • , Valentina Robbiati
    • , Rémi Lasserre
    • , Andrés Alcover
    •  & Maria-Isabel Thoulouze
  2. Institut Pasteur, Plateforme de Microscopie Ultrastructurale, Imagopole, Paris, France.

    • Martin Sachse
    •  & Stéphanie Guadagnini
  3. Institut Pasteur, Unité d′Epidémiologie et Physiopathologie des Virus Oncogènes, CNRS URA 1930, Paris, France.

    • Antoine Gessain
  4. Fondation A. Rothschild, Service de Neurologie, Paris, France.

    • Olivier Gout

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Contributions

A.-M.P.-C. designed and performed experiments. M.S. and S.G. performed electron microscopy experiments. V.R. and R.L. contributed with technical developments for some experiments. O.G. diagnosed and followed subjects with HAM-TSP and provided blood samples. A.G. obtained viroepidemiological data on human samples and collected human cells. A.A. designed the project, designed experiments and wrote the manuscript. M.-I.T. designed the project, designed and performed experiments and wrote the manuscript.

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Correspondence to Andrés Alcover or Maria-Isabel Thoulouze.

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https://doi.org/10.1038/nm.2065