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

Nature Medicine volume 16, pages 83–89 (2010)Cite this article

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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Figure 1: Clusters of viral components are on the surface of infected cells.
Figure 2: Extracellular viral assemblies on the surface of HTLV-1–infected cells.
Figure 3: Extracellular HTLV-1 assemblies are carbohydrate-rich structures.
Figure 4: Extracellular matrix and linker proteins are enriched in HTLV-1 viral assemblies.
Figure 5: HTLV-1 extracellular viral assemblies spread at cell contacts.
Figure 6: Relevance of extracellular HTLV-1 assemblies for cell-to-cell transmission.

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References

  1. Verdonck, K. et al. Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis 7, 266–81 (2007).

    Article  CAS  Google Scholar 

  2. Okochi, K., Sato, H. & Hinuma, Y. A retrospective study on transmission of adult T cell leukemia virus by blood transfusion: seroconversion in recipients. Vox Sang. 46, 245–253 (1984).

    Article  CAS  Google Scholar 

  3. Donegan, E. et al. Transfusion transmission of retroviruses: human T-lymphotropic virus types I and II compared with human immunodeficiency virus type 1. Transfusion 34, 478–483 (1994).

    Article  CAS  Google Scholar 

  4. Igakura, T. et al. Spread of HTLV-1 between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299, 1713–1716 (2003).

    Article  CAS  Google Scholar 

  5. Barnard, A.L., Igakura, T., Tanaka, Y., Taylor, G.P. & Bangham, C.R. Engagement of specific T-cell surface molecules regulates cytoskeletal polarization in HTLV-1–infected lymphocytes. Blood 106, 988–995 (2005).

    Article  CAS  Google Scholar 

  6. Nejmeddine, M., Barnard, A.L., Tanaka, Y., Taylor, G.P. & Bangham, C.R.M. Human T-lymphotropic virus type 1 Tax protein triggers micotubule reorientation in the virological synapse. J. Biol. Chem. 280, 29653–29660 (2005).

    Article  CAS  Google Scholar 

  7. Majorovits, E. et al. Human T-lymphotropic virus-1 visualized at the virological synapse by electron tomography. PLoS One 3, e2251 (2008).

    Article  Google Scholar 

  8. Jolly, C., Kashefi, K., Hollinshead, M. & Sattentau, Q.J. HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J. Exp. Med. 199, 283–293 (2004).

    Article  CAS  Google Scholar 

  9. Sol-Foulon, N. et al. ZAP-70 kinase regulates HIV cell-to-cell spread and virological synapse formation. EMBO J. 26, 516–526 (2007).

    Article  CAS  Google Scholar 

  10. Piguet, V. & Sattentau, Q.J. Dangerous liaisons at the virological synapse. J. Clin. Invest. 114, 605–610 (2004).

    Article  CAS  Google Scholar 

  11. Rudnicka, D. et al. Simultaneous cell-to-cell transmission of human immunodeficiency virus to multiple targets through polysynapses. J. Virol. 83, 6234–6246 (2009).

    Article  CAS  Google Scholar 

  12. Jones, K.S., Petrow-Sadowski, C., Huang, Y.K., Bertolette, D.C. & Ruscetti, F.W. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4+ T cells. Nat. Med. 14, 429–436 (2008).

    Article  CAS  Google Scholar 

  13. Stewart, P.S. & Franklin, M.J. Physiological heterogeneity in biofilms. Nat. Rev. Microbiol. 6, 199–210 (2008).

    Article  CAS  Google Scholar 

  14. Mazurov, D., Heidecker, G. & Derse, D. HTLV-1 Gag protein associates with CD82 tetraspanin microdomains at the plasma membrane. Virology 346, 194–204 (2006).

    Article  CAS  Google Scholar 

  15. Jones, K.S., Petrow-Sadowski, C., Bertolette, D.C., Huang, Y. & Ruscetti, F.W. Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells. J. Virol. 79, 12692–12702 (2005).

    Article  CAS  Google Scholar 

  16. Piñon, J.D. et al. Human T-cell leukemia virus type 1 envelope glycoprotein gp46 interacts with cell surface heparan sulfate proteoglycans. J. Virol. 77, 9922–9930 (2003).

    Article  Google Scholar 

  17. Neu, T.R. & Lawrence, J.R. Lectin-binding analysis in biofilm systems. Methods Enzymol. 310, 145–152 (1999).

    Article  CAS  Google Scholar 

  18. McClure, S.F., Stoddart, R.W. & McClure, J. A comparative study of lectin binding to cultured chick sternal chondrocytes and intact chick sternum. Glycoconj. J. 14, 365–377 (1997).

    Article  CAS  Google Scholar 

  19. Le Blanc, I. et al. HTLV-1 structural proteins. Virus Res. 78, 5–16 (2001).

    Article  CAS  Google Scholar 

  20. Coffin, J.M., Hughes, S.H. & Varmus, H.E. Retroviruses Ch. 2, 27–70 (Cold Spring Harbor Laboratory Press, 1997).

  21. Hiraiwa, N. et al. Transactivation of the fucosyltransferase VII gene by human T-cell leukemia virus type 1 Tax through a variant cAMP-responsive element. Blood 101, 3615–3621 (2003).

    Article  CAS  Google Scholar 

  22. Kambara, C. et al. Increased sialyl Lewisx antigen–positive cells mediated by HTLV-1 infection in peripheral blood CD4+ T lymphocytes in patients with HTLV-1–associated myelopathy. J. Neuroimmunol. 125, 179–184 (2002).

    Article  CAS  Google Scholar 

  23. Muñoz, E., Suri, D., Amini, S., Khalili, K. & Jimenez, S.A. Stimulation of alpha 1 (I) procollagen gene expression in NIH-3T3 cells by the human T cell leukemia virus type 1 (HTLV-1) Tax gene. J. Clin. Invest. 96, 2413–2420 (1995).

    Article  Google Scholar 

  24. Yi, T., Lee, B.H., Park, R.W. & Kim, I.S. Transactivation of fibronectin promoter by HTLV-I Tax through NF-κB pathway. Biochem. Biophys. Res. Commun. 276, 579–586 (2000).

    Article  CAS  Google Scholar 

  25. Dityatev, A. & Schachner, M. The extracellular matrix and synapses. Cell Tissue Res. 326, 647–654 (2006).

    Article  CAS  Google Scholar 

  26. Khan, A.A., Bose, C., Yam, L.S., Soloski, M.J. & Rupp, F. Physiological regulation of the immunological synapse by agrin. Science 292, 1681–1686 (2001).

    Article  CAS  Google Scholar 

  27. Alfsen, A., Yu, H., Magerus-Chatinet, A., Schmitt, A. & Bomsel, M. HIV-1–infected blood mononuclear cells form an integrin- and agrin-dependent viral synapse to induce efficient HIV-1 transcytosis across epithelial cell monolayer. Mol. Biol. Cell 16, 4267–4279 (2005).

    Article  CAS  Google Scholar 

  28. Zhang, J. et al. Agrin is involved in lymphocytes activation that is mediated by α-dystroglycan. FASEB J. 20, 50–58 (2006).

    Article  Google Scholar 

  29. Ghez, D. et al. Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J. Virol. 80, 6844–6854 (2006).

    Article  CAS  Google Scholar 

  30. Tordjman, R. et al. A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat. Immunol. 3, 477–482 (2002).

    Article  CAS  Google Scholar 

  31. Rabinovich, G.A. & Toscano, M.A. Turning 'sweet' on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat. Rev. Immunol. 9, 338–352 (2009).

    Article  CAS  Google Scholar 

  32. Hsu, D.K., Hammes, S.R., Kuwabara, I., Greene, W.C. & Liu, F.T. Human T lymphotropic virus-I infection of human T lymphocytes induces expression of the β-galactoside–binding lectin, galectin-3. Am. J. Pathol. 148, 1661–1670 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gauthier, S. et al. Induction of galectin-1 expression by HTLV-I Tax and its impact on HTLV-I infectivity. Retrovirology 5, 105 (2008).

    Article  Google Scholar 

  34. Neil, S.J., Zang, T. & Bieniasz, P.D. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451, 425–430 (2008).

    Article  CAS  Google Scholar 

  35. Van Damme, N. et al. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 3, 245–252 (2008).

    Article  CAS  Google Scholar 

  36. Jouvenet, N. et al. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J. Virol. 83, 1837–1844 (2009).

    Article  CAS  Google Scholar 

  37. Gessain, A. et al. Cell surface phenotype and human T lymphotropic virus type 1 antigen expression in 12 T cell lines derived from peripheral blood and cerebrospinal fluid of West Indian, Guyanese and African patients with tropical spastic paraparesis. J. Gen. Virol. 71, 333–341 (1990).

    Article  CAS  Google Scholar 

  38. Poiesz, B.J. et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl. Acad. Sci. USA 77, 7415–7419 (1980).

    Article  CAS  Google Scholar 

  39. Zacharopoulos, V.R., Perotti, M.E. & Phillips, D.M. Lymphocyte-facilitated infection of epithelia by human T-cell lymphotropic virus type I. J. Virol. 66, 4601–4605 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fowler, M., Thomas, R.J., Atherton, J., Roberts, I.S. & High, N.J. Galectin-3 binds to Helicobacter pylori O-antigen: it is upregulated and rapidly secreted by gastric epithelial cells in response to H. pylori adhesion. Cell. Microbiol. 8, 44–54 (2006).

    Article  CAS  Google Scholar 

  41. Moran, A.P. Relevance of fucosylation and Lewis antigen expression in the bacterial gastroduodenal pathogen Helicobacter pylori. Carbohydr. Res. 343, 1952–1965 (2008).

    Article  CAS  Google Scholar 

  42. Gupta, S.K., Masinick, S., Garrett, M. & Hazlett, L.D. Pseudomonas aeruginosa lipopolysaccharide binds galectin-3 and other human corneal epithelial proteins. Infect. Immun. 65, 2747–2753 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bonifait, L., Grignon, L. & Grenier, D. Fibrinogen induces biofilm formation by Streptococcus suis and enhances its antibiotic resistance. Appl. Environ. Microbiol. 74, 4969–4972 (2008).

    Article  CAS  Google Scholar 

  44. Humbert, M. & Dietrich, U. The role of neutralizing antibodies in HIV infection. AIDS Rev. 8, 51–59 (2006).

    PubMed  Google Scholar 

  45. el Nabout, R. et al. Collagen synthesis and deposition in cultured fibroblasts from subcutaneous radiation-induced fibrosis. Modification as a function of cell aging. Matrix 9, 411–420 (1989).

    Article  CAS  Google Scholar 

  46. Joo, H.G. et al. Expression and function of galectin-3, a β-galactoside–binding protein in activated T lymphocytes. J. Leukoc. Biol. 69, 555–564 (2001).

    CAS  PubMed  Google Scholar 

  47. Mikaty, G. et al. Extracellular bacterial pathogen induces host cell surface reorganization to resist shear stress. PLoS Pathog. 5, e1000314 (2009).

    Article  Google Scholar 

  48. Thoulouze, M.I. et al. Human immunodeficiency virus type-1 infection impairs the formation of the immunological synapse. Immunity 24, 547–561 (2006).

    Article  CAS  Google Scholar 

  49. Grange, M.P., Rosenberg, A.R., Horal, P. & Desgranges, C. Identification of exposed epitopes on the envelope glycoproteins of human T cell lymphotropic virus type I (HTLV-I). Int. J. Cancer 75, 804–813 (1998).

    Article  CAS  Google Scholar 

  50. Mahieux, R. et al. Extensive editing of a small fraction of human T-cell leukemia virus type 1 genomes by four APOBEC3 cytidine deaminases. J. Gen. Virol. 86, 2489–2494 (2005).

    Article  CAS  Google Scholar 

  51. Slot, J.W., Geuze, H.J., Gigengack, S., Lienhard, G.E. & James, D.E. Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat. J. Cell Biol. 113, 123–135 (1991).

    Article  CAS  Google Scholar 

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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.

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Authors and 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, Paris, CNRS URA 1930, 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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Pais-Correia, AM., Sachse, M., Guadagnini, S. et al. Biofilm-like extracellular viral assemblies mediate HTLV-1 cell-to-cell transmission at virological synapses. Nat Med 16, 83–89 (2010). https://doi.org/10.1038/nm.2065

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