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Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission

Abstract

Transmission of HIV-1 via intercellular connections has been estimated as 100–1000 times more efficient than a cell-free process, perhaps in part explaining persistent viral spread in the presence of neutralizing antibodies1,2. Such effective intercellular transfer of HIV-1 could occur through virological synapses3,4,5 or target-cell filopodia connected to infected cells6. Here we report that membrane nanotubes, formed when T cells make contact and subsequently part, provide a new route for HIV-1 transmission. Membrane nanotubes are known to connect various cell types, including neuronal and immune cells7,8,9,10,11,12,13, and allow calcium-mediated signals to spread between connected myeloid cells9. However, T-cell nanotubes are distinct from open-ended membranous tethers between other cell types7,12, as a dynamic junction persists within T-cell nanotubes or at their contact with cell bodies. We also report that an extracellular matrix scaffold allows T-cell nanotubes to adopt variably shaped contours. HIV-1 transfers to uninfected T cells through nanotubes in a receptor-dependent manner. These data lead us to propose that HIV-1 can spread using nanotubular connections formed by short-term intercellular unions in which T cells specialize.

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Figure 1: Membrane nanotubes connect human T cells.
Figure 2: T-cell nanotubes are not open-ended tunnels and contain a junction.
Figure 3: The ultrastructure of T-cell nanotubes reveals a novel class of membranous connection between cells.
Figure 4: Membrane nanotubes present a novel route for HIV-1 to spread between T cells.
Figure 5: HIV-1 spread via membrane nanotubes is receptor dependent.

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References

  1. Dimitrov, D. S. et al. Quantitation of human immunodeficiency virus type 1 infection kinetics. J. Virol. 67, 2182–2190 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Sourisseau, M., Sol-Foulon, N., Porrot, F., Blanchet, F. & Schwartz, O. Inefficient human immunodeficiency virus replication in mobile lymphocytes. J. Virol. 81, 1000–1012 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  PubMed Central  Google Scholar 

  4. 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  PubMed  PubMed Central  Google Scholar 

  5. McDonald, D. et al. Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 300, 1295–1297 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Sherer, N. M. et al. Retroviruses can establish filopodial bridges for efficient cell-to-cell transmission. Nature Cell Biol. 9, 310–315 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Onfelt, B., Nedvetzki, S., Yanagi, K. & Davis, D. M. Cutting edge: Membrane nanotubes connect immune cells. J. Immunol. 173, 1511–1513 (2004).

    Article  PubMed  Google Scholar 

  9. Watkins, S. C. & Salter, R. D. Functional connectivity between immune cells mediated by tunneling nanotubules. Immunity 23, 309–318 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Stinchcombe, J. C., Bossi, G., Booth, S. & Griffiths, G. M. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15, 751–761 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Onfelt, B. et al. Structurally distinct membrane nanotubes between human macrophages support long-distance vesicular traffic or surfing of bacteria. J. Immunol. 177, 8476–8483 (2006).

    Article  PubMed  Google Scholar 

  12. Gerdes, H. H., Bukoreshtliev, N. V. & Barroso, J. F. Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett. 581, 2194–2201 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Davis, D. M. Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nature Rev. Immunol. 7, 238–243 (2007).

    Article  CAS  Google Scholar 

  14. Faix, J. & Rottner, K. The making of filopodia. Curr. Opin. Cell Biol. 18, 18–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Miller, M. J., Safrina, O., Parker, I. & Cahalan, M. D. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200, 847–856 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Allen, C. D., Okada, T., Tang, H. L. & Cyster, J. G. Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Gunzer, M. et al. Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity 13, 323–332 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Daniels, D. R. & Turner, M. S. Diffusion on membrane tubes: a highly discriminatory test of the Saffman-Delbruck theory. Langmuir 23, 6667–6670 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Roux, A. et al. Role of curvature and phase transition in lipid sorting and fission of membrane tubules. EMBO J. 24, 1537–1545 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Roux, A., Uyhazi, K., Frost, A. & De Camilli, P. GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission. Nature 441, 528–531 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Freed, E. O. HIV-1 gag proteins: diverse functions in the virus life cycle. Virology 251, 1–15 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Greene, W. C. & Peterlin, B. M. Charting HIV's remarkable voyage through the cell: Basic science as a passport to future therapy. Nature Med. 8, 673–680 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Muller, B. et al. Construction and characterization of a fluorescently labeled infectious human immunodeficiency virus type 1 derivative. J. Virol. 78, 10803–10813 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cramer, L. P. & Mitchison, T. J. Investigation of the mechanism of retraction of the cell margin and rearward flow of nodules during mitotic cell rounding. Mol. Biol. Cell 8, 109–119 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mitchison, T. J. Actin based motility on retraction fibers in mitotic PtK2 cells. Cell Motil. Cytoskel. 22, 135–151 (1992).

    Article  CAS  Google Scholar 

  26. Lehmann, M. J., Sherer, N. M., Marks, C. B., Pypaert, M. & Mothes, W. Actin- and myosin-driven movement of viruses along filopodia precedes their entry into cells. J. Cell Biol. 170, 317–325 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mattapallil, J. J. et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093–1097 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Li, Q. et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434, 1148–1152 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Favoreel, H. W., Van Minnebruggen, G., Adriaensen, D. & Nauwynck, H. J. Cytoskeletal rearrangements and cell extensions induced by the US3 kinase of an alphaherpesvirus are associated with enhanced spread. Proc. Natl Acad. Sci. USA 102, 8990–8995 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. La Boissiere, S., Izeta, A., Malcomber, S. & O'Hare, P. Compartmentalization of VP16 in cells infected with recombinant herpes simplex virus expressing VP16-green fluorescent protein fusion proteins. J. Virol. 78, 8002–8014 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Huang, F., Khvorova, A., Marshall, W. & Sorkin, A. Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J. Biol. Chem. 279, 16657–16661 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. A. A. Neil, P. M. W. French, N. J. Burroughs, E. Vivier and members of our laboratories for useful discussions. This research was funded by The Biotechnology and Biological Sciences Research Council, a Wellcome Trust studentship (to S.S.), The Medical Research Council, grant P01-AI064520 from the National Institutes of Health and a Lister Institute Research Prize.

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S.S., C.J., O.B., M.A.P., A.C., K.K. and P.E. designed and performed experiments. S.O. and B.Ö. helped analyse data. F.B., C.H., B.Ö., Q.S. and D.M.D. helped design experiments. D.M.D conceived the project and wrote the paper with S.S. and important input from all co-authors.

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Correspondence to Daniel M. Davis.

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The authors declare no competing financial interests.

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Sowinski, S., Jolly, C., Berninghausen, O. et al. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat Cell Biol 10, 211–219 (2008). https://doi.org/10.1038/ncb1682

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