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

Nature Cell Biology volume 10, pages 211219 (2008) | Download Citation

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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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References

  1. 1.

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

  2. 2.

    , , , & Inefficient human immunodeficiency virus replication in mobile lymphocytes. J. Virol. 81, 1000–1012 (2007).

  3. 3.

    , , & HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J. Exp. Med. 199, 283–293 (2004).

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    , , , & Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).

  8. 8.

    , , & Cutting edge: Membrane nanotubes connect immune cells. J. Immunol. 173, 1511–1513 (2004).

  9. 9.

    & Functional connectivity between immune cells mediated by tunneling nanotubules. Immunity 23, 309–318 (2005).

  10. 10.

    , , & The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15, 751–761 (2001).

  11. 11.

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

  12. 12.

    , & Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett. 581, 2194–2201 (2007).

  13. 13.

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

  14. 14.

    & The making of filopodia. Curr. Opin. Cell Biol. 18, 18–25 (2006).

  15. 15.

    , , & Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200, 847–856 (2004).

  16. 16.

    , , & Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007).

  17. 17.

    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).

  18. 18.

    & Diffusion on membrane tubes: a highly discriminatory test of the Saffman-Delbruck theory. Langmuir 23, 6667–6670 (2007).

  19. 19.

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

  20. 20.

    , , & GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission. Nature 441, 528–531 (2006).

  21. 21.

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

  22. 22.

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

  23. 23.

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

  24. 24.

    & 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).

  25. 25.

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

  26. 26.

    , , , & Actin- and myosin-driven movement of viruses along filopodia precedes their entry into cells. J. Cell Biol. 170, 317–325 (2005).

  27. 27.

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

  28. 28.

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

  29. 29.

    , , & 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).

  30. 30.

    , , & Compartmentalization of VP16 in cells infected with recombinant herpes simplex virus expressing VP16-green fluorescent protein fusion proteins. J. Virol. 78, 8002–8014 (2004).

  31. 31.

    , , & Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J. Biol. Chem. 279, 16657–16661 (2004).

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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.

Author information

Affiliations

  1. Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College London, SW7 2AZ, UK.

    • Stefanie Sowinski
    • , Otto Berninghausen
    • , Marco A. Purbhoo
    • , Anne Chauveau
    • , Karsten Köhler
    • , Stephane Oddos
    • , Philipp Eissmann
    • , Colin Hopkins
    •  & Daniel M. Davis
  2. Sir William Dunn School of Pathology, University of Oxford, OX1 3RE, UK.

    • Clare Jolly
    •  & Quentin Sattentau
  3. The G. W. Hooper Foundation, Box 0552, 513 Parnassus Avenue, UCSF, San Francisco, CA 94143–0552, USA.

    • Frances M. Brodsky
  4. Microbiology and Tumor Biology Center, Karolinska Institute, Box 280, S-171 77 Stockholm, Sweden.

    • Björn Önfelt

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel M. Davis.

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DOI

https://doi.org/10.1038/ncb1682

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