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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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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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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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