HIV-infected T cells are migratory vehicles for viral dissemination


After host entry through mucosal surfaces, human immunodeficiency virus-1 (HIV-1) disseminates to lymphoid tissues to establish a generalized infection of the immune system. The mechanisms by which this virus spreads among permissive target cells locally during the early stages of transmission and systemically during subsequent dissemination are not known1. In vitro studies suggest that the formation of virological synapses during stable contacts between infected and uninfected T cells greatly increases the efficiency of viral transfer2. It is unclear, however, whether T-cell contacts are sufficiently stable in vivo to allow for functional synapse formation under the conditions of perpetual cell motility in epithelial3 and lymphoid tissues4. Here, using multiphoton intravital microscopy, we examine the dynamic behaviour of HIV-infected T cells in the lymph nodes of humanized mice. We find that most productively infected T cells migrate robustly, resulting in their even distribution throughout the lymph node cortex. A subset of infected cells formed multinucleated syncytia through HIV envelope-dependent cell fusion. Both uncoordinated motility of syncytia and adhesion to CD4+ lymph node cells led to the formation of long membrane tethers, increasing cell lengths to up to ten times that of migrating uninfected T cells. Blocking the egress of migratory T cells from the lymph nodes into efferent lymph vessels, and thus interrupting T-cell recirculation, limited HIV dissemination and strongly reduced plasma viraemia. Thus, we have found that HIV-infected T cells are motile, form syncytia and establish tethering interactions that may facilitate cell-to-cell transmission through virological synapses. Migration of T cells in lymph nodes therefore spreads infection locally, whereas their recirculation through tissues is important for efficient systemic viral spread, suggesting new molecular targets to antagonize HIV infection.

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Figure 1: Human T-cell migration in lymph nodes of BLT mice.
Figure 2: In vivo dynamics and phenotype of HIV-infected lymph node cells.
Figure 3: HIV induces an elongated phenotype in infected T cells.
Figure 4: HIV-infected T cells tether to other lymph node cells and form syncytia through Env, and migrate to distant tissues to disseminate infection.


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We thank J. Sodroski for the pSVIIIexE7 plasmid and A. Brown for HIV SF162R3; H. S. Shin, T. Tivey, K. Bankert and S. Tanno for technical assistance with the generation of humanized mice; A. Peixoto and D. Alvarez for management of the BL2+ multiphoton microscopy facility; A. Brass, T. Allen and T. Dudek for assistance with virological techniques; and N. Elpek, M. Byrne and A. Finzi for technical assistance. Funding for this study was through National Institutes of Health (NIH) grants P01 AI0178897, R56 AI097052, R01 CA150975 and P30 AI060354, and a Platform Award from the Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard. T.T.M. was supported by the MGH ECOR Tosteson Postdoctoral Fellowship Award and NIH training grant T32 AI007387.

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T.T.M., M.D. and T.R.M. performed all experiments. F.M. developed software for data analysis. E.S. and V.D.V. generated humanized mice. A.M.T., A.D.L. and U.H.v.A. contributed to the overall study design. T.T.M. and T.R.M. designed the experiments and wrote the manuscript.

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Correspondence to Thorsten R. Mempel.

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Murooka, T., Deruaz, M., Marangoni, F. et al. HIV-infected T cells are migratory vehicles for viral dissemination. Nature 490, 283–287 (2012).

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