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Modulation of the immunological synapse: a key to HIV-1 pathogenesis?

Nature Reviews Immunology volume 7, pages 310–317 (2007)Cite this article

Abstract

AIDS is the result of a constant struggle between the lentivirus HIV and the immune system. Infection with HIV interferes directly with the function of CD4+ T cells and manipulates the host immune response to the virus. Recent studies indicate that the viral protein Nef, a central player in HIV pathogenesis, impairs the ability of infected lymphocytes to form immunological synapses with antigen-presenting cells and affects T-cell-receptor-mediated stimulation. An integrative picture of the abnormal behaviour of HIV-infected lymphocytes is therefore emerging. We propose that modulating lymphocyte signalling, apoptosis and intracellular trafficking ensures efficient spread of the virus in the hostile environment of the immune system.

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Figure 1: HIV-1 impairs the formation of the immunological synapse: impact on TCR and LCK.
Figure 2: HIV-1 downmodulates actin cytoskeleton dynamics at the immunological synapse.
Figure 3: HIV-1 infection impairs immunological synapses and favours virological synapses.

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References

  1. Stevenson, M. HIV-1 pathogenesis. Nature Med. 9, 853–860 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Zack, J. A. et al. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell 61, 213–222 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Bukrinsky, M. I., Stanwick, T. L., Dempsey, M. P. & Stevenson, M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 254, 423–427 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Stevenson, M., Stanwick, T. L., Dempsey, M. P. & Lamonica, C. A. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 9, 1551–1560 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Spina, C. A., Guatelli, J. C. & Richman, D. D. Establishment of a stable, inducible form of human immunodeficiency virus type 1 DNA in quiescent CD4 lymphocytes in vitro. J. Virol. 69, 2977–2988 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lassen, K. G., Ramyar, K. X., Bailey, J. R., Zhou, Y. & Siliciano, R. F. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog. 2, e68 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Williams, S. A. et al. NF-κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25, 139–149 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Jordan, A., Bisgrove, D. & Verdin, E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 22, 1868–1877 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tong-Starksen, S. E., Luciw, P. A. & Peterlin, B. M. Human immunodeficiency virus long terminal repeat responds to T-cell activation signals. Proc. Natl Acad. Sci. USA 84, 6845–6849 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adams, M. et al. Cellular latency in human immunodeficiency virus-infected individuals with high CD4 levels can be detected by the presence of promoter-proximal transcripts. Proc. Natl Acad. Sci. USA 91, 3862–3866 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chiu, Y. L. et al. Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature 435, 108–114 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Kreisberg, J. F., Yonemoto, W. & Greene, W. C. Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation. J. Exp. Med. 203, 865–870 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kinoshita, S., Chen, B. K., Kaneshima, H. & Nolan, G. P. Host control of HIV-1 parasitism in T cells by the nuclear factor of activated T cells. Cell 95, 595–604 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Ganesh, L. et al. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 426, 853–857 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Blaak, H. et al. In vivo HIV-1 infection of CD45RA+CD4+ T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4+ T cell decline. Proc. Natl Acad. Sci. USA 97, 1269–1274 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ostrowski, M. A. et al. Both memory and CD45RA+/CD62L+ naive CD4+ T cells are infected in human immunodeficiency virus type 1-infected individuals. J. Virol. 73, 6430–6435 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, Z. et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286, 1353–1357 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Haase, A. T. Perils at mucosal front lines for HIV and SIV and their hosts. Nature Rev. Immunol. 5, 783–792 (2005).

    Article  CAS  Google Scholar 

  19. Eckstein, D. A. et al. HIV-1 actively replicates in naive CD4+ T cells residing within human lymphoid tissues. Immunity 15, 671–682 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Scales, D. et al. Nonproliferating bystander CD4+ T cells lacking activation markers support HIV replication during immune activation. J. Immunol. 166, 6437–6443 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Unutmaz, D., KewalRamani, V. N., Marmon, S. & Littman, D. R. Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. J. Exp. Med. 189, 1735–1746 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Arnold, R., Brenner, D., Becker, M., Frey, C. R. & Krammer, P. H. How T lymphocytes switch between life and death. Eur. J. Immunol. 36, 1654–1658 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Bourgeois, C. & Stockinger, B. T cell homeostasis in steady state and lymphopenic conditions. Immunol. Lett. 107, 89–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Baur, A. S. et al. HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. Immunity 1, 373–384 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Simmons, A., Aluvihare, V. & McMichael, A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity 14, 763–777 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Wolf, D. et al. HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nature Med. 7, 1217–1224 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Wu, Y. & Marsh, J. W. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 293, 1503–1506 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Geleziunas, R., Xu, W., Takeda, K., Ichijo, H. & Greene, W. C. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature 410, 834–838 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Keppler, O. T., Tibroni, N., Venzke, S., Rauch, S. & Fackler, O. T. Modulation of specific surface receptors and activation sensitization in primary resting CD4+ T lymphocytes by the Nef protein of HIV-1. J. Leukoc. Biol. 79, 616–627 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Ott, M. et al. Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. Science 275, 1481–1485 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Williams, S. A. & Greene, W. C. Host factors regulating post-integration latency of HIV. Trends Microbiol. 13, 137–139 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. 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 

  34. Phillips, D. M. The role of cell-to-cell transmission in HIV infection. AIDS 8, 719–731 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. 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  PubMed  Google Scholar 

  38. Haller, C. et al. The HIV-1 pathogenicity factor Nef interferes with maturation of stimulatory T-lymphocyte contacts by modulation of N-Wasp activity. J. Biol. Chem. 281, 19618–19630 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Fenard, D. et al. Nef is physically recruited into the immunological synapse and potentiates T cell activation early after TCR engagement. J. Immunol. 175, 6050–6057 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Deacon, N. J. et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270, 988–991 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Kestler, H. W. 3rd, et al. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65, 651–662 (1991).

    Article  CAS  PubMed  Google Scholar 

  42. Kirchhoff, F., Greenough, T. C., Brettler, D. B., Sullivan, J. L. & Desrosiers, R. C. Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N. Engl. J. Med. 332, 228–232 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Geyer, M., Fackler, O. T. & Peterlin, B. M. Structure–function relationships in HIV-1 Nef. EMBO Rep. 2, 580–585 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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 

  45. Tolstrup, M., Ostergaard, L., Laursen, A. L., Pedersen, S. F. & Duch, M. HIV/SIV escape from immune surveillance: focus on Nef. Curr. HIV Res. 2, 141–151 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Roeth, J. F. & Collins, K. L. Human immunodeficiency virus type 1 Nef: adapting to intracellular trafficking pathways. Microbiol. Mol. Biol. Rev. 70, 548–563 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fackler, O. T. et al. A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells. Curr. Biol. 11, 1294–1299 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Messmer, D., Ignatius, R., Santisteban, C., Steinman, R. M. & Pope, M. The decreased replicative capacity of simian immunodeficiency virus SIVmac239Δnef is manifest in cultures of immature dendritic cells and T cells. J. Virol. 74, 2406–2413 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Petit, C. et al. Nef is required for efficient HIV-1 replication in cocultures of dendritic cells and lymphocytes. Virology 286, 225–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Choi, J. et al. Human endothelial cells enhance human immunodeficiency virus type 1 replication in CD4+ T cells in a Nef-dependent manner in vitro and in vivo. J. Virol. 79, 264–276 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Choi, J. et al. Endothelial cells promote human immunodeficiency virus replication in nondividing memory T cells via Nef-, Vpr-, and T-cell receptor-dependent activation of NFAT. J. Virol. 79, 11194–11204 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Glushakova, S. et al. Nef enhances human immunodeficiency virus replication and responsiveness to interleukin-2 in human lymphoid tissue ex vivo. J. Virol. 73, 3968–3974 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Friedl, P., den Boer, A. T. & Gunzer, M. Tuning immune responses: diversity and adaptation of the immunological synapse. Nature Rev. Immunol. 5, 532–545 (2005).

    Article  CAS  Google Scholar 

  54. Sancho, D. et al. TCR engagement induces proline-rich tyrosine kinase-2 (Pyk2) translocation to the T cell–APC interface independently of Pyk2 activity and in an immunoreceptor tyrosine-based activation motif-mediated fashion. J. Immunol. 169, 292–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Holdorf, A. D., Lee, K. H., Burack, W. R., Allen, P. M. & Shaw, A. S. Regulation of Lck activity by CD4 and CD28 in the immunological synapse. Nature Immunol. 3, 259–264 (2002).

    Article  CAS  Google Scholar 

  56. Li, Q. J. et al. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nature Immunol. 5, 791–799 (2004).

    Article  CAS  Google Scholar 

  57. Fortin, J. F., Barat, C., Beausejour, Y., Barbeau, B. & Tremblay, M. J. Hyper-responsiveness to stimulation of human immunodeficiency virus-infected CD4+ T cells requires Nef and Tat virus gene products and results from higher NFAT, NF-κB, and AP-1 induction. J. Biol. Chem. 279, 39520–39531 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Manninen, A., Huotari, P., Hiipakka, M., Renkema, G. H. & Saksela, K. Activation of NFAT-dependent gene expression by Nef: conservation among divergent Nef alleles, dependence on SH3 binding and membrane association, and cooperation with protein kinase C-θ. J. Virol. 75, 3034–3037 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schrager, J. A. & Marsh, J. W. HIV-1 Nef increases T cell activation in a stimulus-dependent manner. Proc. Natl Acad. Sci. USA 96, 8167–8172 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, J. K., Kiyokawa, E., Verdin, E. & Trono, D. The Nef protein of HIV-1 associates with rafts and primes T cells for activation. Proc. Natl Acad. Sci. USA 97, 394–399 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Alcover, A. & Alarcon, B. Internalization and intracellular fate of TCR–CD3 complexes. Crit. Rev. Immunol. 20, 325–346 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Naramura, M. et al. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nature Immunol. 3, 1192–1199 (2002).

    Article  CAS  Google Scholar 

  63. Valitutti, S., Muller, S., Salio, M. & Lanzavecchia, A. Degradation of T cell receptor (TCR)–CD3-ζ complexes after antigenic stimulation. J. Exp. Med. 185, 1859–1864 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Das, V. et al. Activation-induced polarized recycling targets T cell antigen receptors to the immunological synapse; involvement of SNARE complexes. Immunity 20, 577–588 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Varma, R., Campi, G., Yokosuka, T., Saito, T. & Dustin, M. L. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25, 117–127 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ehrlich, L. I., Ebert, P. J., Krummel, M. F., Weiss, A. & Davis, M. M. Dynamics of p56lck translocation to the T cell immunological synapse following agonist and antagonist stimulation. Immunity 17, 809–822 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Salghetti, S., Mariani, R. & Skowronski, J. Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail. Proc. Natl Acad. Sci. USA 92, 349–353 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. D'Oro, U., Vacchio, M. S., Weissman, A. M. & Ashwell, J. D. Activation of the Lck tyrosine kinase targets cell surface T cell antigen receptors for lysosomal degradation. Immunity 7, 619–628 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Simmons, A. et al. Nef-mediated lipid raft exclusion of UbcH7 inhibits Cbl activity in T cells to positively regulate signaling. Immunity 23, 621–634 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Yang, P. & Henderson, A. J. Nef enhances c-Cbl phosphorylation in HIV-infected CD4+ T lymphocytes. Virology 336, 219–228 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Campbell, E. M., Nunez, R. & Hope, T. J. Disruption of the actin cytoskeleton can complement the ability of Nef to enhance human immunodeficiency virus type 1 infectivity. J. Virol. 78, 5745–5755 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Fackler, O. T., Luo, W., Geyer, M., Alberts, A. S. & Peterlin, B. M. Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Mol. Cell 3, 729–739 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Quaranta, M. G. et al. HIV-1 Nef triggers Vav-mediated signaling pathway leading to functional and morphological differentiation of dendritic cells. FASEB J. 17, 2025–2036 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Snapper, S. B. et al. Wiskott–Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Immunity 9, 81–91 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Zhang, J. et al. Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott–Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190, 1329–1342 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Arora, V. K. et al. Lentivirus Nef specifically activates Pak2. J. Virol. 74, 11081–11087 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Renkema, G. H., Manninen, A., Mann, D. A., Harris, M. & Saksela, K. Identification of the Nef-associated kinase as p21-activated kinase 2. Curr. Biol. 9, 1407–1410 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Krautkramer, E., Giese, S. I., Gasteier, J. E., Muranyi, W. & Fackler, O. T. Human immunodeficiency virus type 1 Nef activates p21-activated kinase via recruitment into lipid rafts. J. Virol. 78, 4085–4097 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Pulkkinen, K., Renkema, G. H., Kirchhoff, F. & Saksela, K. Nef associates with p21-activated kinase 2 in a p21-GTPase-dependent dynamic activation complex within lipid rafts. J. Virol. 78, 12773–12780 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Monjas, A., Alcover, A. & Alarcon, B. Engaged and bystander T cell receptors are down-modulated by different endocytotic pathways. J. Biol. Chem. 279, 55376–55384 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. McGavin, M. K. et al. The intersectin 2 adaptor links Wiskott Aldrich syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis. J. Exp. Med. 194, 1777–1787 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chang, F. S., Han, G. S., Carman, G. M. & Blumer, K. J. A WASp-binding type II phosphatidylinositol 4-kinase required for actin polymerization-driven endosome motility. J. Cell Biol. 171, 133–142 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chang, F. S., Stefan, C. J. & Blumer, K. J. A WASp homolog powers actin polymerization-dependent motility of endosomes in vivo. Curr. Biol. 13, 455–463 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Taunton, J. et al. Actin-dependent propulsion of endosomes and lysosomes by recruitment of N-WASP. J. Cell Biol. 148, 519–530 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Schindler, M. et al. Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 125, 1055–1067 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Bell, I. et al. Association of simian immunodeficiency virus Nef with the T-cell receptor (TCR) ζ chain leads to TCR down-modulation. J. Gen. Virol. 79, 2717–2727 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Howe, A. Y., Jung, J. U. & Desrosiers, R. C. ζ chain of the T-cell receptor interacts with nef of simian immunodeficiency virus and human immunodeficiency virus type 2. J. Virol. 72, 9827–9834 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Xu, X. N. et al. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor ζ chain. J. Exp. Med. 189, 1489–1496 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Swingler, S. et al. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nature Med. 5, 997–1003 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. Messmer, D. et al. Endogenously expressed nef uncouples cytokine and chemokine production from membrane phenotypic maturation in dendritic cells. J. Immunol. 169, 4172–4182 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Briggs, S. D. et al. HIV-1 Nef promotes survival of myeloid cells by a STAT3-dependent pathway. J. Biol. Chem. 276, 25605–25611 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Percario, Z. et al. Human immunodeficiency virus type 1 (HIV-1) Nef activates STAT3 in primary human monocyte/macrophages through the release of soluble factors: involvement of Nef domains interacting with the cell endocytotic machinery. J. Leukoc. Biol. 74, 821–832 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Swingler, S. et al. HIV-1 Nef intersects the macrophage CD40L signalling pathway to promote resting-cell infection. Nature 424, 213–219 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Hayes, S. M. & Love, P. E. Strength of signal: a fundamental mechanism for cell fate specification. Immunol. Rev. 209, 170–175 (2006).

    Article  PubMed  Google Scholar 

  95. Hugues, S. et al. Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nature Immunol. 5, 1235–1242 (2004).

    Article  CAS  Google Scholar 

  96. Langenkamp, A. et al. T cell priming by dendritic cells: thresholds for proliferation, differentiation and death and intraclonal functional diversification. Eur. J. Immunol. 32, 2046–2054 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Viola, A. & Lanzavecchia, A. T cell activation determined by T cell receptor number and tunable thresholds. Science 273, 104–106 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Bousso, P. & Robey, E. A. Dynamic behavior of T cells and thymocytes in lymphoid organs as revealed by two-photon microscopy. Immunity 21, 349–355 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Collins, K. L., Chen, B. K., Kalams, S. A., Walker, B. D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Schwartz, O., Marechal, V., Le Gall, S., Lemonnier, F. & Heard, J. M. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nature Med. 2, 338–342 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. Sugimoto, C. et al. nef gene is required for robust productive infection by simian immunodeficiency virus of T-cell-rich paracortex in lymph nodes. J. Virol. 77, 4169–4180 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Roumier, A. et al. The membrane-microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation. Immunity 15, 715–728 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank N. Sol-Foulon, M. Thoulouze, M. Albert, O. Keppler, S. Wain-Hobson and members of our laboratories for discussions and useful comments on the manuscript. Research in our laboratories is financed by grants from the Deutsche Forschungsgemeinschaft and the Chica and Heinz Schaller Stiftung (to O.T.F.), Agence Nationale de Recherche sur le SIDA (ANRS), SIDACTION, Fondation de France, Centre National de la Recherche Scientifique, the European Community, La Ligue Contre le Cancer and the Association pour la Recherche contre le Cancer (ARC), and the Institut Pasteur (to O.S. or A.A.).

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Authors and Affiliations

  1. Oliver T. Fackler is at the Department of Virology, University of Heidelberg, D-69120 Heidelberg, Germany.,

    Oliver T. Fackler

  2. Andres Alcover is at the Unité de Biologie Cellulaire des Lymphocytes, Institut Pasteur, 75724 Paris Cedex 15, France.,

    Andres Alcover

  3. Olivier Schwartz is at the Groupe Virus et Immunité, Institut Pasteur.,

    Olivier Schwartz

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  1. Oliver T. Fackler
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  2. Andres Alcover
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Correspondence to Oliver T. Fackler or Olivier Schwartz.

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Glossary

Activation-induced cell death

A process by which fully activated T cells undergo programmed cell death through engagement of cell-surface-expressed death receptors, such as CD95 (also known as FAS) and the tumour-necrosis-factor receptor, or after exposure to reactive oxygen species. It ensures the rapid elimination of effector cells after their antigen-dependent clonal expansion.

Endocytic recycling compartment

A component of the endocytic recycling system by which cell-surface and extracellular components are internalized and then recycled to the plasma membrane.

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell. It is also known as the supramolecular activation cluster. Important molecules that are involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Immunological synapses are now known to also form between other types of immune cell: for example, between dendritic cells and natural killer cells.

Virological synapse

The cell–cell contact zone between dendritic cells and CD4+ T cells, or between two CD4+ T cells, that facilitates transmission of HIV by locally concentrating virus and viral receptors.

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Fackler, O., Alcover, A. & Schwartz, O. Modulation of the immunological synapse: a key to HIV-1 pathogenesis?. Nat Rev Immunol 7, 310–317 (2007). https://doi.org/10.1038/nri2041

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