Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Dendritic-cell interactions with HIV: infection and viral dissemination

Nature Reviews Immunology volume 6, pages 859–868 (2006)Cite this article

Key Points

  • Dendritic cells (DCs) are located in the mucosae and the lymphoid tissues. They are proposed to be among the first cells to encounter HIV during sexual transmission.

  • The main populations of DCs include myeloid DCs and plasmacytoid DCs in the blood, and Langerhans cells in the tissues. Myeloid DCs, plasmacytoid DCs and Langerhans cells are all susceptible to infection with HIV; they can also transfer HIV to CD4+ T cells.

  • Follicular DCs can trap and maintain large quantities of HIV, thereby functioning as a persistent reservoir of virus.

  • Immunomodulation of DCs by HIV infection is a key aspect of viral pathogenesis, particularly through the modulation or interference of the antigen-presenting function of DCs.

  • DCs express high levels of C-type lectins, including DC-specific intercellular adhesion molecule 3 (ICAM3)-grabbing non-integrin (DC-SIGN; also known as CD209). C-type lectins are the main HIV attachment factors at the surface of dermal and mucosal DCs.

  • DCs have DC-SIGN-dependent and DC-SIGN-independent mechanisms of HIV trans-infection of CD4+ T cells. The efficiency of HIV transmission can be increased by maturation of DCs.

  • The transfer of virus from DCs to CD4+ T cells occurs in three discrete steps. First, DCs capture and bind HIV. Second, HIV traffics within these DCs. And third, HIV is transferred to CD4+ T cells by a process that is known as trans-infection.

  • DC-mediated HIV trans-infection might occur by several distinct processes that can take place concurrently, including rapid HIV trans-infection through infectious synapses and exosome-associated viruses. HIV transmission can also be mediated by de novo viral production in DCs, known as cis-infection.

  • Elucidating the interactions of HIV with DCs will be vital to uncover the contribution of DCs to viral pathogenesis.

Abstract

Dendritic cells (DCs) are crucial for the generation and the regulation of adaptive immunity. Because DCs have a pivotal role in marshalling immune responses, HIV has evolved ways to exploit DCs, thereby facilitating viral dissemination and allowing evasion of antiviral immunity. Defining the mechanisms that underlie cell–cell transmission of HIV and understanding the role of DCs in this process should help us in the fight against HIV infection. This Review highlights the latest advances in our understanding of the interactions between DCs and HIV, focusing on the mechanisms of DC-mediated viral dissemination.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The role of dendritic cells in HIV infection and dissemination.
Figure 2: Dendritic-cell maturation affects HIV transmission.
Figure 3: Mechanisms of dendritic-cell-mediated HIV transmission.

Similar content being viewed by others

References

  1. United Nations Programme on HIV/AIDS. 2006 Report on the Global AIDS epidemic 8 (UNAIDS, Geneva, 2006).

  2. Shattock, R. J. & Moore, J. P. Inhibiting sexual transmission of HIV-1 infection. Nature. Rev. Microbiol. 1, 25–34 (2003).

    Article  CAS  Google Scholar 

  3. Pope, M. & Haase, A. T. Transmission, acute HIV-1 infection and the quest for strategies to prevent infection. Nature Med. 9, 847–852 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Steinman, R. M. et al. The interaction of immunodeficiency viruses with dendritic cells. Curr. Top. Microbiol. Immunol. 276, 1–30 (2003).

    CAS  PubMed  Google Scholar 

  5. 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 

  6. Cameron, P. U. et al. Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science 257, 383–387 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Pope, M. et al. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell 78, 389–398 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. McDonald, D. et al. Recruitment of HIV and its receptors to dendritic cell–T cell junctions. Science 300, 1295–1297 (2003). First paper to describe infectious synapses between DCs and T cells.

    Article  CAS  PubMed  Google Scholar 

  9. Arrighi, J. F. et al. DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. J. Exp. Med. 200, 1279–1288 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wiley, R. D. & Gummuluru, S. Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc. Natl Acad. Sci. USA 103, 738–743 (2006). Recent paper that describes HIV trans -infection mediated by exosome release from immature MDDCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kawamura, T. et al. R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms. Proc. Natl Acad. Sci. USA 100, 8401–8406 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Turville, S. G. et al. Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells. Blood 103, 2170–2179 (2004). Reports the rapid transmission and long-term transmission of HIV by human MDDCs.

    Article  CAS  PubMed  Google Scholar 

  13. Nobile, C. et al. Covert human immunodeficiency virus replication in dendritic cells and in DC-SIGN-expressing cells promotes long-term transmission to lymphocytes. J. Virol. 79, 5386–5399 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lore, K., Smed-Sorensen, A., Vasudevan, J., Mascola, J. R. & Koup, R. A. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells. J. Exp. Med. 201, 2023–2033 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Burleigh, L. et al. Infection of dendritic cells (DCs), not DC-SIGN-mediated internalization of human immunodeficiency virus, is required for long-term transfer of virus to T cells. J. Virol. 80, 2949–2957 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, Y. J. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106, 259–262 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Rissoan, M. C. et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science 283, 1183–1186 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Cella, M. et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nature Med. 5, 919–923 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Siegal, F. P. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Zaitseva, M. et al. Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nature Med. 3, 1369–1375 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Valladeau, J. et al. The monoclonal antibody DCGM4 recognizes Langerin, a protein specific of Langerhans cells, and is rapidly internalized from the cell surface. Eur. J. Immunol. 29, 2695–2704 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Niedecken, H., Lutz, G., Bauer, R. & Kreysel, H. W. Langerhans cell as primary target and vehicle for transmission of HIV. Lancet 2, 519–520 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Berger, R. et al. Isolation of human immunodeficiency virus type 1 from human epidermis: virus replication and transmission studies. J. Invest. Dermatol. 99, 271–277 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Soto-Ramirez, L. E. et al. HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV. Science 271, 1291–1293 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Ludewig, B., Gelderblom, H. R., Becker, Y., Schafer, A. & Pauli, G. Transmission of HIV-1 from productively infected mature Langerhans cells to primary CD4+ T lymphocytes results in altered T cell responses with enhanced production of IFN-γ and IL-10. Virology 215, 51–60 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Blauvelt, A. et al. Productive infection of dendritic cells by HIV-1 and their ability to capture virus are mediated through separate pathways. J. Clin. Invest. 100, 2043–2053 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Granelli-Piperno, A., Delgado, E., Finkel, V., Paxton, W. & Steinman, R. M. Immature dendritic cells selectively replicate macrophagetropic (M-tropic) human immunodeficiency virus type 1, while mature cells efficiently transmit both M- and T-tropic virus to T cells. J. Virol. 72, 2733–2737 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Granelli-Piperno, A., Finkel, V., Delgado, E. & Steinman, R. M. Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells. Curr. Biol. 9, 21–29 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Kawamura, T. et al. Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J. Exp. Med. 192, 1491–1500 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Patterson, S., Rae, A., Hockey, N., Gilmour, J. & Gotch, F. Plasmacytoid dendritic cells are highly susceptible to human immunodeficiency virus type 1 infection and release infectious virus. J. Virol. 75, 6710–6713 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Donaghy, H. et al. Loss of blood CD11c+ myeloid and CD11c− plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load. Blood 98, 2574–2576 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Smed-Sorensen, A. et al. Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells. J. Virol. 79, 8861–8869 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Granelli-Piperno, A. et al. Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. J. Exp. Med. 184, 2433–2438 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rubbert, A. et al. Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry. J. Immunol. 160, 3933–3941 (1998).

    CAS  PubMed  Google Scholar 

  36. Turville, S. G. et al. HIV gp120 receptors on human dendritic cells. Blood 98, 2482–2488 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Ignatius, R. et al. The immunodeficiency virus coreceptor, Bonzo/STRL33/TYMSTR, is expressed by macaque and human skin- and blood-derived dendritic cells. AIDS Res. Hum. Retroviruses 16, 1055–1059 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Beaulieu, S. et al. Expression of a functional eotaxin (CC chemokine ligand 11) receptor CCR3 by human dendritic cells. J. Immunol. 169, 2925–2936 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Cameron, P. U., Forsum, U., Teppler, H., Granelli-Piperno, A. & Steinman, R. M. During HIV-1 infection most blood dendritic cells are not productively infected and can induce allogeneic CD4+ T cells clonal expansion. Clin. Exp. Immunol. 88, 226–236 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pope, M., Gezelter, S., Gallo, N., Hoffman, L. & Steinman, R. M. Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. J. Exp. Med. 182, 2045–2056 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. McIlroy, D. et al. Infection frequency of dendritic cells and CD4+ T lymphocytes in spleens of human immunodeficiency virus-positive patients. J. Virol. 69, 4737–4745 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Moris, A. et al. DC-SIGN promotes exogenous MHC-I-restricted HIV-1 antigen presentation. Blood 103, 2648–2654 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. 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 

  44. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Tenner-Racz, K. et al. Immunohistochemical, electron microscopic and in situ hybridization evidence for the involvement of lymphatics in the spread of HIV-1. AIDS 2, 299–309 (1988).

    Article  CAS  PubMed  Google Scholar 

  46. Heath, S. L., Tew, J. G., Szakal, A. K. & Burton, G. F. Follicular dendritic cells and human immunodeficiency virus infectivity. Nature 377, 740–744 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Burton, G. F., Keele, B. F., Estes, J. D., Thacker, T. C. & Gartner, S. Follicular dendritic cell contributions to HIV pathogenesis. Semin. Immunol. 14, 275–284 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Schacker, T. et al. Rapid accumulation of human immunodeficiency virus (HIV) in lymphatic tissue reservoirs during acute and early HIV infection: implications for timing of antiretroviral therapy. J. Infect. Dis. 181, 354–357 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Spiegel, H., Herbst, H., Niedobitek, G., Foss, H. D. & Stein, H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am. J. Pathol. 140, 15–22 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith, B. A. et al. Persistence of infectious HIV on follicular dendritic cells. J. Immunol. 166, 690–696 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Popov, S., Chenine, A. L., Gruber, A., Li, P. L. & Ruprecht, R. M. Long-term productive human immunodeficiency virus infection of CD1a-sorted myeloid dendritic cells. J. Virol. 79, 602–608 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Romani, N. et al. Proliferating dendritic cell progenitors in human blood. J. Exp. Med. 180, 83–93 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Geijtenbeek, T. B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585 (2000). First paper to identify DC-SIGN.

    Article  CAS  PubMed  Google Scholar 

  54. de Jong, E. C. et al. Microbial compounds selectively induce TH1 cell-promoting or TH2 cell-promoting dendritic cells in vitro with diverse TH cell-polarizing signals. J. Immunol. 168, 1704–1709 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Sanders, R. W. et al. Differential transmission of human immunodeficiency virus type 1 by distinct subsets of effector dendritic cells. J. Virol. 76, 7812–7821 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Turville, S. G. et al. Diversity of receptors binding HIV on dendritic cell subsets. Nature Immunol. 3, 975–983 (2002). Characterizes a variety of HIV-binding receptors expressed by DC subsets.

    Article  CAS  Google Scholar 

  57. Jefford, M. et al. Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli. Blood 102, 1753–1763 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Granelli-Piperno, A. et al. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin/CD209 is abundant on macrophages in the normal human lymph node and is not required for dendritic cell stimulation of the mixed leukocyte reaction. J. Immunol. 175, 4265–4273 (2005). Reports that DC-SIGN is not required for DCs to transmit HIV and stimulate T cells.

    Article  CAS  PubMed  Google Scholar 

  59. Macatonia, S. E., Lau, R., Patterson, S., Pinching, A. J. & Knight, S. C. Dendritic cell infection, depletion and dysfunction in HIV-infected individuals. Immunology 71, 38–45 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Knight, S. C., Patterson, S. & Macatonia, S. E. Stimulatory and suppressive effects of infection of dendritic cells with HIV-1. Immunol. Lett. 30, 213–218 (1991).

    Article  CAS  PubMed  Google Scholar 

  61. Lore, K. et al. Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection. AIDS 16, 683–692 (2002).

    Article  PubMed  Google Scholar 

  62. Granelli-Piperno, A., Golebiowska, A., Trumpfheller, C., Siegal, F. P. & Steinman, R. M. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc. Natl Acad. Sci. USA 101, 7669–7674 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Granelli-Piperno, A., Shimeliovich, I., Pack, M., Trumpfheller, C. & Steinman, R. M. HIV-1 selectively infects a subset of nonmaturing BDCA1-positive dendritic cells in human blood. J. Immunol. 176, 991–998 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Fidler, S. J. et al. An early antigen-presenting cell defect in HIV-1-infected patients correlates with CD4 dependency in human T-cell clones. Immunology 89, 46–53 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sapp, M. et al. Dendritic cells generated from blood monocytes of HIV-1 patients are not infected and act as competent antigen presenting cells eliciting potent T-cell responses. Immunol. Lett. 66, 121–128 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. 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 

  67. Izmailova, E. et al. HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nature Med. 9, 191–197 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Fanales-Belasio, E. et al. Native HIV-1 Tat protein targets monocyte-derived dendritic cells and enhances their maturation, function, and antigen-specific T cell responses. J. Immunol. 168, 197–206 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Quaranta, M. G., Tritarelli, E., Giordani, L. & Viora, M. HIV-1 Nef induces dendritic cell differentiation: a possible mechanism of uninfected CD4+ T cell activation. Exp. Cell Res. 275, 243–254 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Andrieu, M. et al. Downregulation of major histocompatibility class I on human dendritic cells by HIV Nef impairs antigen presentation to HIV-specific CD8+ T lymphocytes. AIDS Res. Hum. Retroviruses 17, 1365–1370 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Shinya, E. et al. Endogenously expressed HIV-1 nef down-regulates antigen-presenting molecules, not only class I MHC but also CD1a, in immature dendritic cells. Virology 326, 79–89 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Spira, A. I. et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J. Exp. Med. 183, 215–225 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Hu, J., Miller, C. J., O'Doherty, U., Marx, P. A. & Pope, M. The dendritic cell–T cell milieu of the lymphoid tissue of the tonsil provides a locale in which SIV can reside and propagate at chronic stages of infection. AIDS Res. Hum. Retroviruses 15, 1305–1314 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Hu, J., Gardner, M. B. & Miller, C. J. Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J. Virol. 74, 6087–6095 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hu, Q. et al. Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J. Exp. Med. 199, 1065–1075 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lederman, M. M., Offord, R. E. & Hartley, O. Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nature Rev. Immunol. 6, 371–382 (2006).

    Article  CAS  Google Scholar 

  77. Geijtenbeek, T. B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000). Characterizes the role of DC-SIGN in increasing HIV trans -infection.

    Article  CAS  PubMed  Google Scholar 

  78. Lin, G. et al. Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J. Virol. 77, 1337–1346 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pohlmann, S. et al. DC-SIGN interactions with human immunodeficiency virus: virus binding and transfer are dissociable functions. J. Virol. 75, 10523–10526 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wu, L., Martin, T. D., Han, Y. C., Breun, S. K. & KewalRamani, V. N. Trans-dominant cellular inhibition of DC-SIGN-mediated HIV-1 transmission. Retrovirology 1, 14 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lee, B. et al. Cis expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J. Virol. 75, 12028–12038 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Trumpfheller, C., Park, C. G., Finke, J., Steinman, R. M. & Granelli-Piperno, A. Cell type-dependent retention and transmission of HIV-1 by DC-SIGN. Int. Immunol. 15, 289–298 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Nobile, C., Moris, A., Porrot, F., Sol-Foulon, N. & Schwartz, O. Inhibition of human immunodeficiency virus type 1 Env-mediated fusion by DC-SIGN. J. Virol. 77, 5313–5323 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Engering, A., Van Vliet, S. J., Geijtenbeek, T. B. & Van Kooyk, Y. Subset of DC-SIGN+ dendritic cells in human blood transmits HIV-1 to T lymphocytes. Blood 100, 1780–1786 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Gurney, K. B. et al. Binding and transfer of human immunodeficiency virus by DC-SIGN+ cells in human rectal mucosa. J. Virol. 79, 5762–5773 (2005). Shows efficient HIV transmission by DC-SIGN+ immature DCs in human rectal mucosa.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wu, L. et al. Rhesus macaque dendritic cells efficiently transmit primate lentiviruses independently of DC-SIGN. Proc. Natl Acad. Sci. USA 99, 1568–1573 (2002). Shows DC-SIGN-independent transmission of primate lentiviruses by rhesus macaque DCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wu, L., Martin, T. D., Vazeux, R., Unutmaz, D. & KewalRamani, V. N. Functional evaluation of DC-SIGN monoclonal antibodies reveals DC-SIGN interactions with ICAM-3 do not promote human immunodeficiency virus type 1 transmission. J. Virol. 76, 5905–5914 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Baribaud, F., Pohlmann, S., Leslie, G., Mortari, F. & Doms, R. W. Quantitative expression and virus transmission analysis of DC-SIGN on monocyte-derived dendritic cells. J. Virol. 76, 9135–9142 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Gummuluru, S., Rogel, M., Stamatatos, L. & Emerman, M. Binding of human immunodeficiency virus type 1 to immature dendritic cells can occur independently of DC-SIGN and mannose binding C-type lectin receptors via a cholesterol-dependent pathway. J. Virol. 77, 12865–12874 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Soilleux, E. J. et al. Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J. Leukoc. Biol. 71, 445–457 (2002).

    CAS  PubMed  Google Scholar 

  91. Krutzik, S. R. et al. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nature Med. 11, 653–660 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Chehimi, J. et al. HIV-1 transmission and cytokine-induced expression of DC-SIGN in human monocyte-derived macrophages. J. Leukoc. Biol. 74, 757–763 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Nguyen, D. G. & Hildreth, J. E. Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages. Eur. J. Immunol. 33, 483–493 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Kwon, D. S., Gregorio, G., Bitton, N., Hendrickson, W. A. & Littman, D. R. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity 16, 135–144 (2002). Reports that HIV internalization is important for efficient DC-SIGN-mediated transmission of HIV.

    Article  CAS  PubMed  Google Scholar 

  95. Wu, L., Martin, T. D., Carrington, M. & KewalRamani, V. N. Raji B cells, misidentified as THP-1 cells, stimulate DC-SIGN-mediated HIV transmission. Virology 318, 17–23 (2004). Shows that DC-SIGN-mediated transmission of HIV is cell-type dependent and indicates that B cells and DCs that facilitate viral transmission have common features.

    Article  CAS  PubMed  Google Scholar 

  96. Soilleux, E. J. et al. Placental expression of DC-SIGN may mediate intrauterine vertical transmission of HIV. J. Pathol. 195, 586–592 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Jameson, B. et al. Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques. J. Virol. 76, 1866–1875 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Engering, A. et al. Dynamic populations of dendritic cell-specific ICAM-3 grabbing nonintegrin-positive immature dendritic cells and liver/lymph node-specific ICAM-3 grabbing nonintegrin-positive endothelial cells in the outer zones of the paracortex of human lymph nodes. Am. J. Pathol. 164, 1587–1595 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Soilleux, E. J. & Coleman, N. Langerhans cells and the cells of Langerhans cell histiocytosis do not express DC-SIGN. Blood 98, 1987–1988 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Weissman, D., Li, Y., Orenstein, J. M. & Fauci, A. S. Both a precursor and a mature population of dendritic cells can bind HIV. However, only the mature population that expresses CD80 can pass infection to unstimulated CD4+ T cells. J. Immunol. 155, 4111–4117 (1995).

    CAS  PubMed  Google Scholar 

  101. Frank, I. et al. Infectious and whole inactivated simian immunodeficiency viruses interact similarly with primate dendritic cells (DCs): differential intracellular fate of virions in mature and immature DCs. J. Virol. 76, 2936–2951 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Canque, B. et al. The susceptibility to X4 and R5 human immunodeficiency virus-1 strains of dendritic cells derived in vitro from CD34+ hematopoietic progenitor cells is primarily determined by their maturation stage. Blood 93, 3866–3875 (1999).

    CAS  PubMed  Google Scholar 

  103. Cavrois, M. et al. Human immunodeficiency virus fusion to dendritic cells declines as cells mature. J. Virol. 80, 1992–1999 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bakri, Y. et al. The maturation of dendritic cells results in postintegration inhibition of HIV-1 replication. J. Immunol. 166, 3780–3788 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Tsunetsugu-Yokota, Y. et al. Efficient virus transmission from dendritic cells to CD4+ T cells in response to antigen depends on close contact through adhesion molecules. Virology 239, 259–268 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Garcia, E. et al. HIV-1 trafficking to the dendritic cell–T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse. Traffic 6, 488–501 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Bromley, S. K. et al. The immunological synapse. Annu. Rev. Immunol. 19, 375–396 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Arrighi, J. F. et al. Lentivirus-mediated RNA interference of DC-SIGN expression inhibits human immunodeficiency virus transmission from dendritic cells to T cells. J. Virol. 78, 10848–10855 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Thery, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nature Rev. Immunol. 2, 569–579 (2002).

    Article  CAS  Google Scholar 

  110. Pelchen-Matthews, A., Kramer, B. & Marsh, M. Infectious HIV-1 assembles in late endosomes in primary macrophages. J. Cell Biol. 162, 443–455 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nguyen, D. G., Booth, A., Gould, S. J. & Hildreth, J. E. Evidence that HIV budding in primary macrophages occurs through the exosome release pathway. J. Biol. Chem. 278, 52347–52354 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Sharova, N., Swingler, C., Sharkey, M. & Stevenson, M. Macrophages archive HIV-1 virions for dissemination in trans. EMBO J. 24, 2481–2489 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 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 

  114. Moris, A. et al. Dendritic cells and HIV-specific CD4+ T cells: HIV antigen presentation, T cell activation, viral transfer. Blood 108, 1643–1651 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Brenchley, J. M. et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 200, 749–759 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mehandru, S. et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J. Exp. Med. 200, 761–770 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Raposo, G. et al. Human macrophages accumulate HIV-1 particles in MHC II compartments. Traffic 3, 718–729 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Lu, W., Arraes, L. C., Ferreira, W. T. & Andrieu, J. M. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nature Med. 10, 1359–1365 (2004). First paper to report a potential therapeutic, DC-based vaccine against chronic HIV infection.

    Article  CAS  PubMed  Google Scholar 

  119. Kundu, S. K. et al. A pilot clinical trial of HIV antigen-pulsed allogeneic and autologous dendritic cell therapy in HIV-infected patients. AIDS Res. Hum. Retroviruses 14, 551–560 (1998).

    Article  CAS  PubMed  Google Scholar 

  120. Curtis, B. M., Scharnowske, S. & Watson, A. J. Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc. Natl Acad. Sci. USA 89, 8356–8360 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rappocciolo, G. et al. DC-SIGN on B lymphocytes is required for transmission of HIV-1 to T lymphocytes. PLoS Pathog. 2, e70 (2006). Recent report that the induction of DC-SIGN expression on activated primary B cells potentiates HIV transmission to T cells.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Tailleux, L. et al. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J. Exp. Med. 197, 121–127 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mitchell, D. A., Fadden, A. J. & Drickamer, K. A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands. J. Biol. Chem. 276, 28939–28945 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Feinberg, H., Mitchell, D. A., Drickamer, K. & Weis, W. I. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 294, 2163–2166 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Feinberg, H., Guo, Y., Mitchell, D. A., Drickamer, K. & Weis, W. I. Extended neck regions stabilize tetramers of the receptors DC-SIGN and DC-SIGNR. J. Biol. Chem. 280, 1327–1335 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Sol-Foulon, N. et al. HIV-1 Nef-induced upregulation of DC-SIGN in dendritic cells promotes lymphocyte clustering and viral spread. Immunity 16, 145–155 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Pohlmann, S., Baribaud, F. & Doms, R. W. DC-SIGN and DC-SIGNR: helping hands for HIV. Trends Immunol. 22, 643–646 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Ganesh, L. et al. Infection of specific dendritic cells by CCR5-tropic human immunodeficiency virus type 1 promotes cell-mediated transmission of virus resistant to broadly neutralizing antibodies. J. Virol. 78, 11980–11987 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank J. Barbieri for critical reading of the manuscript. L.W. is supported by grants from the National Institutes of Health (United States) and the Research Affairs Committee of the Medical College of Wisconsin (United States). V.N.K. is supported by intramural research funds from the National Institutes of Health. The authors apologize to all those whose work has not been cited as a result of space limitations.

Author information

Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, 53226, Wisconsin, USA

    Li Wu

  2. HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, 21702, Maryland, USA

    Vineet N. KewalRamani

Authors
  1. Li Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vineet N. KewalRamani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li Wu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Li Wu's homepage

Vineet N. KewalRamani's homepage

Glossary

Infectious synapse

Also known as the virological synapse. The cell–cell contact zone between dendritic cells and CD4+ T cells that facilitates transmission of HIV by locally concentrating virus and viral receptors.

Trans-infection

Monocyte-derived dendritic cells and certain types of cell that have been transfected with vectors that encode DC-SIGN (DC-specific intercellular adhesion molecule 3 (ICAM3)-grabbing non-integrin) can capture and transfer HIV to target cells without themselves becoming infected.

Exosomes

Small lipid-bilayer vesicles that are released from dendritic cells and other cells. They are composed of plasma membranes or are derived from the membranes of intracellular vesicles. They might contain antigen–MHC complexes and interact with antigen-specific lymphocytes directly, or they might be taken up by antigen-presenting cells.

C-type lectins

A family of transmembrane proteins (with calcium-dependent activities) that function as cell-adhesion molecules. C-type lectins are involved in the regulation of signalling pathways and recognize specific carbohydrate structures of pathogens and self antigens.

R5 HIV

An HIV strain that uses CC-chemokine receptor 5 (CCR5) as the co-receptor to gain entry to target cells.

X4 HIV

An HIV strain that uses CXC-chemokine receptor 4 (CXCR4) as the co-receptor to gain entry to target cells.

Simian immunodeficiency virus

(SIV). Collectively, different HIV-related lentiviruses isolated from non-human primates. SIV infection of rhesus macaques is an experimental model for HIV infection of humans.

Cis-infection

HIV infection of permissive cells through viral-receptor-mediated entry, resulting in the production of progeny viruses. HIV transmission to target cells can be mediated after infection of dendritic cells.

Macropinocytosis

An actin-dependent process by which cells engulf large volumes of fluid.

Immunological synapse

A junctional structure that is formed between an antigen-presenting cell and a T cell. Important molecules involved in T-cell activation — including the T-cell receptor, signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Mobilization of the actin cytoskeleton is required for formation of the immunological synapse.

Multivesicular body

An endocytic organelle that contains small vesicles generated from budding of an endosomal membrane into the lumen of the compartment.

Tetraspanins

A family of transmembrane proteins that have transmembrane and extracellular domains of different sizes. The function of tetraspanins has not been properly established, but they seem to interact with many other transmembrane proteins and seem to form large multimeric protein networks, which might be involved in intracellular signalling.

Single-cycle reporter HIV

An infectious HIV vector that can establish an integrated provirus but cannot undergo additional cycles of replication, owing to an inactivated viral envelope gene. The viral genome encodes a reporter gene (such as firefly luciferase or green fluorescent protein), and this gene is expressed on integration of viral DNA in permissive target cells, enabling measurement of infectivity.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, L., KewalRamani, V. Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol 6, 859–868 (2006). https://doi.org/10.1038/nri1960

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1960

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing