The Interaction of Immunodeficiency Viruses with Dendritic Cells

  • R. M. Steinman
  • A. Granelli-Piperno
  • M. Pope
  • C. Trumpfheller
  • R. Ignatius
  • G. Arrode
  • P. Racz
  • K. Tenner-Racz
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 276)


Dendritic cells (DCs) can influence HIV-1 and SIV pathogenesis and protective mechanisms at several levels. First, HIV-1 productively infects select populations of DCs in culture, particularly immature DCs derived from blood monocytes and skin (Langerhans cells). However, there exist only a few instances in which HIV-1- or SIV-infected DCs have been identified in vivo in tissue sections. Second, different types of DCs reliably sequester and transmit infectious HIV-1 and SIV in culture, setting up a productive infection in T cells interacting with the DCs. This stimulation of infection in T cells may explain the observation that CD4+ T lymphocytes are the principal cell type observed to be infected with HIV-1 in lymphoid tissues in vivo. DCs express a C-type lectin, DC-SIGN/CD209, that functions to bind HIV-1 (and other infectious agents) and transmit virus to T cells. When transfected into the THP-1 cell line, the cytosolic domain of DC-SIGN is needed for HIV-1 sequestration and transmission. However, DCs lacking DC-SIGN (Langerhans cells) or expressing very low levels of DC-SIGN (rhesus macaque monocyte-derived DCs) may use additional molecules to bind and transmit immunodeficiency viruses to T cells. Third, DCs are efficient antigen-presenting cells for HIV-1 and SIV antigens. Infection with several recombinant viral vectors as well as attenuated virus is followed by antigen presentation to CD4+ and CD8+ T cells. An intriguing pathway that is well developed in DCs is the exogenous pathway for nonreplicating viral antigens to be presented on class I MHC products. This should allow DCs to stimulate CD8+ T cells after uptake of antibody-coated HIV-1 and dying infected T cells. It has been proposed that DCs, in addition to expanding effector helper and killer T cells, induce tolerance through T cell deletion and suppressor T cell formation, but this must be evaluated directly. Fourth, DCs are likely to be valuable in improving vaccine design. Increasing DC uptake of a vaccine, as well as increasing their numbers and maturation, should enhance efficacy. However, DCs can also capture antigens from other cells that are initially transduced with a DNA vaccine or a recombinant viral vector. The interaction of HIV-1 and SIV with DCs is therefore intricate but pertinent to understanding how these viruses disrupt immune function and elicit immune responses.


Dendritic Cell Rhesus Macaque Simian Immunodeficiency Virus Productive Infection Human Dendritic Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akbari O, Panjwani N, Garcia S, Tascon R, Lowrie D, and Stockinger B. (1999). DNA vaccination: transfection and activation of dendritic cells as key events for immunity. J Exp Med 189 169–178PubMedCrossRefGoogle Scholar
  2. Albert M. L, Sauter B, and Bhardwaj N. (1998). Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392 86–89PubMedCrossRefGoogle Scholar
  3. Alvarez C. P, Lasala F, Carrillo J, Muniz O, Corbi A. L, and Delgado R. (2002). C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. J Virol 76 6841–4PubMedCrossRefGoogle Scholar
  4. Amara R. R, Villinger F, Altman J. D, Lydy S. L, O’Neil S. P, Staprans S. I, Monte-fiori D. C, Xu Y, Herndon J. G, Wyatt L. S, et al. (2001). Control of musosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292 69–74PubMedCrossRefGoogle Scholar
  5. Andrieu M, Loing E, Desoutter J. F, Connan F, Choppin J, Gras-Masse H, Hanau D, Dautry-Varsat A, Guillet J. G, and Hosmalin A. (2000). Endocytosis of an HIV-derived lipopeptide into human dendritic cells followed by class I-restricted CD8(+) T lymphocyte activation. Eur J Immunol 30 3256–3265PubMedCrossRefGoogle Scholar
  6. Arrode G, Boccaccio C, Lule J, Allart S, Moinard N, Abastado J. P, Alam A, and Davrinche C. (2000). Incoming human cytomegalovirus pp65 (UL83) contained in apoptotic infected fibroblasts is cross-presented to CD8+ T cells by dendritic cells. J Virol 74 10018–24PubMedCrossRefGoogle Scholar
  7. Bakri Y, Schiffer C, Zennou V, Charneau P, Kahn E, Benjouad A, Gluckman J. C, and Canque B. (2001). The maturation of dendritic cells results in postintegration inhibition of HIV-1 replication. J Immunol 166 3780–3788PubMedGoogle Scholar
  8. Barouch D. H, Santra S, Schmitz J. E, Kuroda M. J, Fu T. M, Wagner W, Bilska M, Craiu A, Zheng X. X, Krivulka G. R, et al. (2000). Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290 486–92PubMedCrossRefGoogle Scholar
  9. Becker J, Ulrich P, Kunze R, Gelderblom H, Langford A, and Reichart P. (1988). Immunohistochemical detection of HIV structural proteins and distribution of T-lymphocytes and Langerhans cells in the oral mucosa of HIV infected patients. Virchows Arch A Pathol Anat Histopathol 412 413–419PubMedCrossRefGoogle Scholar
  10. Bender A, Sapp M, Schuler G, Steinman R. M, and Bhardwaj N. (1996). Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Methods 196 121–135PubMedCrossRefGoogle Scholar
  11. Berger R, Gartner S, Rappersberger K, Foster C. A, Wolff K, and Stingl G. (1992). Isolation of human immunodeficiency virus type 1 from human epidermis: virus replication and transmission studies. J Invest Dermatol 99 271–277PubMedCrossRefGoogle Scholar
  12. Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Enk A. H, Nussenzweig M. C, and Steinman R. M. (2002). Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 leads in the steady state to antigen presentation on MHC class 1 and peripheral CD8+ T cell tolerance. J Exp Med 196 1627–1638PubMedCrossRefGoogle Scholar
  13. Bot A, Stan A. C, Inaba K, Steinman R. M, and Bona C. (2000). Dendritic cells at a DNA vaccination site express the encoded influenza nucleoprotein and prime MHC class I-restricted cytolytic lymphocytes upon adoptive transfer. Int Immunol 12 825–832PubMedCrossRefGoogle Scholar
  14. Buseyne F, Gall S. L, Boccaccio C, Abastado J. P, Lifson J. D, Arthur L. O, Riviere Y, Heard J. M, and Schwartz O. (2001). MHC-I-restricted presentation of HIV-1 virion antigens without viral replication. Nat Med 7 344–349PubMedCrossRefGoogle Scholar
  15. Cameron P. U, Freudenthal P. S, Barker J. M, Gezelter S, Inaba K, and Steinman R. M. (1992). Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science 257 383–387PubMedCrossRefGoogle Scholar
  16. Cameron P. U, Pope M, Gezelter S, and Steinman R. M. (1994). Infection and apoptotic cell death of CD4+ T cells during an immune response to HIV-1 pulsed dendritic cells. AIDS Res Hum Retroviruses 10 61–71PubMedCrossRefGoogle Scholar
  17. Casares S, Inaba K, Brumeanu T.-D, Steinman R. M, and Bona C. A. (1997). Antigen presentation by dendritic cells following immunization with DNA encoding a class II-restricted viral epitope. J Exp Med 186 1481–1486PubMedCrossRefGoogle Scholar
  18. Chattergoon M. A, Kim J. J, Yang J. S, Robinson T. M, Lee D. J, Dentchev T, Wilson D. M, Ayyavoo V, and Weiner D. B. (2000). Targeted antigen delivery to antigen-presenting cells including dendritic cells by engineered fas-mediated apoptosis. Nat Biotechnol 18 974–9PubMedCrossRefGoogle Scholar
  19. Cimarelli A, Zambruno G, Marconi A, Girolomoni G, Bertazzoni U, and Giannetti A. (1994). Quantitation by competitive PCR of HIV-1 proviral DNA in epidermal Langerhans Cells of HIV-infected patients. J Acquir Immune Defic Syndr 7 230–235PubMedGoogle Scholar
  20. Colino J, Shen Y, and Snapper C. M. (2001). Dendritic cells pulsed with intact Streptococcus pneumoniae elicit both protein-and polysaccharide-specific immunoglobulin isotype responses in vivo through distinct mechanisms. J Exp Med 195 1–14CrossRefGoogle Scholar
  21. Colmenares M, Puig-Kroger A, Muniz Pello O, Corbi A. L, and Rivas L. (2002). Dendritic-cell specific ICAM-3 grabbing nonintegrin (DC-SIGN CD209) a C-type surface lectin in human dendritic cells is a receptor for Leishmania amastigotes. J Biol Chem 16 16Google Scholar
  22. Delgado E, Finkel V, Baggiolini M, Clark-Lewis I, Mackay C. R, Steinman R. M, and Granelli-Piperno A. (1998). Mature dendritic cells respond to SDF-1 but not to several P chemokines. Immunobiology 198 490–500PubMedCrossRefGoogle Scholar
  23. Dhodapkar K. M, Krasovsky J, Williamson B, and Dhodapkar M. V. (2002). Antitumor monoclonal antibodies enhance cross-presentation of cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells. J Exp Med 195 125–133PubMedCrossRefGoogle Scholar
  24. Dhodapkar M. V, Krasovsky J, Steinman R. M, and Bhardwaj N. (2000). Mature dendritic cells boost functionally superior T cells in humans without foreign helper epitopes. J Clin Invest 105 R9 - R14PubMedCrossRefGoogle Scholar
  25. Dhodapkar M. V, Steinman R. M, Krasovsky J, Munz C, and Bhardwaj N. (2001). Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193 233–8PubMedCrossRefGoogle Scholar
  26. Dittmar M. T, Simmons G, Hibbitts S, O’Hare M, Louisirirotchanakul S, Beddows S, Weber J, Clapham P. R, and Weiss R. A. (1997). Langerhans cell tropism of human immunodeficiency virus type 1 subtype A through F isolates derived from different transmission groups. J Virol 718008–8013Google Scholar
  27. Engelmayer J, Larsson M, Lee M, Cox W. I, Steinman R. M, and Bhardwaj N. (2001). Mature dendritic cells infected with canarypox virus elicit strong anti-human immunodeficiency virus CD8+ and CD4+ T cell responses from chronically infected individuals. J Virol 75 2142–2153PubMedCrossRefGoogle Scholar
  28. Engelmayer J, Larsson M, Subklewe M, Chahroudi A, Schmaljohn A, William C, Steinman R. M, and Bhardwaj N. (1999). Vaccinia virus inhibits the maturation of human dendritic cells: a novel mechanism of immune evasion. J Immunol 163 6762–6768PubMedGoogle Scholar
  29. Fayette J, Dubois B, Vandenabelle S, Bridon J.-M, Vanbervliet B, Durand I, Banchereau J, Caux C, and Briere F. (1997). Human dendritic cells skew isotype switching of CD40-activated naive B cells towards IgA1 and IgA2. J Exp Med 185 1909–1918PubMedCrossRefGoogle Scholar
  30. Frank I, Piatak M, Jr, Stoessel H, Romani N, Bonnyay D, Lifson J. D, and Pope M. (2002). 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 2936–2951Google Scholar
  31. Frank I, and Pope M. (2002). The enigma of dendritic cell-immunodeficiency virus interplay. Curr Molec Med 2 229–248CrossRefGoogle Scholar
  32. Frankel S. S, Tenner-Racz K, Racz P, Wenig B. M, Hansen C. H, Listinsky C, Heffner D, Nelson A. M, Pope M, and Steinman R. M. (1997). Active replication of HIV-1 at the lymphoepithelial surface of the tonsil. Am J Pathol 15189–96Google Scholar
  33. Frankel S. S, Wenig B. M, Burke A. P, Mannan P, Thompson L. D. R, Abbondanzo S. L, Nelson A. M, Pope M, and Steinman R. M. (1996). Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid. Science 272 115–117PubMedCrossRefGoogle Scholar
  34. Garrett W. S, Chen L. M, Kroschewski R, Ebersold M, Turley S, Trombetta S, Galan J. E, and Mellman I. (2000). Developmental control of endocytosis in dendritic cells by Cdc42. Cell 102 325–34PubMedCrossRefGoogle Scholar
  35. Geijtenbeek T. B. H, Kwon D. S, Torensma R, van Vliet S. J, van Duijnhoven G. C. F, Middel J, Cornelissen I. L. M. H. A, Nottet H. S. L. M, KewalRamani V. N, Littman D. R, et al. (2000a). DC-SIGN a dendritic cell specific HIV-1 binding protein that enhances trans-infection of T cells. Cell 100 587–597PubMedCrossRefGoogle Scholar
  36. Geijtenbeek T. B. H, Torensma R, van Vliet S. J, van Duijnhoven G. C. F, Adema G. J, van Kooyk Y, and Figdor C. G. (2000b). Identification of DC-SIGN a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100 575–585PubMedCrossRefGoogle Scholar
  37. Giannetti A, Zambruno G, Cimarelli A, Marconi A, Negroni M, Girolomoni G, and Bertazzoni U. (1993). Direct detection of HIV-1 RNA in epidermal Langerhans cells of HIV-infected patients. J Acquir Immune Defic Syndr 6 329–33PubMedGoogle Scholar
  38. Granelli-Piperno A, Delgado E, Finkel V, Paxton W, and Steinman R. M. (1998). Immature dendritic cells selectively replicate M-tropic HIV-1 while mature cells efficiently transmit both M- and T-tropic virus to T cells. J Virol 72 2733–2737PubMedGoogle Scholar
  39. Granelli-Piperno A, Finkel V, Delgado E, and Steinman R. M. (1999). Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells. Current Biol 9 21–29CrossRefGoogle Scholar
  40. Granelli-Piperno A, Moser B, Pope M, Chen D, Wei Y, Isdell F, O’Doherty U, Paxton W, Koup R, Mojsov S, et al. (1996). Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. J Exp Med 184 2433–8PubMedCrossRefGoogle Scholar
  41. Granelli-Piperno A, Zhong L, Haslett P, Jacobson J, and Steinman R. M. (2000). Dendritic cells infected with VSV-pseudotyped HIV-1 present antigens to CD4+ and CD8+T cells from HIV-1 infected individuals. J Immunol 165 6620–6626PubMedGoogle Scholar
  42. Guo M, Gong S, Maric S, Misulovin Z, Pack M, Mahnke K, Nussenzweig M, and Steinman R. M. (2000). A monoclonal antibody to the DEC-205 endocytosis receptor on human dendritic cells. Hum Immunol 61729–738Google Scholar
  43. Hawiger D, Inaba K, Dorsett Y, Guo K, Mahnke K, Rivera M, Ravetch J. V, Steinman R. M, and Nussenzweig M. C. (2001). Dendritic cells induce peripheral Tcell unresponsiveness under steady state conditions in vivo. J Exp Med 194 769–780PubMedCrossRefGoogle Scholar
  44. Henry M, Uthman A, Ballaun C, Stingl G, and Tschachler E. (1994). Epidermal Langerhans cells of AIDS patients express HIV-1 regulatory and structural genes. J Invest Dermatol 103 593–596PubMedCrossRefGoogle Scholar
  45. Horton H, Vogel T. U, Carter D. K, Vielhuber K, Fuller D. H, Shipley T, Fuller J. T, Kunstman K. J, Sutter G, Montefiori D. C, et al. (2002). Immunization of rhesus macaques with a DNA prime/modified vaccinia virus ankara boost regimen induces broad simian immunodeficiency virus (SIV)-specific T-cell responses and reduces initial viral replication but does not prevent disease progression following challenge with pathogenic SIVmac239. J Virol 76 7187–7202PubMedCrossRefGoogle Scholar
  46. Hu J, Gardner M. B, and Miller C. J. (2000). Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 74 6087–6095PubMedCrossRefGoogle Scholar
  47. Hu J, Miller C. J, O’Doherty U, Marx P. A, and Pope M. (1999). 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 1305–14PubMedCrossRefGoogle Scholar
  48. Hu J, Pope M, O’Doherty U, Brown C, and Miller C. J. (1998). Immunophenotypic characterization of SIV-infected cells in cervix vagina and draining lymph nodes of chronically infected rhesus macaques. Lab Invest 78 435–451PubMedGoogle Scholar
  49. Igarashi T, Brown C. R, Endo Y, Buckler-White A, Plishka R, Bischofberger N, Hirsch V, and Martin M. A. (2001). Macrophages are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): Implications for HIV-1 infections of humans. Proc Natl Acad Sci USA 98 658–663PubMedCrossRefGoogle Scholar
  50. Ignatius R, Isdell F, O’Doherty U, and Pope M. (1998). Dendritic cells from skin and blood of macaques both promote SIV replication with T cells from different anatomical sites. J Med Primatol 27 121–128PubMedCrossRefGoogle Scholar
  51. Ignatius R, Marovich M, Mehlhop E, Villamide L, Mahnke K, Cox W. I, Isdell F, Frankel S, Mascola J. R, Steinman R. M, and Pope M. (2000). Canarypox-induced maturation of dendritic cells is mediated by apoptotic cell death and tumor necrosis factor-a secretion. J Virol 74 11329–11338PubMedCrossRefGoogle Scholar
  52. Ignatius R, Tenner-Racz K, Messmer D, Gettie A, Blanchard J, Luckay A, Russo C, Smith S, Marx P. A, Steinman R. M, Racz P, and Pope M. (2002). Increased macrophage infection upon subcutaneous inoculation of rhesus macaques with simian immunodeficiency virus-loaded dendritic cells or T cells but not with cell-free virus. J Virol 76 9787–9797PubMedCrossRefGoogle Scholar
  53. Inaba K, Schuler G, Witmer M. D, Valinsky J, Atassi B, and Steinman R. M. (1986). The immunologic properties of purified Langerhans cells: distinct requirements for the stimulation of unprimed and sensitized T lymphocytes. J Exp Med 164 605–613PubMedCrossRefGoogle Scholar
  54. Jenne L, Schuler G, and Steinkasserer A. (2001). Viral vectors for dendritic cell-based immunotherapy. Trends Immunol 22 102–107PubMedCrossRefGoogle Scholar
  55. Julia V, Hessel E. M, Malherbe L, Glaichenhaus N, O’Garra A, and Coffman R. L. (2002). A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure. Immunity 16 271–83PubMedCrossRefGoogle Scholar
  56. Kadowaki N, Ho S, Antonenko S, de Waal Malefyt R, Kastelein R. A, Bazan F, and Liu Y.-J. (2001). Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194 863–70PubMedCrossRefGoogle Scholar
  57. Kalter D. C, Greenhouse J. J, Orenstein J. M, Schnittman S. M, Gendelman H. E, and Meltzer M. S. (1991). Epidermal Langerhans cells are not principal reservoirs of virus in HIV disease. J Immunol 146 3396–3404PubMedGoogle Scholar
  58. Kanitakis J, Escaich S, Trepo C, and Thivolet J. (1991). Detection of human immunodeficiency virus-DNA and RNA in the skin of HIV-1 infected patients using the polymerase chain reaction. J Invest Dermatol 97 91–96PubMedCrossRefGoogle Scholar
  59. Kanitakis J, Marchand C, Su H, Trivolet J, Zambruno G, Schmitt D, and Gazzolo L. (1989). Immunohistochemical study of normal skin of HIV-1 infected patients shows no evidence of infection of epidermal Langerhans cells by HIV. Aids Res Hum Retroviruses 5 293–302PubMedCrossRefGoogle Scholar
  60. Kawamura T, Cohen S. S, Borris D. L, Aquilino E. A, Glushakova S, Margolis L. B, Orenstein J. M, Offord R. E, Neurath A. R, and Blauvelt A. (2000). Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J Exp Med 192 1491–500PubMedCrossRefGoogle Scholar
  61. Krug A, Towarowski A, Britsch S, Rothenfusser S, Hornung V, Bals R, Giese T, Engelmann H, Endres S, Krieg A. M, and Hartmann G. (2001). Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol 313026–37Google Scholar
  62. Kwon D. S, Gregario G, Bitton N, Hendrickson W. A, and Littman D. R. (2002). DC-SIGN mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity 16 135–144PubMedCrossRefGoogle Scholar
  63. Langenkamp A, Messi M, Lanzavecchia A, and Sallusto F. (2000). Kinetics of dendritic cell activation: impact on priming of Th1 Th2 and nonpolarized T cells. Nat Immunol 1311–316Google Scholar
  64. Larsson M, Wilkens D. T, Fonteneau J. F, Beadle T. J, Merritt M. J, Kost R. G, Haslett P. A, Cu-Uvin S, Bhardwaj N, Nixon D. F, and Shacklett B. L. (2002). Amplification of low-frequency antiviral CD8 T cell responses using autologous dendritic cells. AIDS 16 171–80PubMedCrossRefGoogle Scholar
  65. Le Bon A, Schiavoni G, D’Agostinio G, Gresser I, Belardelli F, and Tough D. F. (2001). Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14 461–470PubMedCrossRefGoogle Scholar
  66. Lee B, Leslie G, Soilleux E, O’Doherty U, Baik S, Levroney E, Flummerfelt K, Swiggard W, Coleman N, Malim M, and Doms R. W. (2001). Cis expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J Virol 75 12028–38PubMedCrossRefGoogle Scholar
  67. Liu K, Iyoda T, Saternus M, Kimura Y, Inaba K, and Steinman R. M. (2002). Immune tolerance following delivery of dying cells to dendritic cells in situ. J Exp Med 196 1091–1097PubMedCrossRefGoogle Scholar
  68. McDyer J. F, Dybul M, Goletz T. J, Kinter A. L, Thomas E. K, Berzofsky J. A, Fauci A. S, and Seder R. A. (1999). Differential effects of CD40 ligand/trimer stimulation on the ability of dendritic cells to replicate and transmit HIV infection: evidence for CC-chemokine-dependent and -independent mechanisms. J Immunol 162 3711–7PubMedGoogle Scholar
  69. McIlroy D, Autran B, Cheynier R, Wain-Hobson S, Clauvel J.-P, Oksenhendler E, Debre P, and Hosmalin A. (1995). Infection frequency of dendritic cells and CD4+ T lymphocytes in spleens of human immunodeficiency virus-positive patients. J Virol 69 4737–4745PubMedGoogle Scholar
  70. Mehlhop E, Villamide L. A, Frank I, Gettie A, Santisteban C, Messmer D, Ignatius R, Lifson J. D, and Pope M. (2002). Enhanced in vitro stimulation of rhesus macaque dendritic cells for activation of SIV-specific T cell responses. J Immunol Meth 260 219–34CrossRefGoogle Scholar
  71. Messmer D, Ignatius R, Santisteban C, Steinman R. M, and Pope M. (2000). The decreased replicative capacity of SIV mac239 delta nef is manifest in cultures of immature dendritic cells and T cells. J Virol 74 2406–2413PubMedCrossRefGoogle Scholar
  72. Messmer D, Jacque J.-M, Santisteban C, Bristow C, Han S.-Y, Villamide-Herrera L, Mehlhop E, Marx P. A, Steinman R. M, Gettie A, and Pope M. (2002). Endogenously expressed Nef uncouples cytokine and chemokine production from membrane phenotypic maturation in dendritic cells. J Immunol 169 4172–41PubMedGoogle Scholar
  73. Miller C. J, and Hu J. (1999). Tcell-tropic simian immunodeficiency virus (SIV) and simian-human immunodeficiency viruses are readily transmitted by vaginal inoculation of rhesus macaques and Langerhans’ cells of the female genital tract are infected with SIV. J Infect Dis 179 Suppl 3 S413–7CrossRefGoogle Scholar
  74. Motta I, Andre F, Lim A, Tartaglia J, Cox W. I, Zitvogel L, Angevin E, and Kourilsky P. (2001). Cross-presentation by dendritic cells of tumor antigen expressed in apoptotic recombinant canarypox virus-infected dendritic cells. J Immunol 167 1795– 802Google Scholar
  75. Muller J. G, Krenn V, Schindler C, Czub S, Stahl-Hennig C, Coulibaly C, Hunsmann G, Kneitz C, Kerkau T, Rethwilm A, and et al. (1993). Alterations of thymus cortical epithelium and interdigitating dendritic cells but no increase of thymocyte cell death in the early course of simian immunodeficiency virus infection. Am J Pathol 143699–713Google Scholar
  76. Pamer E, and Cresswell P. (1998). Mechanisms of MHC class I-restricted antigen processing. Annu Rev Immunol 16 323–58PubMedCrossRefGoogle Scholar
  77. Patterson B. K, Landay A, Andersson J, Brown C, Behbahani H, Jiyamapa D, Burki Z, Stanislawski D, Czerniewski M. A, and Garcia P. (1998). Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission. Am J Pathol 153 481–90PubMedCrossRefGoogle Scholar
  78. Petit C, Buseyne F, Boccaccio C, Abastado J. P, Heard J. M, and Schwartz O. (2001). Nef is required for efficient HIV-1 replication in cocultures of dendritic cells and lymphocytes. Virology 286 225–36PubMedCrossRefGoogle Scholar
  79. Pitcher C. J, Quittner C, Peterson D. M, Connors M, and Koup R. A. (1999). HIV-1- specific CD4+ T cells are detectable in most individuals with active HIV-1 infection but decline with prolonged viral suppression. Nat Med 5 518–525PubMedCrossRefGoogle Scholar
  80. Pope M, Betjes M. G. H, Romani N, Hirmand H, Cameron P. U, Hoffman L, Gezelter S, Schuler G, and Steinman R. M. (1994). Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell 78389–398Google Scholar
  81. Pope M, Elmore D, Ho D, and Marx P. (1997a). Dendritic cell-T cell mixtures isolated from the skin and mucosae of macaques support the replication of SIV. AIDS Res Hum Retroviruses 13 819–827PubMedCrossRefGoogle Scholar
  82. Pope M, Frankel S. S, Mascola J. R, Trkola A, Isdell F, Birx D. L, Burke D. S, Ho D. D, and Moore J. P. (1997b). HIV-1 strains from subtypes B and E replicate in cutaneous dendritic cell-T cell mixtures without displaying subtype-specific tropism. J Virol 718001–8007Google Scholar
  83. Pope M, Gezelter S, Gallo N, Hoffman L, and Steinman R. M. (1995). Low levels of HIV-1 in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. J Exp Med 182 2045–2056PubMedCrossRefGoogle Scholar
  84. Porgador A, Irvine K. R, Iwasaki A, Barber B. H, Restifo N. P, and Germain R. N. (1998). Predominant role for directly transfected dendritic cells in antigen presentation to CD8(+) T cells after gene gun immunization. J Exp Med 188 1075– 1082Google Scholar
  85. Ramsauer J, Tenner-Racz K, Meigel W, and Racz P. (1991). Immunohistochemical study of Langerhans’ cells in the skin of HIV-1 infected patients with and without Kaposi’s sarcoma. In Accessory Cells in HIV and Other Retroviral Infections P. Racz C. D. Dijkstra and J. C. Gluckman eds. (Basel Karger) pp. 155–161Google Scholar
  86. Randolph G. J, Beaulieu S, Steinman R. M, and Muller W. A. (1998). Differentiation of monocytes into dendritic cells in a model that mimics entry of cells into afferent lymph. Science 282 480–483PubMedCrossRefGoogle Scholar
  87. Randolph G. J, Inaba K, Robbiani D. F, Steinman R. M, and Muller W. A. (1999). Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity 11753–761Google Scholar
  88. Rappersberger K, Gartner S, Schenk P, Stingl G, Groh V, Tschachler E, Mann D. L, Wolff K, Konrad K, and Popovic M. (1988). Langerhans cells are an actual site of HIV-1 replication. Intervirol 29 185–194Google Scholar
  89. Rasola A, Gramaglia D, Boccaccio C, and Comoglio P. M. (2001). Apoptosis enhancement by the HIV-1 Nef protein. J Immunol 166 81–8PubMedGoogle Scholar
  90. Reece J. C, Handley A, Anstee J, Morrison W, Crowe S. M, and Cameron P. U. (1998). HIV-1 selection by epidermal dendritic cells during transmission across human skin. J Exp Med 187 1623–1631PubMedCrossRefGoogle Scholar
  91. Regnault A, Lankar D, Lacabanne V, Rodriguez A, Thery C, Rescigno M, Saito T, Verbeek S, Bonnerot C, Ricciardi-Castagnoli P, and Amigorena S. (1999). Fcy receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J Exp Med 189 371–80PubMedCrossRefGoogle Scholar
  92. Romani N, Reider D, Heuer M, Ebner S, Eibl B, Niederwieser D, and Schuler G. (1996). Generation of mature dendritic cells from human blood: an improved method with special regard to clinical applicability. J Immunol Methods 196 137– 151Google Scholar
  93. Sallusto F, Cella M, Danieli C, and Lanzavecchia A. (1995). Dendritic cells use macropinocytosis and the mannose receptor to concentrate antigen in the major histocompatibility class II compartment. Downregulation by cytokines and bacterial products. J Exp Med 182 389–400Google Scholar
  94. Sallusto F, Palermo B, Lenig D, Miettinen M, Matikainen S, Julkunen I, Forster R, Burgstahler R, Lipp M, and Lanzavecchia A. (1999). Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol 29 1617–25PubMedCrossRefGoogle Scholar
  95. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, Mackay C. R, Qin S, and Lanzavecchia A. (1998). Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 28 2760–2769PubMedCrossRefGoogle Scholar
  96. Sasaki S, Amara R. R, Oran A. E, Smith J. M, and Robinson H. L. (2001). Apoptosismediated enhancement of DNA-raised immune responses by mutant caspases. Nat Biotechnol 19 543–547PubMedCrossRefGoogle Scholar
  97. Schuler G, and Steinman R. M. (1985). Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med 161526–546Google Scholar
  98. Schuler-Thurner B, Schultz E. S, Berger T. G, Weinlich G, Ebner S, Woerl P, Bender A, Feuerstein B, Fritsch P. O, Romani N, and Schuler G. (2002). Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature cryopreserved peptide-loaded monocyte-derived dendritic cells. J Exp Med 195 1279–88PubMedCrossRefGoogle Scholar
  99. Shiver J. W, Fu T. M, Chen L, Casimiro D. R, Davies M. E, Evans R. K, Zhang Z. Q, Simon A. J, Trigona W. L, Dubey S. A, et al. (2002). Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415 331–5PubMedCrossRefGoogle Scholar
  100. Simonitsch I, Geusau A, Chott A, and Jurecka W. (2000). Cutaneous dendritic cells are main targets in acute HIV-1-infection. Mod Pathol 13 1232–7PubMedCrossRefGoogle Scholar
  101. Sol-Foulon N, Moris A, Engering A, Abastado J.-P, Heard J.-M, van Kooyk Y, and Schwartz O. (2002). HIV-1 nef-induced upregulation of DC-SIGN in dendritic cells promotes lymphocyte clustering and viral spread. Immunity 16 145–155PubMedCrossRefGoogle Scholar
  102. Soto-Ramirez L. E, Renijifo B, McLane M. F, Marlink R, O’Hara C, Sutthent R, Wasi C, Vithayassai P, Vithayassai V, Apichartpiyakui C, et al. (1996). HIV-1 Langerhans cells tropism associated with heterosexual transmission of HIV. Science 271 1291–1293PubMedCrossRefGoogle Scholar
  103. Spira A. I, Marx P. A, Patterson B. K, Mahoney J, Koup R. A, Wolinsky S. M, and Ho D. D. (1996). Cellular targets of infection and route of viral dissemination following an intravaginal inoculation of SIV into rhesus macaques. J Exp Med 183 215–225PubMedCrossRefGoogle Scholar
  104. Stahl-Hennig C, Steinman R. M, Ten Haaft P, Uberla K, Stolte N, Saeland S, TennerRacz K, and Racz P. (2002). The SIVAnef vaccine after application to the tonsils of Rhesus macaques replicates primarily within CD4+ T cells and elicits a local perforin positive CD8+ T cell response. J Virol 76 688–696PubMedCrossRefGoogle Scholar
  105. Stahl-Hennig C, Steinman R. M, Tenner-Racz K, Pope M, Stolte N, Matz-Rensing K, Grobschupff G, Raschdorff B, Hunsmann G, and Racz P. (1999). Rapid infection of oral mucosal-associated lymphoid tissue with simian immunodeficiency virus. Science 285 1261–1265PubMedCrossRefGoogle Scholar
  106. Steinman R. M, and Nussenzweig M. C. (2002). Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 99351–358Google Scholar
  107. Steinman R. M, and Pope M. (2002). Exploiting dendritic cells to improve vaccine efficacy. J Clin Invest 109 1519–26PubMedGoogle Scholar
  108. Stemm v A. M, Ramsauer J, Tenner-Racz K, Schmidt H. F, Gigli I, and Racz P. (1993). Langerhans cells and interdigitating cells in HIV-infection. Adv Exp Med Biol 329 539–544CrossRefGoogle Scholar
  109. Subklewe M, Chahroudi A, Schmaljohn A, Kurilla M. G, Bhardwaj N, and Steinman R. M. (1999). Induction of Epstein-Barr Virus-specific cytotoxic T-lymphocyte responses using dendritic cells pulsed with EBNA-3A peptides or UV-inactivated recombinant EBNA-3A vaccinia virus. Blood 94 1372–1381PubMedGoogle Scholar
  110. Tenner-Racz K, Racz P, Schmidt H, Dietrich M, Kern P, Louie A, Gartner S, and Popovic M. (1988). Immunohistochemical electron microscopic and in situ hybridization evidence for the involvement of lymphatics in the spread of HIV-1. AIDS 2 299–309PubMedCrossRefGoogle Scholar
  111. Tenner-Racz K, Stellbrink H.-J, van Lunzen J, Schneider C, Jacobs J.-P, Raschodorff B, Grobschupff G, Steinman R. M, and Racz P. (1998). The unenlarged lymph nodes of HIV-1 infected asymptomatic patients with high CD4 T cell counts are sites for virus replication and CD4 T cell proliferation. The impact of active antiretroviral therapy. J Exp Med 187 949–959Google Scholar
  112. Tenner-Racz K, von Stemm A. M, Guhlk B, Schmitz J, and Racz P. (1994). Are follicular dendritic cells macrophages and interdigitating cells of the lymphoid tissue productively infected by HIV? Res Virol 145 177–82PubMedCrossRefGoogle Scholar
  113. Trumpfheller C, Park C.-G, Finke J, Steinman R. M, and Granelli-Piperno A. (2002). Cell type dependent interactions of DC-SIGN with HIV-1. Int Immunol (in press)Google Scholar
  114. Tschachler E, Groh V, Popovic M, Mann D. L, Konrad K, Safai B, Eron L, diMarzo Veronese F, Wolff K, and Stingl G. (1987). Epidermal Langerhans cells–a target for HTLV-III/LAV infection. J Invest Dermatol 88 233–237PubMedCrossRefGoogle Scholar
  115. Tsunetsugu-Yokota Y, Akagawa K, Kimoto H, Suzuki K, Iwasaki M, Yasuda S, Hausser G, Hultgren C, Meyerhans A, and Takemori T. (1995). Monocyte-derived cultured dendritic cells are susceptible to human immunodeficiency virus infection and transmit virus to resting T cells in the process of nominal antigen presentation. J Virol 69 4544–4547PubMedGoogle Scholar
  116. Valladeau J, Duvert-Frances V, Pin J.-J, Kleijmeer M. J, Ait-Yahia S, Ravel O, Vincent C, Vega F, Jr, Helms A, Gorman D, et al. (2001). Immature human dendritic cells express asialoglycoprotein receptor isoforms for efficient receptor-mediated endocytosis. J Immunol 167 5767–74PubMedGoogle Scholar
  117. van der Ende M. E, Schutten M, Raschdorff B, Grossschupff G, Racz P, Osterhaus A. D, and Tenner-Racz K. (1999). CD4 Tcells remain the major source of HIV-1 during end stage disease. AIDS 13 1015–9CrossRefGoogle Scholar
  118. Veazey R. S, DeMaria M, Chalifoux L. V, Shvetz D. E, Pauley D. R, Knight H. L, Rosenzweig M, Johnson R. P, Desrosiers R. C, and Lackner A. A. (1998). Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280 427–31PubMedCrossRefGoogle Scholar
  119. Veazey R. S, Tham I. C, Mansfield K. G, DeMaria M, Forand A. E, Shvetz D. E, Chalifoux L. V, Sehgal P. K, and Lackner A. A. (2000). Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4+ T cells are rapidly eliminated in early SIV infection in vivo. J Virol 74 57–64PubMedCrossRefGoogle Scholar
  120. Weissman D, Ni H, Scales D, Dude A, Capodici J, McGibney K, Abdool A, Isaacs S. N, Cannon G, and Kariko K. (2000). HIV gag mRNA transfection of dendritic cells (DC) delivers encoded antigen to MHC class I and II molecules causes DC maturation and induces a potent human in vitro primary immune response. J Immunol 1654710–7Google Scholar
  121. Wu L, Bashirova A. A, Martin T. D, Villamide L, Mehlhop E, Chertov A. O, Unutmaz D, Pope M, Carrington M, and KewalRamani V. N. (2002). Rhesus macaque dendritic cells efficiently transmit primate lentiviruses independently of DC-SIGN. Proc Natl Acad Sci USA 99 1568–1573PubMedCrossRefGoogle Scholar
  122. Zaitseva M, Blauvelt A, Lee S, Lapham C. K, Klaus-Kovtun V, Mostowski H, Manischewitz J, and Golding H. (1997). Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nat Med 3 1369–1375PubMedCrossRefGoogle Scholar
  123. Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus K. A, Reimann K. A, Reinhart T. A, Rogan M, Cavert W, Miller C. J, et al. (1999). Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286 1353–1357PubMedCrossRefGoogle Scholar
  124. Zhao X. Q, Huang X. L, Gupta P, Borowski L, Fan Z, Watkins S. C, Thomas E. K, and Rinaldo C. R, Jr. (2002). Induction of anti-human immunodeficiency virus type 1 (HIV-1) CD8+ and CD4+T-cell reactivity by dendritic cells loaded with HIV-1 X4- infected apoptotic cells. J Virol 76 3007–14PubMedCrossRefGoogle Scholar
  125. Zheng L, Huang X. L, Fan Z, Borowski L, Wilson C. C, and Rinaldo C. R, Jr. (1999). Delivery of liposome-encapsulated HIV type 1 proteins to human dendritic cells for stimulation of HIV type 1-specific memory cytotoxic T lymphocyte responses. AIDS Res Hum Retroviruses 15 1011–20PubMedCrossRefGoogle Scholar
  126. Zhong L, Granelli-Piperno A, Pope M, Ignatius R, Lewis M, Frankel S. S, and Steinman R. M. (2000). Presentation of SIVgag to monkey T cells using dendritic cells transfected with a recombinant adenovirus. Eur J Immunol 30 3281–3290PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • R. M. Steinman
    • 1
  • A. Granelli-Piperno
    • 1
  • M. Pope
    • 2
  • C. Trumpfheller
    • 1
  • R. Ignatius
    • 3
  • G. Arrode
    • 1
  • P. Racz
    • 4
  • K. Tenner-Racz
    • 4
  1. 1.Laboratory of Cellular Physiology and ImmunologyThe Rockefeller UniversityNew YorkUSA
  2. 2.Center for Biomedical ResearchPopulation CouncilNew YorkUSA
  3. 3.Department of Medical Microbiology and Immunology of Infection, Benjamin Franklin Medical CenterFree University of BerlinBerlinGermany
  4. 4.Bernhard Nocht Institute for Tropical MedicineKorber AIDS Research UnitHamburgGermany

Personalised recommendations