Skip to main content

Advertisement

SpringerLink
Log in

Dendritic Cell Immune Responses in HIV-1 Controllers

  • HIV Pathogenesis and Treatment (AL Landay and N Utay, Section Editors)
  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Robust HIV-1-specific CD8 T cell responses are currently regarded as the main correlate of immune defense in rare individuals who achieve natural, drug-free control of HIV-1; however, the mechanisms that support evolution of such powerful immune responses are not well understood. Dendritic cells (DCs) are specialized innate immune cells critical for immune recognition, immune regulation, and immune induction, but their possible contribution to HIV-1 immune defense in controllers remains ill-defined.

Recent Findings

Recent studies suggest that myeloid DCs from controllers have improved abilities to recognize HIV-1 through cytoplasmic immune sensors, resulting in more potent, cell-intrinsic type I interferon secretion in response to viral infection. This innate immune response may facilitate DC-mediated induction of highly potent antiviral HIV-1-specific T cells. Moreover, protective HLA class I isotypes restricting HIV-1-specific CD8 T cells may influence DC function through specific interactions with innate myelomonocytic MHC class I receptors from the leukocyte immunoglobulin-like receptor family.

Summary

Bi-directional interactions between dendritic cells and HIV-1-specific T cells may contribute to natural HIV-1 immune control, highlighting the importance of a fine-tuned interplay between innate and adaptive immune activities for effective antiviral immune defense.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nat Rev Immunol. 2002;2:151–61.

    Article  CAS  PubMed  Google Scholar 

  2. Marcenaro E, Carlomagno S, Pesce S, Moretta A, Sivori S. NK/DC crosstalk in anti-viral response. Adv Exp Med Biol. 2012;946:295–308.

    Article  CAS  PubMed  Google Scholar 

  3. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol. 2001;31:3388–93.

    Article  CAS  PubMed  Google Scholar 

  4. Szabo A, Rajnavolgyi E. Collaboration of Toll-like and RIG-I-like receptors in human dendritic cells: tRIGgering antiviral innate immune responses. Am J Clin Exp Immunol. 2013;2:195–207.

    PubMed  PubMed Central  Google Scholar 

  5. Unterholzner L. The interferon response to intracellular DNA: why so many receptors? Immunobiology. 2013;218:1312–21.

    Article  CAS  PubMed  Google Scholar 

  6. Kadowaki N, Ho S, Antonenko S, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001;194:863–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Blankson JN. Effector mechanisms in HIV-1 infected elite controllers: highly active immune responses? Antivir Res. 2010;85:295–302.

    Article  CAS  PubMed  Google Scholar 

  8. Hersperger AR, Martin JN, Shin LY, et al. Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression. Blood. 2011;117:3799–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Saez-Cirion A, Lacabaratz C, Lambotte O, et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci U S A. 2007;104:6776–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kijewski SD, Gummuluru S. A mechanistic overview of dendritic cell-mediated HIV-1 trans infection: the story so far. Futur Virol. 2015;10:257–69.

    Article  CAS  Google Scholar 

  11. Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell. 2000;100:587–97.

    Article  CAS  PubMed  Google Scholar 

  12. Kwon DS, Gregorio G, Bitton N, Hendrickson WA, Littman DR. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity. 2002;16:135–44.

    Article  CAS  PubMed  Google Scholar 

  13. •• Dale BM, Alvarez RA, Chen BK. Mechanisms of enhanced HIV spread through T-cell virological synapses. Immunol Rev. 2013;251:113–24. This study shows that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169) is highly expressed on mature DCs, specifically binds HIV-1, and is essential for trans-infection of CD4 T cells by mature DCs.

  14. Izquierdo-Useros N, Lorizate M, Puertas MC, et al. Siglec-1 is a novel dendritic cell receptor that mediates HIV-1 trans-infection through recognition of viral membrane gangliosides. PLoS Biol. 2012;10:e1001448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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. 2001;75:6710–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lahouassa H, Daddacha W, Hofmann H, et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol. 2012;13:223–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. •• Ryoo J, Choi J, Oh C, et al. The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med. 2014;20:936–41. This work showed that SAMHD1 can restrict HIV-1 replication by degrading HIV-1 RNA during early stages of infection through direct RNAse activity.

  18. Cribier A, Descours B, Valadao AL, Laguette N, Benkirane M. Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Rep. 2013;3:1036–43.

    Article  CAS  PubMed  Google Scholar 

  19. Saez-Cirion A, Hamimi C, Bergamaschi A, et al. Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers. Blood. 2011;118:955–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hamimi C, David A, Versmisse P, et al. Dendritic cells from HIV controllers have low susceptibility to HIV-1 infection in vitro but high capacity to capture HIV-1 particles. PLoS One. 2016;11:e0160251.

    Article  PubMed  PubMed Central  Google Scholar 

  21. •• Martin-Gayo E, Buzon MJ, Ouyang Z, et al. Potent cell-intrinsic immune responses in dendritic cells facilitate HIV-1-specific T cell immunity in HIV-1 elite controllers. PLoS Pathog. 2015;11:e1004930. This study describes the susceptibility of primary myeloid DCs from elite controllers to HIV-1 and investigates cell-intrinsic immune responses to HIV-1 in DC from such patients.

  22. Su B, Biedma ME, Lederle A, et al. Dendritic cell-lymphocyte cross talk downregulates host restriction factor SAMHD1 and stimulates HIV-1 replication in dendritic cells. J Virol. 2014;88:5109–21.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Goldfeld AE, Birch-Limberger K, Schooley RT, Walker BD. HIV-1 infection does not induce tumor necrosis factor-alpha or interferon-beta gene transcription. J Acquir Immune Defic Syndr. 1991;4:41–7.

    Article  CAS  PubMed  Google Scholar 

  24. Harman AN, Lai J, Turville S, et al. HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production. Blood. 2011;118:298–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Manel N, Hogstad B, Wang Y, Levy DE, Unutmaz D, Littman DR. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature. 2010;467:214–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sunseri N, O’Brien M, Bhardwaj N, Landau NR. Human immunodeficiency virus type 1 modified to package Simian immunodeficiency virus Vpx efficiently infects macrophages and dendritic cells. J Virol. 2011;85:6263–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. •• Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339:786–91. This study identified cyclic GMP-AMP synthase (cGAS) as a new cytoplasmic DNA sensor able to induce potent cell-intrinsic type I IFN responses.

  28. •• Gao D, Wu J, Wu YT, et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science. 2013;341:903–6. This study demonstrated that cGAS is involved in innate sensing of HIV-1 DNA.

  29. Zhang H, Tang K, Zhang Y, et al. Cell-free tumor microparticle vaccines stimulate dendritic cells via cGAS/STING signaling. Cancer Immunol Res. 2015;3:196–205.

    Article  CAS  PubMed  Google Scholar 

  30. Shu C, Li X, Li P. The mechanism of double-stranded DNA sensing through the cGAS-STING pathway. Cytokine Growth Factor Rev. 2014;25:641–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lahaye X, Satoh T, Gentili M, et al. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells. Immunity. 2013;39:1132–42.

    Article  CAS  PubMed  Google Scholar 

  32. Paijo J, Doring M, Spanier J, et al. cGAS senses human cytomegalovirus and induces type I interferon responses in human monocyte-derived cells. PLoS Pathog. 2016;12:e1005546.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Harman AN, Nasr N, Feetham A, et al. HIV blocks interferon induction in human dendritic cells and macrophages by dysregulation of TBK1. J Virol. 2015;89:6575–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huang J, Burke PS, Cung TD, et al. Leukocyte immunoglobulin-like receptors maintain unique antigen-presenting properties of circulating myeloid dendritic cells in HIV-1-infected elite controllers. J Virol. 2010;84:9463–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. •• Dinter J, Duong E, Lai NY, et al. Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape. PLoS Pathog. 2015;11:e1004725. This work describes antigen processing pathways in DC that shape and structure immuno-dominance patterns of HIV-1-specific T cell responses.

  36. Coulon PG, Richetta C, Rouers A, et al. HIV-infected dendritic cells present endogenous MHC class II-restricted antigens to HIV-specific CD4+ T cells. J Immunol. 2016;197:517–32.

    Article  CAS  PubMed  Google Scholar 

  37. Potter SJ, Lacabaratz C, Lambotte O, et al. Preserved central memory and activated effector memory CD4+ T-cell subsets in human immunodeficiency virus controllers: an ANRS EP36 study. J Virol. 2007;81:13904–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Benati D, Galperin M, Lambotte O, et al. Public T cell receptors confer high-avidity CD4 responses to HIV controllers. J Clin Invest. 2016;126:2093–108.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ferre AL, Hunt PW, McConnell DH, et al. HIV controllers with HLA-DRB1*13 and HLA-DQB1*06 alleles have strong, polyfunctional mucosal CD4+ T-cell responses. J Virol. 2010;84:11020–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vingert B, Benati D, Lambotte O, et al. HIV controllers maintain a population of highly efficient Th1 effector cells in contrast to patients treated in the long term. J Virol. 2012;86:10661–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Borhis G, Burelout C, Chaoul N, et al. Plasmacytoid dendritic cells and myeloid cells differently contribute to B-cell-activating factor belonging to the tumor necrosis factor superfamily overexpression during primary HIV infection. AIDS. 2016;30:365–76.

    CAS  PubMed  Google Scholar 

  42. Ferlazzo G, Morandi B. Cross-talks between natural killer cells and distinct subsets of dendritic cells. Front Immunol. 2014;5:159.

    Article  PubMed  PubMed Central  Google Scholar 

  43. •• Moreno-Nieves UY, Didier C, Levy Y, Barre-Sinoussi F, Scott-Algara D. NK cells are primed by ANRS MVA(HIV)-infected DCs, via a mechanism involving NKG2D and membrane-bound IL-15, to control HIV-1 infection in CD4+ T cells. Eur J Immunol. 2014;44:2370–9. This work demonstrates the ability of HIV-1-exposed DC to stimulate antiviral activities of NK cells.

  44. Karrich JJ, Jachimowski LC, Uittenbogaart CH, Blom B. The plasmacytoid dendritic cell as the Swiss army knife of the immune system: molecular regulation of its multifaceted functions. J Immunol. 2014;193:5772–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tavano B, Galao RP, Graham DR, et al. Ig-like transcript 7, but not bone marrow stromal cell antigen 2 (also known as HM1.24, tetherin, or CD317), modulates plasmacytoid dendritic cell function in primary human blood leukocytes. J Immunol. 2013;190:2622–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lehmann C, Harper JM, Taubert D, et al. Increased interferon alpha expression in circulating plasmacytoid dendritic cells of HIV-1-infected patients. J Acquir Immune Defic Syndr. 2008;48:522–30.

    Article  CAS  PubMed  Google Scholar 

  47. Boichuk SV, Khaiboullina SF, Ramazanov BR, et al. Gut-associated plasmacytoid dendritic cells display an immature phenotype and upregulated granzyme B in subjects with HIV/AIDS. Front Immunol. 2015;6:485.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Royle CM, Graham DR, Sharma S, Fuchs D, Boasso A. HIV-1 and HIV-2 differentially mature plasmacytoid dendritic cells into IFN-producing cells or APCs. J Immunol. 2014;193:3538–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tel J, Schreibelt G, Sittig SP, et al. Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets. Blood. 2013;121:459–67.

    Article  CAS  PubMed  Google Scholar 

  50. Tel J, Smits EL, Anguille S, Joshi RN, Figdor CG, de Vries IJ. Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities. Blood. 2012;120:3936–44.

    Article  CAS  PubMed  Google Scholar 

  51. Donaghy H, Pozniak A, Gazzard B, 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. 2001;98:2574–6.

    Article  CAS  PubMed  Google Scholar 

  52. Lehmann C, Jung N, Forster K, et al. Longitudinal analysis of distribution and function of plasmacytoid dendritic cells in peripheral blood and gut mucosa of HIV infected patients. J Infect Dis. 2014;209:940–9.

    Article  CAS  PubMed  Google Scholar 

  53. Barblu L, Machmach K, Gras C, et al. Plasmacytoid dendritic cells (pDCs) from HIV controllers produce interferon-alpha and differentiate into functional killer pDCs under HIV activation. J Infect Dis. 2012;206:790–801.

    Article  CAS  PubMed  Google Scholar 

  54. Machmach K, Leal M, Gras C, et al. Plasmacytoid dendritic cells reduce HIV production in elite controllers. J Virol. 2012;86:4245–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Saidi H, Bras M, Formaglio P, et al. HMGB1 is involved in IFN-alpha production and TRAIL expression by HIV-1-exposed plasmacytoid dendritic cells: impact of the crosstalk with NK cells. PLoS Pathog. 2016;12:e1005407.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lichtner M, Rossi R, Rizza MC, et al. Plasmacytoid dendritic cells count in antiretroviral-treated patients is predictive of HIV load control independent of CD4+ T-cell count. Curr HIV Res. 2008;6:19–27.

    Article  CAS  PubMed  Google Scholar 

  57. Beignon AS, McKenna K, Skoberne M, et al. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest. 2005;115:3265–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bode C, Fox M, Tewary P, et al. Human plasmacytoid dentritic cells elicit a Type I Interferon response by sensing DNA via the cGAS-STING signaling pathway. Eur J Immunol. 2016;46:1615–21.

    Article  CAS  PubMed  Google Scholar 

  59. Manches O, Fernandez MV, Plumas J, Chaperot L, Bhardwaj N. Activation of the noncanonical NF-kappaB pathway by HIV controls a dendritic cell immunoregulatory phenotype. Proc Natl Acad Sci U S A. 2012;109:14122–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tomescu C, Liu Q, Ross BN, et al. A correlate of HIV-1 control consisting of both innate and adaptive immune parameters best predicts viral load by multivariable analysis in HIV-1 infected viremic controllers and chronically-infected non-controllers. PLoS One. 2014;9:e103209.

    Article  PubMed  PubMed Central  Google Scholar 

  61. HIVCS International, Pereyra F, Jia X, et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 2010;330:1551–7.

    Article  Google Scholar 

  62. Fellay J, Shianna KV, Ge D, et al. A whole-genome association study of major determinants for host control of HIV-1. Science. 2007;317:944–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pereyra F, Addo MM, Kaufmann DE, et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis. 2008;197:563–71.

    Article  PubMed  Google Scholar 

  64. Carriere M, Lacabaratz C, Kok A, et al. HIV “elite controllers” are characterized by a high frequency of memory CD8+ CD73+ T cells involved in the antigen-specific CD8+ T-cell response. J Infect Dis. 2014;209:1321–30.

    Article  CAS  PubMed  Google Scholar 

  65. Brennan CA, Ibarrondo FJ, Sugar CA, et al. Early HLA-B*57-restricted CD8+ T lymphocyte responses predict HIV-1 disease progression. J Virol. 2012;86:10505–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ndhlovu ZM, Chibnik LB, Proudfoot J, et al. High-dimensional immunomonitoring models of HIV-1-specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control. Blood. 2013;121:801–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lichterfeld M, Yu XG. The emerging role of leukocyte immunoglobulin-like receptors (LILRs) in HIV-1 infection. J Leukoc Biol. 2012;91:27–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hudson LE, Allen RL. Leukocyte Ig-like receptors—a model for MHC class I disease associations. Front Immunol. 2016;7:281.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Bashirova AA, Martin-Gayo E, Jones DC, et al. LILRB2 interaction with HLA class I correlates with control of HIV-1 infection. PLoS Genet. 2014;10:e1004196.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Bego MG, Cote E, Aschman N, Mercier J, Weissenhorn W, Cohen EA. Vpu exploits the cross-talk between BST2 and the ILT7 receptor to suppress anti-HIV-1 responses by plasmacytoid dendritic cells. PLoS Pathog. 2015;11:e1005024.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, 400 Technology Square, Cambridge, MA, 02139, USA

    Enrique Martin-Gayo & Xu G. Yu

Authors
  1. Enrique Martin-Gayo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xu G. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xu G. Yu.

Ethics declarations

Conflict of Interest

Enrique Martin-Gayo and Xu G. Yu declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on HIV Pathogenesis and Treatment

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin-Gayo, E., Yu, X.G. Dendritic Cell Immune Responses in HIV-1 Controllers. Curr HIV/AIDS Rep 14, 1–7 (2017). https://doi.org/10.1007/s11904-017-0345-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-017-0345-0

Keywords

Search

Navigation