Skip to main content

Advertisement

SpringerLink
Log in

Trans-dissemination of exosomes from HIV-1-infected cells fosters both HIV-1 trans-infection in resting CD4+ T lymphocytes and reactivation of the HIV-1 reservoir

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Intact HIV-1 and exosomes can be internalized by dendritic cells (DCs) through a common pathway leading to their transmission to CD4+ T lymphocytes by means of mechanisms defined as trans-infection and trans-dissemination, respectively. We previously reported that exosomes from HIV-1-infected cells activate both uninfected quiescent CD4+ T lymphocytes, which become permissive to HIV-1, and latently infected cells, with release of HIV-1 particles. However, nothing is known about the effects of trans-dissemination of exosomes produced by HIV-1-infected cells on uninfected or latently HIV-1-infected CD4+ T lymphocytes. Here, we report that trans-dissemination of exosomes from HIV-1-infected cells induces cell activation in resting CD4+ T lymphocytes, which appears stronger with mature than immature DCs. Using purified preparations of both HIV-1 and exosomes, we observed that mDC-mediated trans-dissemination of exosomes from HIV-1-infected cells to resting CD4+ T lymphocytes induces efficient trans-infection and HIV-1 expression in target cells. Most relevant, when both mDCs and CD4+ T lymphocytes were isolated from combination anti-retroviral therapy (ART)-treated HIV-1-infected patients, trans-dissemination of exosomes from HIV-1-infected cells led to HIV-1 reactivation from the viral reservoir. In sum, our data suggest a role of exosome trans-dissemination in both HIV-1 spread in the infected host and reactivation of the HIV-1 reservoir.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Cameron PU, Freudenthal PS, Barker JM, Gezelter S, Inaba K, Steinman RM (1992) Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytophathic infection to CD4+ T cells. Science 257:383–386

    Article  CAS  PubMed  Google Scholar 

  2. Geijtenbeek TBH, Kwon DS, Torensma R et al (2000) DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100:587–597

    Article  CAS  PubMed  Google Scholar 

  3. McDonald D, Wu L, Bohks SM, KewalRamani VN, Unutmaz D, Hope TJ (2003) Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 300:1295–1297

    Article  CAS  PubMed  Google Scholar 

  4. Piguet V, Sattentau Q (2004) Dangerous liaisons at the virological synapse. J Clin Investig 114:605–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Laguette N, Sobhian B, Casartelli N et al (2011) SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474:654–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ryoo J, Choi J, Oh C et al (2014) The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med 20:936–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Garcia E, Pion M, Pelchen-Matthews A et al (2005) 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

    Article  CAS  PubMed  Google Scholar 

  8. Yu HJ, Reuter MA, McDonald D (2008) HIV traffics through a specialized, surface-accessible intracellular compartment during trans-infection of T cells by mature dendritic cells. PloS Pathog 4:e1000134

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sagar M, Akiyama H, Etemad B, Ramirez N, Freitas I, Gummuluru S (2012) Transmembrane domain membrane proximal external region but not surface unit-directed broadly neutralizing HIV-1 antibodies can restrict dendritic cell-mediated HIV-1 trans-infection. J Infect Dis 205:1248–1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sanders RW, de Jong EC, Baldwin CE, Schuitemaker JHN, Kapsenberg ML, Berkhout B (2002) Differential transmission of human immunodeficiency virus type I by distinct subsets of effector dendritic cells. J Virol 76:7812–7821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Puryear WB, Akiyama H, Geer SD, Ramirez NP, Yu XW, Reinhard BM, Gummuluru S (2013) Interferon-inducible mechanism of dendritic cell-mediated HIV-1 dissemination is dependent on siglec-1/CD169. PloS Pathog 9(4):e1003291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Izquierdo-Useros N, Lorizate M, Puertas MC et al (2012) Siglec-1 is a novel dendritic cell receptor that mediates HIV-1 trans-infection through recognition of viral membrane gangliosides. PloS Biol 10(12):e1001448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Izquierdo-Useros N, Lorizate M, Contreras FX et al (2012) Sialyllactose in viral membrane gangliosides is a novel molecular recognition pattern for mature dendritic cell capture of HIV-1. PLoS Biol 10(4):e1001315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Puryear WB, Yu XW, Ramirez NP, Reinhard BM, Gummuluru S (2012) HIV-1 incorporation of host-cell-derived glycosphingolipid GM3 allows for capture by mature dendritic cells. Proc Natl Acad Sci USA 109:7475–7480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schorey JS, Cheng Y, Singh PP, Smith VL (2015) Exosomes and other extracellular vesicles in host–pathogen interactions. EMBO Rep 16:24–43

    Article  CAS  PubMed  Google Scholar 

  16. Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteom 73:1907–1920

    Article  CAS  Google Scholar 

  17. Skog J, Wurdinger T, van Rijn S et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hubert A, Barbeau B, Subra C, Bissonnette L, Gilbert C (2015) Role and future applications of extracellular vesicles in HIV-1 pathogenesis. Future Virol 10:357–370

    Article  CAS  Google Scholar 

  19. Madison MN, Okeoma CM (2015) Exosomes: implications in HIV-1 pathogenesis. Viruses 7:4093–4118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Teow SY, Nordin AC, Khoo ASB (2016) Exosomes in human immunodeficiency virus type I pathogenesis: threat or opportunity? Adv Virol. doi:10.1155/2016/9852494

    PubMed  PubMed Central  Google Scholar 

  21. Lee JH, Wittki S, Brau T et al (2013) HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases. Mol Cell 49:668–679

    Article  CAS  PubMed  Google Scholar 

  22. Gooz M (2010) ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol 45:146–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Arenaccio C, Chiozzini C, Columba-Cabezas S et al (2014) Exosomes from human immunodeficiency virus type 1 (HIV-1)-infected cells license quiescent CD4(+) T lymphocytes to replicate HIV-1 through a Nef- and ADAM17-dependent mechanism. J Virol 88:11529–11539

    Article  PubMed  PubMed Central  Google Scholar 

  24. Arenaccio C, Chiozzini C, Columba-Cabezas S, Manfredi F, Federico M (2014) Cell activation and HIV-1 replication in unstimulated CD4+ T lymphocytes ingesting exosomes from cells expressing defective HIV-1. Retrovirology 11:46. doi:10.1186/1742-4690-11-46

    Article  PubMed  PubMed Central  Google Scholar 

  25. Arenaccio C, Anticoli S, Manfredi F, Chiozzini C, Olivetta E, Federico M (2015) Latent HIV-1 is activated by exosomes from cells infected with either replication-competent or defective HIV-1. Retrovirology 12:87. doi:10.1186/s12977-015-0216-y

    Article  PubMed  PubMed Central  Google Scholar 

  26. Izquierdo-Useros N, Naranjo-Gomez M, Archer J et al (2009) Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. Blood 113:2732–2741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Adachi A, Gendelman HE, Koenig S et al (1986) Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol 59:284–2891

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Federico M, Titti F, Butto S et al (1989) Biologic and molecular characterization of producer and non-producer clones from HUT-78 cells infected with a patient HIV isolate. AIDS Res Hum Retrovir 5:385–396

    Article  CAS  PubMed  Google Scholar 

  29. Sparacio S, Pfeiffer T, Schaal H, Bosch V (2001) Generation of a flexible cell line with regulatable, high-level expression of HIV Gag/Pol particles capable of packaging HIV-derived vectors. Mol Ther 3:602–612

    Article  CAS  PubMed  Google Scholar 

  30. Federico M, Percario Z, Olivetta E et al (2001) HIV-1 Nef activates STAT1 in human monocytes/macrophages through the release of soluble factors. Blood 8:2752–2761

    Article  Google Scholar 

  31. Dettenhofer M, Yu XF (1999) Highly purified human immunodeficiency virus type 1 reveals a virtual absence of vif in virions. J Virol 73:1460–1467

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006 Chapter 3, Unit 3.22

  33. Wu L, KewalRamani VN (2006) Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol 6:859–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ (2010) Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol 190:1079–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kogure T, Lin WL, Yan IK, Braconi C, Patel T (2011) Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 54:1237–1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285:17442–17452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kosaka N, Iguchi H, Yoshioka Y, Hagiwara K, Takeshita F, Ochiya T (2012) Competitive interactions of cancer cells and normal cells via secretory microRNAs. J Biol Chem 287:1397–1405

    Article  CAS  PubMed  Google Scholar 

  38. Trajkovic K, Hsu C, Chiantia S et al (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247

    Article  CAS  PubMed  Google Scholar 

  39. Yuyama K, Sun H, Mitsutake S, Igarashi Y (2012) Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. J Biol Chem 287:10977–10989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu YJ, Kanzler H, Soumeli V, Gilliet M (2001) Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2:585–589

    Article  CAS  PubMed  Google Scholar 

  41. Sanchez G, Xu XY, Chermann JC, Hirsch I (1997) Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J Virol 71:2233–2240

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Fourati S, Lambert-Niclot S, Soulie C et al (2012) HIV-1 genome is often defective in PBMCs and rectal tissues after long-term HAART as a result of APOBEC3 editing and correlates with the size of reservoirs. J Antimicrob Chemother 67:2323–2326

    Article  CAS  PubMed  Google Scholar 

  43. Janini M, Rogers M, Birx DR, McCutchan F (2001) Human immunodeficiency virus type 1 DNA sequences genetically damaged by hypermutation are often abundant in patient peripheral blood mononuclear cells and may be generated during near-simultaneous infection and activation of CD4(+) T cells. J Virol 75:7973–7986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cantin R, Diou J, Belanger D, Tremblay AM, Gilbert C (2008) Discrimination between exosomes and HIV-1: Purification of both vesicles from cell-free supernatants. J Immunol Methods 338:21–30

    Article  CAS  PubMed  Google Scholar 

  45. Rieu S, Geminard C, Rabesandratana H, Sainte-Marie J, Vidal M (2000) Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha 4 beta 1. Eur J Biochem 267:583–590

    Article  CAS  PubMed  Google Scholar 

  46. Wiley RD, Gummuluru S (2006) Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc Natl Acad Sci USA 103:738–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sagar D, Foss C, El Baz R, Pomper MG, Khan ZK, Jain P (2012) Mechanisms of dendritic cell trafficking across the blood–brain barrier. J Neuroimmune Pharmacol 7:74–94

    Article  PubMed  Google Scholar 

  48. Cohn LB, Silva IT, Oliveira TY et al (2015) HIV-1 integration landscape during latent and active infection. Cell 160:420–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Barton K, Winckelmann A, Palmer S (2016) HIV-1 reservoirs during suppressive therapy. Trends Microbiol 24:345–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Palmer S, Maldarelli F, Wiegand A et al (2001) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci USA 105:3879–3884

    Article  Google Scholar 

Download references

Acknowledgements

We thank Massimo Sanchez, Istituto Superiore di Sanità, for the support in FACS analysis, and Pietro Arciero and Stefania de Menna, Istituto Superiore di Sanità, for their excellent technical support. Both AZT and anti-Env gp120 mAb were obtained from the NIH AIDS Research and Reference Program.

Author information

Authors and Affiliations

  1. National Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy

    Chiara Chiozzini, Claudia Arenaccio, Eleonora Olivetta, Simona Anticoli, Francesco Manfredi, Flavia Ferrantelli, Mauro Andreotti & Maurizio Federico

  2. Department of Public Health and Infectious Diseases, ‘Sapienza’ University of Rome, Rome, Italy

    Gabriella d’Ettorre & Ivan Schietroma

Authors
  1. Chiara Chiozzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Arenaccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eleonora Olivetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simona Anticoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Manfredi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Flavia Ferrantelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabriella d’Ettorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ivan Schietroma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mauro Andreotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maurizio Federico
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maurizio Federico.

Ethics declarations

This work was supported by a Grant from “Ricerca Finalizzata” project RF-2010-2308334 from the Ministry of Health, Italy. CC, CA, EO, SA, FM, FF, G d’E, IS, MA, and MF declare that they have no conflict of interest. This article does not contain studies with animals. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chiozzini, C., Arenaccio, C., Olivetta, E. et al. Trans-dissemination of exosomes from HIV-1-infected cells fosters both HIV-1 trans-infection in resting CD4+ T lymphocytes and reactivation of the HIV-1 reservoir. Arch Virol 162, 2565–2577 (2017). https://doi.org/10.1007/s00705-017-3391-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-017-3391-4

Keywords

Search

Navigation