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.

  • Article
  • Published:

Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: A mechanism for cellular human immunodeficiency virus 1 infection

Abstract

The release of microparticles from eukaryotic cells is a well-recognized phenomenon. We demonstrate here that the chemokine receptor CCR5, the principal co-receptor for macrophage-tropic human immunodeficiency virus (HIV)-1, can be released through microparticles from the surface of CCR5+ Chinese hamster ovary cells and peripheral blood mononuclear cells. Microparticles containing CCR5 can transfer the receptor to CCR5 cells and render them CCR5+. The CCR5 transfer to CCR5-deficient peripheral blood mononuclear cells homozygous for a 32-base-pair deletion in the CCR5 gene enabled infection of these cells with macrophage-tropic HIV-1. In monocytes, the transfer of CCR5 could be inhibited by cytochalasin D, and transferred CCR5 could be downmodulated by chemokines. A transfer of CCR5 from peripheral blood mononuclear cells to endothelial cells during transendothelial migration could be demonstrated. Thus, the transfer of CCR5 may lead to infection of tissues without endogenous CCR5 expression. Moreover, the intercellular transfer of membrane proteins by microparticles might have broader consequences for intercellular communication beyond the effects seen for HIV-1.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Release of CCR5+ microparticles from stably transfected CHO cells and PBMCs.
Figure 2: Transfer of CCR5 from CHO cells to other CCR5 cells.
Figure 3: Transferred CCR5 can be downmodulated from the surface of monocytes (right), whereas there is little downmodulation on CD4+ T cells (left).
Figure 4: Effect of cytochalasin D on the transfer of CCR5 to monocytes and CD4+ T cells.
Figure 5: During transendothelial migration, CCR5 is transferred from PBMCs to endothelial cells.
Figure 6: Transferred CCR5 can function as co-receptor for M-tropic HIV-1 on Δ32/Δ32 PBMCs.

Similar content being viewed by others

References

  1. Berger, E.A., Murphy, P.M. & Farber, J.M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17, 657–700 (1999).

    Article  CAS  Google Scholar 

  2. Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).

    Article  CAS  Google Scholar 

  3. Edinger, A.L. et al. CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain . Proc. Natl. Acad. Sci. USA 94, 14742– 7 (1997).

    Article  CAS  Google Scholar 

  4. Wiley, C.A., Schrier, R.D., Nelson, J.A., Lampert, P.W. & Oldstone, M.B. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc. Natl. Acad. Sci. USA 83, 7089–7093 (1986).

    Article  CAS  Google Scholar 

  5. Nuovo, G.J., Gallery, F., MacConnell, P. & Braun, A. In situ detection of polymerase chain reaction-amplified HIV-1 nucleic acids and tumor necrosis factor-alpha RNA in the central nervous system. Am. J. Pathol. 144, 659–666 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bagasra, O. et al. Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction and immunohistochemistry. AIDS 10, 573–585 (1996).

    Article  CAS  Google Scholar 

  7. Ray, P.E. et al. Infection of human primary renal epithelial cells with HIV-1 from children with HIV-associated nephropathy. Kidney Int. 53, 1217–1229 (1998).

    Article  CAS  Google Scholar 

  8. Schrager, L.K. & D'Souza, M.P. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. J. Am. Med. Assoc. 280, 67–71 (1998).

    Article  CAS  Google Scholar 

  9. Brack-Werner, R. Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis . AIDS 13, 1–22 (1999).

    Article  CAS  Google Scholar 

  10. Rottman, J.B. et al. Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am. J. Pathol. 151, 1341–1351 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Segerer, S., Mack, M., Regele, H., Kerjaschki, D. & Schlondorff, D. Expression of the C-C chemokine receptor 5 in human kidney diseases. Kidney Int. 56, 52– 64 (1999).

    Article  CAS  Google Scholar 

  12. Sabri, F. et al. Nonproductive human immunodeficiency virus type 1 infection of human fetal astrocytes: independence from CD4 and major chemokine receptors . Virology 264, 370–384 (1999).

    Article  CAS  Google Scholar 

  13. Klein, R.S. et al. Chemokine receptor expression and signaling in macaque and human fetal neurons and astrocytes: implications for the neuropathogenesis of AIDS. J. Immunol. 163, 1636– 1646 (1999).

    CAS  PubMed  Google Scholar 

  14. Armstrong, M.J., Storch, J. & Dainiak, N. Structurally distinct plasma membrane regions give rise to extracellular membrane vesicles in normal and transformed lymphocytes. Biochim. Biophys. Acta. 946, 106–112 (1988).

    Article  CAS  Google Scholar 

  15. Beaudoin, A.R. & Grondin, G. Shedding of vesicular material from the cell surface of eukaryotic cells: different cellular phenomena . Biochim. Biophys. Acta. 1071, 203– 219 (1991).

    Article  CAS  Google Scholar 

  16. Zwaal, R.F. & Schroit, A.J. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 89, 1121–1132 (1997).

    CAS  PubMed  Google Scholar 

  17. Combes, V. et al. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J. Clin. Invest. 104, 93–102 (1999).

    Article  CAS  Google Scholar 

  18. George, J.N., Thoi, L.L., McManus, L.M. & Reimann, T.A. Isolation of human platelet membrane microparticles from plasma and serum . Blood 60, 834–840 (1982).

    CAS  PubMed  Google Scholar 

  19. Barry, O.P., Pratico, D., Lawson, J.A. & FitzGerald, G.A. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J. Clin. Invest. 99, 2118–2127 (1997).

    Article  CAS  Google Scholar 

  20. Barry, O.P., Pratico, D., Savani, R.C. & FitzGerald, G.A. Modulation of monocyte-endothelial cell interactions by platelet microparticles . J. Clin. Invest. 102, 136– 144 (1998).

    Article  CAS  Google Scholar 

  21. Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).

    Article  CAS  Google Scholar 

  22. Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nature Med. 4, 594–600 (1998).

    Article  CAS  Google Scholar 

  23. Mesri, M. & Altieri, D.C. Endothelial cell activation by leukocyte microparticles. J. Immunol. 161, 4382–4387 (1998).

    CAS  PubMed  Google Scholar 

  24. Mallat, Z. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity . Circulation 99, 348–353 (1999).

    Article  CAS  Google Scholar 

  25. Mallat, Z. et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 101, 841– 843 (2000).

    Article  CAS  Google Scholar 

  26. Gluschankof, P., Mondor, I., Gelderblom, H.R. & Sattentau, Q.J. Cell membrane vesicles are a major contaminant of gradient-enriched human immunodeficiency virus type-1 preparations. Virology 230, 125–133 (1997).

    Article  CAS  Google Scholar 

  27. Xiao, X. et al. Constitutive cell surface association between CD4 and CCR5. Proc. Natl. Acad. Sci. USA 96, 7496– 7501 (1999).

    Article  CAS  Google Scholar 

  28. Mack, M. et al. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J. Exp. Med. 187, 1215–1224 (1998).

    Article  CAS  Google Scholar 

  29. Levene, R.B. & Rabellino, E.M. Platelet glycoproteins IIb and IIIa associated with blood monocytes are derived from platelets. Blood 67, 207–213 ( 1986).

    CAS  PubMed  Google Scholar 

  30. Satta, N. et al. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J. Immunol. 153, 3245–3255 (1994).

    CAS  PubMed  Google Scholar 

  31. Speck, R.F. et al. A trans-receptor mechanism for infection of CD4-negative cells by human immunodeficiency virus type 1. Curr. Biol. 9, 547–550 (1999).

    Article  CAS  Google Scholar 

  32. Gosling, J. et al. Molecular uncoupling of C-C chemokine receptor 5-induced chemotaxis and signal transduction from HIV-1 coreceptor activity. Proc. Natl. Acad. Sci. USA 94, 5061–5066 (1997).

    Article  CAS  Google Scholar 

  33. Alkhatib, G., Locati, M., Kennedy, P.E., Murphy, P.M. & Berger, E.A. HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: independence from G protein signaling and importance of coreceptor downmodulation. Virology 234 , 340–348 (1997).

    Article  CAS  Google Scholar 

  34. Farzan, M. et al. HIV-1 entry and macrophage inflammatory protein-1beta-mediated signaling are independent functions of the chemokine receptor CCR5. J. Biol. Chem. 272, 6854–6857 (1997).

    Article  CAS  Google Scholar 

  35. Marechal, V., Clavel, F., Heard, J.M. & Schwartz, O. Cytosolic Gag p24 as an index of productive entry of human immunodeficiency virus type 1 . J. Virol. 72, 2208–2212 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wiley, C.A. & Achim, C. Human immunodeficiency virus encephalitis is the pathological correlate of dementia in acquired immunodeficiency syndrome . Ann. Neurol. 36, 673– 676 (1994).

    Article  CAS  Google Scholar 

  37. Conant, K. et al. Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc. Natl. Acad. Sci. USA 95, 3117–3121 ( 1998).

    Article  CAS  Google Scholar 

  38. Ostrowski, M.A. et al. Expression of chemokine receptors CXCR4 and CCR5 in HIV-1-infected and uninfected individuals. J. Immunol. 161, 3195–3201 (1998).

    CAS  PubMed  Google Scholar 

  39. de Roda Husman, A.M., Blaak, H., Brouwer, M. & Schuitemaker, H. CC chemokine receptor 5 cell-surface expression in relation to CC chemokine receptor 5 genotype and the clinical course of HIV-1 infection. J. Immunol. 163, 4597–4603 ( 1999).

    CAS  PubMed  Google Scholar 

  40. Fritsch, L. et al. Production of HIV-1 by human B cells infected in vitro : characterization of an EBV genome-negative B cell line chronically synthetizing a low level of HIV-1 after infection. Virology 244, 542–551 (1998).

    Article  CAS  Google Scholar 

  41. Lopalco, L. et al. CCR5-reactive antibodies in seronegative partners of HIV-seropositive individuals down-modulate surface CCR5 in vivo and neutralize the infectivity of R5 strains of HIV-1 In vitro. J. Immunol. 164, 3426–3433 (2000).

    Article  CAS  Google Scholar 

  42. Oppermann, M., Mack, M., Proudfoot, A.E. & Olbrich, H. Differential effects of CC chemokines on CC chemokine receptor 5 (CCR5) phosphorylation and identification of phosphorylation sites on the CCR5 carboxyl terminus . J. Biol. Chem. 274, 8875– 8885 (1999).

    Article  CAS  Google Scholar 

  43. Rieber, E.P. et al. The monoclonal CD4 antibody M-T413 inhibits cellular infection with human immunodeficiency virus after viral attachment to the cell membrane: an approach to postexposure prophylaxis. Proc. Natl. Acad. Sci. USA 89, 10792–10796 ( 1992).

    Article  CAS  Google Scholar 

  44. Rubsamen-Waigmann, H., Willems, W.R., Bertram, U. & von Briesen, H. Reversal of HIV-phenotype to fulminant replication on macrophages in perinatal transmission. Lancet 2, 1155– 1156 (1989).

    Article  CAS  Google Scholar 

  45. Popovic, M., Sarngadharan, M.G., Read, E. & Gallo, R.C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science 224, 497–500 (1984).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Schellerer and T. Rupp for technical assistance. This work was supported by Deutsche Forschungsgemeinschaft grant MA2198/1-1 and Sonderforschungsbereich 464.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mack, M., Kleinschmidt, A., Brühl, H. et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: A mechanism for cellular human immunodeficiency virus 1 infection . Nat Med 6, 769–775 (2000). https://doi.org/10.1038/77498

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/77498

This article is cited by

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