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:

MHC-I–restricted presentation of HIV-1 virion antigens without viral replication

Nature Medicine volume 7, pages 344–349 (2001)Cite this article

Abstract

Dendritic cells and macrophages can process extracellular antigens for presentation by MHC-I molecules. This exogenous pathway may have a crucial role in the activation of CD8+ cytotoxic T lymphocytes during human viral infections. We show here that HIV-1 epitopes derived from incoming virions are presented through the exogenous MHC-I pathway in primary human dendritic cells, and to a lower extent in macrophages, leading to cytotoxic T-lymphocyte activation in the absence of viral protein synthesis. Exogenous antigen presentation required adequate virus-receptor interactions and fusion of viral and cellular membranes. These results provide new insights into how anti-HIV cytotoxic T lymphocytes can be activated and have implications for anti-HIV vaccine design.

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: MHC-I presentation of a Gag p17 epitope derived from incoming HIV-1 virions (▪, medium; □, peptide SL9; squshf;, HIVBRU(VSV); ▨, HIVJRCSF; ▪, HIVBRU).
Figure 2: Characteristics of exogenous presentation of HIV-1 antigens by MHC-I.
Figure 3: MHC-I presentation of a Gag p24 epitope derived from incoming HIV-1 virions (●, peptide; ▪, HIV-Vector; □, HIVNL43(VSV); ○, medium; ▴, HIVNL43Δenv).
Figure 4: Analysis of CTL response to incoming HIV-1 virions.

Similar content being viewed by others

References

  1. Rock, K.L. A new foreign policy: MHC class I molecules monitor the outside world. Immunol. Today 17, 129–137 (1996).

    Article  Google Scholar 

  2. Jondal, M., Schirmbeck, R. & Reimann, J. MHC class I-restricted CTL responses to exogenous antigens. Immunity 5, 295–302 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Yewdell, J.W., Norbury, C.C., Bennink, J.R. Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: Implications for generating CD8+ T cell responses to infectious agents, tumors, transplants, and vaccines. Adv. Immunol. 73, 1–77 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Lanzavecchia, A. Mechanisms of antigen uptake for presentation. Curr. Op. Immunol. 8, 348–354 (1996).

    Article  CAS  Google Scholar 

  5. Watts, C. Capture and processing of exogenous antigens for presentation on MHC molecules. Ann. Rev. Immunol. 15, 821–850 (1997).

    Article  CAS  Google Scholar 

  6. Kovacsovics-Bankowski, M. & Rock, K.L. A phagosome to cytosol pathway for exogenous antigens presented on MHC class I molecules. Science 267, 243–246 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Singh-Jasuja, H. et al. Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. J. Exp. Med. 191, 1965–1974 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Castellino, F. et al. Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class 1 antigen presentation via two distinct processing pathways. J. Exp. Med. 191, 1957–1964 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Regnault, A. et al. Fcγ receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J. Exp. Med. 189, 371–380 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rodriguez, A., Regnault, A., Kleijmeer, M., Ricciardi-Castagnoli, P. & Amigorena, S. Selective transport of internalized antigens to the cytosol for MHC class I presentation in dendritic cells. Nature Cell Biol. 1, 362–368 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Gromme, M. et al. Recycling MHC class I molecules and endosomal peptide loading. Proc. Nat. Acad. Sci. USA 96, 10326–10331 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Albert, M.L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Sigal, L.J., Crotty, S., Andino, R. & Rock, K.L. Cytotoxic T-cell immunity to virus-infected non-hematopoietic cells requires presentation of exogenous antigen. Nature 398, 77–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Yewdell, J.W., Bennink, J.R. & Hosaka, Y. Cells process exogenous proteins for recognition by cytotoxic T lymphocytes. Science 239, 637–640 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Reimann, J. & Schirmbeck, R. Alternative pathways for processing exogenous and endogenous antigens that can generate peptides for MHC class I-restricted presentation. Immunol. Rev. 172, 131–152 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Cameron, P., Pope, M., Granelli-Piperno, A. & Steinman, R.M. Dendritic cells and the replication of HIV-1. J. Leuk. Biol. 59, 158–171 (1996).

    Article  CAS  Google Scholar 

  18. Knight, S.C. & Patterson, S. Bone marrow-derived dendritic cells, infection with human immunodeficiency virus, and immunopathology. Annu. Rev. Immunol. 15, 593–615 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. 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 

  20. Ayehunie, S. et al. Human immunodeficiency virus-1 entry into purified blood dendritic cells through CC and CXC chemokine coreceptors. Blood 90, 1379–1386 (1997).

    CAS  PubMed  Google Scholar 

  21. Klagge, I.M. & Schneider-Schaulies, S. Virus interactions with dendritic cells. J. Gen. Virol. 80, 823–833 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. Lapham, C.K., Zaitseva, M.B., Lee, S., Romanstseva, T. & Golding, H. Fusion of monocytes and macrophages with HIV-1 correlates with biochemical properties of CXCR4 and CCR5. Nature Med. 5, 303–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Aiken, C. Pseudotyping HIV-1 by the glycoprotein of VSV targets HIV-1 entry to an endocytic pathway and suppresses both the requirement for Nef and the sensitivity to cyclosporin A. J. Virol. 71, 5871–5877 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang, O.O. et al. Efficient lysis of Human Immunodeficiency Virus type 1-infected cells by cytotoxic T lymphocytes. J. Virol. 70, 5799–5806 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Naldini, L. et al. In vivo gene delivery and stable transduction of non dividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Rossio, J.L. et al. Inactivation of human immunodeficiency virus type 1 infectivity with preservation of conformational and functional integrity of virion surface proteins. J. Virol. 72, 7992–8001 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Arthur, L.O. et al. Chemical inactivation of retroviral infectivity by targeting nucleocapsid protein zinc fingers: a candidate SIV vaccine. AIDS Res. Hum. Retrov. 14, s311–s319 (1998).

    Article  CAS  Google Scholar 

  30. Bergeron, L., Sullivan, N. & Sodroski, J. Target cell-specific determinants of membrane fusion within the Human Immunodeficiency virus type 1 gp120 third variable region and gp41 amino terminus. J. Virol. 66, 2389–2397 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Whitt, M.A., Zagouras, P., Crise, B. & Rose, J.K. A fusion-defective mutant of the Vesicular Stomatitis Virus glycoprotein. J. Virol. 64, 4907–4913 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Buseyne, F., Février, M., Garcia, S., Gougeon, M.L. & Rivière, Y. Dual function of a human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte clone: inhibition of HIV replication by noncytolytic mechanisms and lysis of HIV-infected CD4+ cells. Virology 225, 248–253 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Piatak, M., Jr . et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259, 1749–1754 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Embreston, J. et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362, 359–362 (1993).

    Article  Google Scholar 

  35. Schwartz, O., Marechal, V., Friguet, B., Arenzana-Seisdedos, F. & Heard, J.M. Antiviral activity of the proteasome on incoming HIV-1. J. Virol. 72, 3845–3850 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Schwartz, O., Maréchal, V., Le Gall, S., Lemonnier, F. & Heard, J.M. Endocytosis of MHC-I molecules is induced by HIV-1 Nef. Nature Med. 2, 338–342 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Collins, K.L., Chen, B.K., Kalams, S.A., Walker, B.D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Pinto, L.A. et al. Env-specific cytotoxic T lymphocytes responses in HIV seronegative health care workers occupationally exposed to HIV-contaminated body fluids. J. Clin. Invest. 96, 867–876 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rowland-Jones, S. et al. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women. Nature Med. 1, 59–64 (1995).

    Article  PubMed  Google Scholar 

  40. Rowland-Jones, S., Tan, R. & McMichael, A. Role of cellular immunity in protection against HIV infection. Adv. Immunol. 65, 277–346 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Brander, C. & Walker, B.D. T lymphocyte responses in HIV-1 infection: implications for vaccine development. Curr. Op. Immunol. 11, 451–459 (1999).

    Article  CAS  Google Scholar 

  42. Goxe, B., Latour, N., Bartholeyns, J., Romet-Lemonne, J.L. & Chokri, M. Monocyte-derived dendritic cells: development of a cellular processor for clinical applications. Res. Immunol. 149, 643–646 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Buseyne, F. et al. Cross-clade-specific cytotoxic T lymphocytes in HIV-1-infected children. Virology 250, 316–324 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Tsomides, T.J. et al. Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by Human Immunodeficiency Virus type 1. J. Exp. Med. 180, 1283–1293 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Czerkinsky, C. et al. Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gamma-interferon-secreting cells. J. Immunol. Meth. 110, 29–36 (1988).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank F. Lemonnier and S. Michelson for critical reading of the manuscript; C. Petit and M.L. Michel for discussions; V. Maréchal for preparation of macrophages; F. Mammano, F. Romagné, F. Latron, M. Takigushi, Chiron and Novartis for gifts of reagents; C. Rouzioux and S. Blanche for their support; and J. Bess Jr for preparation of inactivated HIV-1MN. This work was supported by grants from the Agence Nationale de Recherche sur le SIDA (ANRS), SIDACTION, the Pediatric AIDS Foundation and the Pasteur Institute, and in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-56000.

Author information

Authors and Affiliations

  1. Laboratoire d'Immunopathologie Viralem, Institut Pasteur, Paris, France

    Florence Buseyne & Yves Rivière

  2. Unité Rétrovirus et Transfert Génétique, Institut Pasteur, Paris, France

    Sylvie Le Gall, Jean-Michel Heard & Olivier Schwartz

  3. ImmunoDesigned Molecules Research Laboratories, Institut des Cordeliers, Paris, France

    Claire Boccaccio & Jean-Pierre Abastado

  4. Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland, USA

    Jeffrey D. Lifson & Larry O. Arthur

Authors
  1. Florence Buseyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylvie Le Gall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claire Boccaccio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Pierre Abastado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey D. Lifson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Larry O. Arthur
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yves Rivière
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-Michel Heard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Olivier Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Olivier Schwartz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buseyne, F., Gall, S., Boccaccio, C. et al. MHC-I–restricted presentation of HIV-1 virion antigens without viral replication. Nat Med 7, 344–349 (2001). https://doi.org/10.1038/85493

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/85493

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