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:

Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4+ T cells

Nature Medicine volume 14, pages 429–436 (2008)Cite this article

Abstract

Cell-free human T-lymphotropic virus type 1 (HTLV-1) virions are poorly infectious in vitro for their primary target cells, CD4+ T cells. Here, we show that HTLV-1 can efficiently infect myeloid and plasmacytoid dendritic cells (DCs). Moreover, DCs exposed to HTLV-1, both before and after being productively infected, can rapidly, efficiently and reproducibly transfer virus to autologous primary CD4+ T cells. This DC-mediated transfer of HTLV-1 involves heparan sulfate proteoglycans and neuropilin-1 and results in long-term productive infection and interleukin-2–independent transformation of the CD4+ T cells. These studies, along with observations of HTLV-1–infected DCs in the peripheral blood of infected individuals, indicate that DCs have a central role in HTLV-1 transmission, dissemination and persistence in vivo. In addition to altering the current paradigm concerning how HTLV-1 transmission occurs, these studies suggest that impairment of DC function after HTLV-1 infection plays a part in pathogenesis.

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: HTLV-1 efficiently infects DCs.
Figure 2: DCs are stably and productively infected by HTLV-1.
Figure 3: HTLV-1–exposed DCs productively infect CD4+ T cells.
Figure 4: DC-mediated HTLV-1 infection of CD4+ T cells occurs in a biphasic manner.
Figure 5: DC-mediated HTLV-1 infection of CD4+ T cells involves HSPGs and NP-1.
Figure 6: Transformation of CD4+ T cells after DC-mediated HTLV-1 infection.

Similar content being viewed by others

References

  1. Poiesz, B.J. et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc. Natl. Acad. Sci. USA 77, 7415–7419 (1980).

    Article  CAS  Google Scholar 

  2. Feuer, G. & Green, P.L. Comparative biology of human T-cell lymphotropic virus type 1 (HTLV-1) and HTLV-2. Oncogene 24, 5996–6004 (2005).

    Article  CAS  Google Scholar 

  3. Fan, N. et al. Infection of peripheral blood mononuclear cells and cell lines by cell-free human T-cell lymphoma/leukemia virus type I. J. Clin. Microbiol. 30, 905–910 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Donegan, E. et al. Transfusion transmission of retroviruses: human T-lymphotropic virus types I and II compared with human immunodeficiency virus type 1. Transfusion 34, 478–483 (1994).

    Article  CAS  Google Scholar 

  5. Igakura, T. et al. Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299, 1713–1716 (2003).

    Article  CAS  Google Scholar 

  6. Overbaugh, J. HTLV-1 sweet-talks its way into cells. Nat. Med. 10, 20–21 (2004).

    Article  CAS  Google Scholar 

  7. Steinman, R.M. & Hemmi, H. Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 311, 17–58 (2006).

    CAS  PubMed  Google Scholar 

  8. Courreges, M.C., Burzyn, D., Nepomnaschy, I., Piazzon, I. & Ross, S.R. Critical role of dendritic cells in mouse mammary tumor virus in vivo infection. J. Virol. 81, 3769–3777 (2007).

    Article  CAS  Google Scholar 

  9. Pohl, C., Shishkova, J. & Schneider-Schaulies, S. Viruses and dendritic cells: enemy mine. Cell. Microbiol. 9, 279–289 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Hishizawa, M. et al. Depletion and impaired interferon-α–producing capacity of blood plasmacytoid dendritic cells in human T-cell leukaemia virus type I–infected individuals. Br. J. Haematol. 125, 568–575 (2004).

    Article  CAS  Google Scholar 

  12. Kampani, K. et al. A novel high throughput quantum dot–based fluorescence assay for quantitation of virus binding and attachment. J. Virol. Methods 141, 125–132 (2007).

    Article  CAS  Google Scholar 

  13. Ceccaldi, P.E. et al. DC-SIGN facilitates fusion of dendritic cells with human T-cell leukemia virus type 1–infected cells. J. Virol. 80, 4771–4780 (2006).

    Article  CAS  Google Scholar 

  14. Makino, M., Shimokubo, S., Wakamatsu, S.I., Izumo, S. & Baba, M. The role of human T-lymphotropic virus type 1 (HTLV-1)-infected dendritic cells in the development of HTLV-1–associated myelopathy/tropical spastic paraparesis. J. Virol. 73, 4575–4581 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ehrlich, G.D. et al. Detection of anti–HTLV-I Tax antibodies in HTLV-I enzyme-linked immunosorbent assay–negative individuals. Blood 74, 1066–1072 (1989).

    CAS  PubMed  Google Scholar 

  16. Shinzato, O. et al. Semiquantitative analysis of integrated genomes of human T-lymphotropic virus type I in asymptomatic virus carriers. Blood 78, 2082–2088 (1991).

    CAS  PubMed  Google Scholar 

  17. Silva, M.T. et al. Human T lymphotropic virus type 1 (HTLV-1) proviral load in asymptomatic carriers, HTLV-1–associated myelopathy/tropical spastic paraparesis, and other neurological abnormalities associated with HTLV-1 infection. Clin. Infect. Dis. 44, 689–692 (2007).

    Article  Google Scholar 

  18. Ureta-Vidal, A. et al. Human T cell leukemia virus type I (HTLV-I) infection induces greater expansions of CD8 T lymphocytes in persons with HTLV-I–associated myelopathy/tropical spastic paraparesis than in asymptomatic carriers. J. Infect. Dis. 183, 857–864 (2001).

    Article  CAS  Google Scholar 

  19. Zhang, L., Liu, M., Merling, R. & Giam, C.Z. Versatile reporter systems show that transactivation by human T-cell leukemia virus type 1 Tax occurs independently of chromatin remodeling factor BRG1. J. Virol. 80, 7459–7468 (2006).

    Article  CAS  Google Scholar 

  20. Turville, S.G. et al. Immunodeficiency virus uptake, turnover, and 2-phase transfer in human dendritic cells. Blood 103, 2170–2179 (2004).

    Article  CAS  Google Scholar 

  21. Ghez, D. et al. Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J. Virol. 80, 6844–6854 (2006).

    Article  CAS  Google Scholar 

  22. Jones, K.S., Petrow-Sadowski, C., Bertolette, D.C., Huang, Y. & Ruscetti, F.W. Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells. J. Virol. 79, 12692–12702 (2005).

    Article  CAS  Google Scholar 

  23. Pinon, J.D. et al. Human T-cell leukemia virus type 1 envelope glycoprotein gp46 interacts with cell surface heparan sulfate proteoglycans. J. Virol. 77, 9922–9930 (2003).

    Article  CAS  Google Scholar 

  24. Chung, J.S., Dougherty, I., Cruz, P.D., Jr. & Ariizumi, K. Syndecan-4 mediates the coinhibitory function of DC-HIL on T cell activation. J. Immunol. 179, 5778–5784 (2007).

    Article  CAS  Google Scholar 

  25. Tordjman, R. et al. A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response. Nat. Immunol. 3, 477–482 (2002).

    Article  CAS  Google Scholar 

  26. Barr, M.P. et al. A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1–expressing breast tumour cells. Br. J. Cancer 92, 328–333 (2005).

    Article  CAS  Google Scholar 

  27. Nath, M.D., Ruscetti, F.W., Petrow-Sadowski, C. & Jones, K.S. Regulation of the cell-surface expression of an HTLV-I binding protein in human T cells during immune activation. Blood 101, 3085–3092 (2003).

    Article  CAS  Google Scholar 

  28. Green, P.L., Ross, T.M., Chen, I.S. & Pettiford, S. Human T-cell leukemia virus type II nucleotide sequences between env and the last exon of tax/rex are not required for viral replication or cellular transformation. J. Virol. 69, 387–394 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Persaud, D., Munoz, J.L., Tarsis, S.L., Parks, E.S. & Parks, W.P. Time course and cytokine dependence of human T-cell lymphotropic virus type 1 T-lymphocyte transformation as revealed by a microtiter infectivity assay. J. Virol. 69, 6297–6303 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Li, M. & Green, P.L. Detection and quantitation of HTLV-1 and HTLV-2 mRNA species by real-time RT-PCR. J. Virol. Methods 142, 159–168 (2007).

    Article  CAS  Google Scholar 

  31. Thomas, J.A., Ott, D.E. & Gorelick, R.J. Efficiency of human immunodeficiency virus type 1 postentry infection processes: evidence against disproportionate numbers of defective virions. J. Virol. 81, 4367–4370 (2007).

    Article  CAS  Google Scholar 

  32. Gummuluru, S., KewalRamani, V.N. & Emerman, M. Dendritic cell–mediated viral transfer to T cells is required for human immunodeficiency virus type 1 persistence in the face of rapid cell turnover. J. Virol. 76, 10692–10701 (2002).

    Article  CAS  Google Scholar 

  33. Piguet, V. & Sattentau, Q. Dangerous liaisons at the virological synapse. J. Clin. Invest. 114, 605–610 (2004).

    Article  CAS  Google Scholar 

  34. Zucker-Franklin, D., Fraig, M. & Grusky, G. Interaction of human immunodeficiency virus type 1, human T-cell leukemia/lymphoma virus type I (HTLV-I), and HTLV-II with in vitro–generated dendritic cells. Clin. Diagn. Lab. Immunol. 2, 343–348 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Macatonia, S.E., Cruickshank, J.K., Rudge, P. & Knight, S.C. Dendritic cells from patients with tropical spastic paraparesis are infected with HTLV-1 and stimulate autologous lymphocyte proliferation. AIDS Res. Hum. Retroviruses 8, 1699–1706 (1992).

    Article  CAS  Google Scholar 

  36. Al-Dahoodi, Z.M., Takemoto, S., Kataoka, S. & Taguchi, T. Dysfunction of dendritic and T cells as the cause of immune suppression in HTLV-I infected individuals. J. Clin. Exp. Hematop. 43, 43–48 (2003).

    Article  Google Scholar 

  37. Katsuki, T., Katsuki, K., Imai, J. & Hinuma, Y. Immune suppression in healthy carriers of adult T-cell leukemia retrovirus (HTLV-I): impairment of T-cell control of Epstein-Barr virus–infected B cells. Jpn. J. Cancer Res. 78, 639–642 (1987).

    CAS  PubMed  Google Scholar 

  38. Makino, M., Wakamatsu, S., Shimokubo, S., Arima, N. & Baba, M. Production of functionally deficient dendritic cells from HTLV-I–infected monocytes: implications for the dendritic cell defect in adult T cell leukemia. Virology 274, 140–148 (2000).

    Article  CAS  Google Scholar 

  39. Mascarenhas, R.E. et al. Peripheral blood mononuclear cells from individuals infected with human T-cell lymphotropic virus type 1 have a reduced capacity to respond to recall antigens. Clin. Vaccine Immunol. 13, 547–552 (2006).

    Article  CAS  Google Scholar 

  40. Makino, M. et al. Association of CD40 ligand expression on HTLV-I–infected T cells and maturation of dendritic cells. Scand. J. Immunol. 54, 574–581 (2001).

    Article  CAS  Google Scholar 

  41. Taguchi, H. & Miyoshi, I. Immune suppression in HTLV-I carriers: a predictive sign of adult T-cell leukemia. Acta Med. Okayama 43, 317–321 (1989).

    CAS  PubMed  Google Scholar 

  42. Arnulf, B. et al. Loss of the ex vivo but not the reinducible CD8. T-cell response to Tax in human T-cell leukemia virus type 1-infected patients with adult T-cell leukemia/lymphoma. Leukemia 18, 126–132 (2004).

    Article  CAS  Google Scholar 

  43. Furukawa, Y., Kubota, R., Tara, M., Izumo, S. & Osame, M. Existence of escape mutant in HTLV-I tax during the development of adult T-cell leukemia. Blood 97, 987–993 (2001).

    Article  CAS  Google Scholar 

  44. Kubota, R., Furukawa, Y., Izumo, S., Usuku, K. & Osame, M. Degenerate specificity of HTLV-1–specific CD8. T cells during viral replication in patients with HTLV-1-associated myelopathy (HAM-TSP). Blood 101, 3074–3081 (2003).

    Article  CAS  Google Scholar 

  45. Manel, N. et al. The HTLV receptor is an early T-cell activation marker whose expression requires de novo protein synthesis. Blood 101, 1913–1918 (2003).

    Article  CAS  Google Scholar 

  46. Jones, K.S. et al. Induction of human T cell leukemia virus type I receptors on quiescent naive T lymphocytes by TGF-β. J. Immunol. 174, 4262–4270 (2005).

    Article  CAS  Google Scholar 

  47. Jones, K.S. et al. Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 use different receptor complexes to enter T cells. J. Virol. 80, 8291–8302 (2006).

    Article  CAS  Google Scholar 

  48. Hague, B.F., Zhao, T.M. & Kindt, T.J. Binding of HTLV-1 virions to T cells occurs by a temperature- and calcium-dependent process and is blocked by certain type 2 adenosine receptor antagonists. Virus Res. 93, 31–39 (2003).

    Article  CAS  Google Scholar 

  49. Liu, B., Hong, S., Tang, Z., Yu, H. & Giam, C.Z. HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule. Proc. Natl. Acad. Sci. USA 102, 63–68 (2005).

    Article  CAS  Google Scholar 

  50. Yamano, Y. et al. Correlation of human T-cell lymphotropic virus type 1 (HTLV-1) mRNA with proviral DNA load, virus-specific CD8. T cells, and disease severity in HTLV-1-associated myelopathy (HAM-TSP). Blood 99, 88–94 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to L. Yang, M. Liu and C.-Z. Giam (Uniformed Services University of Health Sciences) for reagents; O. Unsong and S. Jacobson (National Institute of Neurological Disorders and Stroke, National Institutes of Health) for PBMCs from the HTLV-1–infected individual; C. Pique, G. Trinchieri and D. Klinman for critical review of the manuscript; S. Reynolds for technical assistance; and P. Green, V. KewalRamani and C.-Z. Giam for helpful discussions. This project has been funded in whole or in part with federal funds from the US National Cancer Institute and US National Institutes of Health under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, US National Cancer Institute and Center for Cancer Research.

Author information

Authors and Affiliations

  1. Basic Research Program, Science Applications International Corporation-Frederick, Frederick, 21702, Maryland, USA

    Kathryn S Jones & Cari Petrow-Sadowski

  2. Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, 21702, Maryland, USA

    Ying K Huang, Daniel C Bertolette & Francis W Ruscetti

Authors
  1. Kathryn S Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cari Petrow-Sadowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying K Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel C Bertolette
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francis W Ruscetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.S.J. and F.W.R. designed the experiments, performed data analysis and wrote the manuscript. C.P.-S., Y.K.H. and D.C.B. prepared the reagents, conducted the experiments and edited the manuscript.

Corresponding author

Correspondence to Kathryn S Jones.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–6, Supplementary Table 1 and Supplementary Methods (PDF 611 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jones, K., Petrow-Sadowski, C., Huang, Y. et al. Cell-free HTLV-1 infects dendritic cells leading to transmission and transformation of CD4+ T cells. Nat Med 14, 429–436 (2008). https://doi.org/10.1038/nm1745

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1745

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