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.

Therapeutic dendritic-cell vaccine for chronic HIV-1 infection

Abstract

We present the results of a preliminary investigation of the efficacy of a therapeutic dendritic cell (DC)-based vaccine for HIV-1. We immunized 18 chronically HIV-1-infected and currently untreated individuals showing stable viral loads for at least 6 months with autologous monocyte-derived DCs loaded with autologous aldrithiol-2-inactivated HIV-1. Plasma viral load levels were decreased by 80% (median) over the first 112 d following immunization. Prolonged suppression of viral load of more than 90% was seen in 8 individuals for at least 1 year. The suppression of viral load was positively correlated with HIV-1-specifc interleukin-2 or interferon-γ-expressing CD4+ T cells and with HIV-1 gag–specific perforin-expressing CD8+ effector cells, suggesting that a robust virus-specific CD4+ T-helper type 1 (TH1) response is required for inducing and maintaining virus-specific CD8+ effectors to contain HIV-1 in vivo. The results suggest that inactivated whole virus–pulsed DC vaccines could be a promising strategy for treating people with chronic HIV-1 infection.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Immunologic and virologic evolution of the 18 immunized participants.
Figure 2: Intracellular cytokine detection of T cells following stimulation with AT-2-inactivated HIV-1-pulsed DC (patient 13).
Figure 3: HIV-1-specfic T-cell immunity in the 18 immunized patients.
Figure 4: HIV-1-gag tetramer staining and intracellular perforin detection in gated CD3+CD8+ cells.
Figure 5: HIV-1 gag–specific perforin-expressing CD8+ T cells (effectors) in 10 immunized HLA A*0201-positive individuals.

References

  1. Rosenberg, E.S. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278, 1447–1450 (1997).

    Article  CAS  Google Scholar 

  2. Pitcher, C.J. et al. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat. Med. 5, 518–525 (1999).

    Article  CAS  Google Scholar 

  3. Zaunders, J.J. et al. Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term non-progressor and in CMV infection. Blood (2003).

  4. Boaz, M.J., Waters, A., Murad, S., Easterbrook, P.J. & Vyakarnam, A. Presence of HIV-1 Gag-specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection. J. Immunol. 169, 6376–6385 (2002).

    Article  CAS  Google Scholar 

  5. Younes, S.A. et al. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J. Exp. Med. 198, 1909–1922 (2003).

    Article  CAS  Google Scholar 

  6. Harari, A., Petitpierre, S., Vallelian, F. & Pantaleo, G. Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 103, 966–972 (2004).

    Article  CAS  Google Scholar 

  7. Malhotra, U. et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. J. Infect. Dis. 181, 121–131 (2000).

    Article  CAS  Google Scholar 

  8. Oxenius, A. et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl Acad. Sci. USA 97, 3382–3387 (2000).

    Article  CAS  Google Scholar 

  9. Gray, C.M. et al. Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART). J. Immunol. 162, 1780–1788 (1999).

    CAS  PubMed  Google Scholar 

  10. Kalams, S.A. et al. Levels of human immunodeficiency virus type 1-specific cytotoxic T- lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J. Virol. 73, 6721–6728 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Knight, S.C. & Stagg, A.J. Antigen-presenting cell types. Curr. Opin. Immunol. 5, 374–382 (1993).

    Article  CAS  Google Scholar 

  12. McIlroy, D. et al. Low CD83, but normal MHC class II and costimulatory molecule expression, on spleen dendritic cells from HIV+ patients. AIDS Res. Hum. Retroviruses 14, 505–513 (1998).

    Article  CAS  Google Scholar 

  13. Grassi, F. et al. Depletion in blood CD11c-positive dendritic cells from HIV-infected patients. AIDS 13, 759–766 (1999).

    Article  CAS  Google Scholar 

  14. Donaghy, H. 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 98, 2574–2576 (2001).

    Article  CAS  Google Scholar 

  15. Pacanowski, J. et al. Reduced blood CD123+ (lymphoid) and CD11c+ (myeloid) dendritic cell numbers in primary HIV-1 infection. Blood 98, 3016–3021 (2001).

    Article  CAS  Google Scholar 

  16. Lapenta, C. et al. Potent immune response against HIV-1 and protection from virus challenge in hu-PBL-SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-alpha. J. Exp. Med. 198, 361–367 (2003).

    Article  CAS  Google Scholar 

  17. Yoshida, A. et al. Induction of protective immune responses against R5 human immunodeficiency virus type 1 (HIV-1) infection in hu-PBL-SCID mice by intrasplenic immunization with HIV-1-pulsed dendritic cells: possible involvement of a novel factor of human CD4+ T-cell origin. J. Virol. 77, 8719–8728 (2003).

    Article  CAS  Google Scholar 

  18. Lu, W., Wu, X., Lu, Y., Guo, W. & Andrieu, J.M. Therapeutic dendritic-cell vaccine for simian AIDS. Nat. Med. 9, 27–32 (2003).

    Article  CAS  Google Scholar 

  19. Hess, C. et al. HIV-1 specific CD8+ T cells with an effector phenotype and control of viral replication. Lancet 363, 863–866 (2004).

    Article  CAS  Google Scholar 

  20. Pantaleo, G. & Koup, R.A. Correlates of immune protection in HIV-1 infection: what we know, what we don't know, what we should know. Nat. Med. 10, 806–810 (2004).

    Article  CAS  Google Scholar 

  21. Diepolder, H.M. et al. Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 346, 1006–1007 (1995).

    Article  CAS  Google Scholar 

  22. Day, C.L. et al. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J. Clin. Invest. 112, 831–842 (2003).

    Article  CAS  Google Scholar 

  23. Ulsenheimer, A. et al. Detection of functionally altered hepatitis C virus-specific CD4 T cells in acute and chronic hepatitis C. Hepatology 37, 1189–1198 (2003).

    Article  Google Scholar 

  24. Schirren, C.A. et al. Antiviral treatment of recurrent hepatitis C virus (HCV) infection after liver transplantation: association of a strong, multispecific, and long-lasting CD4+ T cell response with HCV-elimination. J. Hepatol. 39, 397–404 (2003).

    Article  CAS  Google Scholar 

  25. Szkaradkiewicz, A. et al. HBcAg-specific cytokine production by CD4 T lymphocytes of children with acute and chronic hepatitis B. Virus Res. 97, 127–133 (2003).

    Article  CAS  Google Scholar 

  26. O'Sullivan, B. & Thomas, R. CD40 and dendritic cell function. Crit. Rev. Immunol. 23, 83–107 (2003).

    Article  CAS  Google Scholar 

  27. Sullivan, N., Sun, Y., Li, J., Hofmann, W. & Sodroski, J. Replicative function and neutralization sensitivity of envelope glycoproteins from primary and T-cell line-passaged human immunodeficiency virus type 1 isolates. J. Virol. 69, 4413–4422 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wrin, T., Loh, T.P., Vennari, J.C., Schuitemaker, H. & Nunberg, J.H. Adaptation to persistent growth in the H9 cell line renders a primary isolate of human immunodeficiency virus type 1 sensitive to neutralization by vaccine sera. J. Virol. 69, 39–48 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Means, R.E., Greenough, T. & Desrosiers, R.C. Neutralization sensitivity of cell culture-passaged simian immunodeficiency virus. J. Virol. 71, 7895–7902 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Miotti, P.G. et al. The influence of HIV infection on antibody responses to a two-dose regimen of influenza vaccine. J. Am. Med. Assoc. 262, 779–783 (1989).

    Article  CAS  Google Scholar 

  31. Lane, H.C. et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 309, 453–458 (1983).

    Article  CAS  Google Scholar 

  32. Terpstra, F.G. et al. Longitudinal study of leukocyte functions in homosexual men seroconverted for HIV: rapid and persistent loss of B cell function after HIV infection. Eur. J. Immunol. 19, 667–673 (1989).

    Article  CAS  Google Scholar 

  33. Goepfert, P.A. et al. A significant number of human immunodeficiency virus epitope-specific cytotoxic T lymphocytes detected by tetramer binding do not produce γ interferon. J. Virol. 74, 10249–10255 (2000).

    Article  CAS  Google Scholar 

  34. Kostense, S. et al. Persistent numbers of tetramer(+) CD8+ T cells, but loss of interferon-γ (+) HIV-specific T cells during progression to AIDS. Blood 99, 2505–2511 (2002).

    Article  CAS  Google Scholar 

  35. Frank, I. et al. Infectious and whole inactivated simian immunodeficiency viruses interact similarly with primate dendritic cells (DCs): differential intracellular fate of virions in mature and immature DCs. J. Virol. 76, 2936–2951 (2002).

    Article  CAS  Google Scholar 

  36. Moris, A. et al. DC-SIGN promotes exogenous MHC-I-restricted HIV-1 antigen presentation. Blood 103, 2648–2654 (2004).

    Article  CAS  Google Scholar 

  37. Lu, W. & Andrieu, J.M. In vitro HIV eradication by autologous CD8+ T cells expanded with inactivated-virus-pulsed dendritic cells. J. Virol. 75, 8949–8956 (2001).

    Article  CAS  Google Scholar 

  38. Buseyne, F. et al. MHC-I-restricted presentation of HIV-1 virion antigens without viral replication. Nat. Med. 7, 344–349 (2001).

    Article  CAS  Google Scholar 

  39. Kundu, S.K. et al. A pilot clinical trial of HIV antigen-pulsed allogeneic and autologous dendritic cell therapy in HIV-infected patients. AIDS Res. Hum. Retroviruses 14, 551–560 (1998).

    Article  CAS  Google Scholar 

  40. Sapp, M. et al. Dendritic cells generated from blood monocytes of HIV-1 patients are not infected and act as competent antigen presenting cells eliciting potent T-cell responses. Immunol. Lett. 66, 121–128 (1999).

    Article  CAS  Google Scholar 

  41. Chougnet, C. et al. Normal immune function of monocyte-derived dendritic cells from HIV- infected individuals: implications for immunotherapy. J. Immunol. 163, 1666–1673 (1999).

    CAS  PubMed  Google Scholar 

  42. Lu, W., Achour, A., Arlie, M., Cao, L. & Andrieu, J.M. Enhanced dendritic-cells-driven proliferation and anti-HIV activity of CD8+ T cells by a new phenothiazine derivative aminoperazine. J. Immunol. 167, 2929–2935 (2001).

    Article  CAS  Google Scholar 

  43. Teleshova, N. et al. CpG-C immunostimulatory oligodeoxyribonucleotide activation of plasmacytoid dendritic cells in rhesus macaques to augment the activation of IFN-gamma-secreting simian immunodeficiency virus-specific T cells. J. Immunol. 173, 1647–1657 (2004).

    Article  CAS  Google Scholar 

  44. Quinn, T.C. et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N. Engl. J. Med. 342, 921–929 (2000).

    Article  CAS  Google Scholar 

  45. Lu, W., Cao, L., Ty, L., Arlie, M. & Andrieu, J.M. Equivalent amplification of intrinsically variable nucleic acid sequences by multiple-primer-induced overlapping amplification assay: applications for universal detection and quantitation. Nat. Med. 5, 1081–1085 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge L. Lapa who performed leukapheresis; M.F. and M.M. Costa Mendes who provided assistance to patients; C. Padilha for clinical assistance; J.L. de Lima Filho who provided administrative support; H. Gozard, V. Jagot, A. Tiafvoon and J. Yuan for technical assistance; and Air France for its travel assistance. This study was supported by the Institut de Recherche sur les Vaccins et l'Immunothérapie des Cancers et du Sida (IRVICS), the Association de Recherche sur les Maladies Tumorales et Virales (AREMAS), the Instituto de Pesquisa en Immunoterapia de Pernambuco (IPIPE), and the Assitance Publique—Hôpitaux de Paris. We would like to express our gratitude to D. Skigin (1956–2003) for his donation.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wei Lu or Jean-Marie Andrieu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Flow cytometry analysis of inactivated virus-pulsed DCs. (PDF 130 kb)

Supplementary Fig. 2

Predictive markers for the viral-load response. (PDF 111 kb)

Supplementary Table 1

Quality control of DC vaccine by flow cytometry (PDF 82 kb)

Supplementary Table 2

Quality control of DC vaccine by ICC (PDF 83 kb)

Supplementary Table 3

Individual plasma viral load evolution (PDF 79 kb)

Supplementary Table 4

Individual CD4+ T-cell evolution (PDF 77 kb)

Supplementary Table 5

Individual anti-HIV antibody titers (PDF 68 kb)

Supplementary Table 6

Individual HIV-1-specific TH1 cytokine evolution (PDF 86 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lu, W., Arraes, L., Ferreira, W. et al. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med 10, 1359–1365 (2004). https://doi.org/10.1038/nm1147

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1147

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