Letter | Published:

Enhancing SIV-specific immunity in vivo by PD-1 blockade

Nature volume 458, pages 206210 (12 March 2009) | Download Citation

Subjects

Abstract

Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses1,2,3. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here we investigate the safety and immune restoration potential of blockade of the co-inhibitory receptor programmed death 1 (PD-1)4,5 during chronic simian immunodeficiency virus (SIV) infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late (week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for control of human immunodeficiency virus infections.

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Accessions

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Sequencing data related to the Tat SL8/TL8 epitope region have been deposited in GenBank (accession numbers FJ268664FJ268704).

References

  1. 1.

    & Immunopathogenesis and immunotherapy in AIDS virus infections. Nature Med. 9, 861–866 (2003)

  2. 2.

    & Correlates of immune protection in HIV-1 infection: what we know, what we don’t know, what we should know. Nature Med. 10, 806–810 (2004)

  3. 3.

    & Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J. Allergy Clin. Immunol. 122, 12–19 (2008)

  4. 4.

    , , & Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 11, 3887–3895 (1992)

  5. 5.

    , , & The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nature Immunol. 8, 239–245 (2007)

  6. 6.

    et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007)

  7. 7.

    & T cells and viral persistence: lessons from diverse infections. Nature Immunol. 6, 873–879 (2005)

  8. 8.

    et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998)

  9. 9.

    et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 187, 1383–1393 (1998)

  10. 10.

    & Immunology of hepatitis B virus and hepatitis C virus infection. Nature Rev. Immunol. 5, 215–229 (2005)

  11. 11.

    et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006)

  12. 12.

    et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281–2292 (2006)

  13. 13.

    et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006)

  14. 14.

    et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Med. 12, 1198–1202 (2006)

  15. 15.

    et al. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J. Virol. 81, 5819–5828 (2007)

  16. 16.

    et al. SIV-specific CD8+ T-cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood 110, 928–936 (2007)

  17. 17.

    et al. Reduction of respiratory syncytial virus (RSV) in tracheal aspirates in intubated infants by use of humanized monoclonal antibody to RSV F protein. J. Infect. Dis. 178, 1555–1561 (1998)

  18. 18.

    et al. Characterization of the peptide binding motif of a rhesus MHC class I molecule (Mamu-A*01) that binds an immunodominant CTL epitope from simian immunodeficiency virus. J. Immunol. 160, 6062–6071 (1998)

  19. 19.

    et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407, 386–390 (2000)

  20. 20.

    et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4, 1191–1198 (2003)

  21. 21.

    , , , & Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999)

  22. 22.

    , & Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu. Rev. Immunol. 18, 665–708 (2000)

  23. 23.

    et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002)

  24. 24.

    et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14, 3044–3051 (2008)

  25. 25.

    et al. Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. J. Immunol. 180, 5439–5447 (2008)

  26. 26.

    , , & Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30, 802–810 (2006)

  27. 27.

    et al. In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell. Immunol. 200, 16–26 (2000)

  28. 28.

    et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292, 69–74 (2001)

  29. 29.

    , , , & Multiple-cytokine-producing antiviral CD4 T cells are functionally superior to single-cytokine-producing cells. J. Virol. 81, 8468–8476 (2007)

  30. 30.

    et al. GM-CSF DNA: an adjuvant for higher avidity IgG, rectal IgA, and increased protection against the acute phase of a SHIV-89.6P challenge by a DNA/MVA immunodeficiency virus vaccine. Virology 369, 153–167 (2007)

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Acknowledgements

The authors thank J. D. Altman for provision of Gag CM9 and Tat SL8 tetramers, H. Drake-Perrow for administrative support, and D. Watkins and Wisconsin National Primate Research Center Genotyping Service for Mamu typing of animals. The authors also thank the Yerkes Division of Research Resources for pathology support, Emory CFAR virology core for viral load assays and the NIH AIDS Research and Reference Reagent Program for the provision of peptides. This work was supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases grants R01 AI057029, R01 AI071852, R01 AI074417 to R.R.A.; the Foundation for the NIH through the Grand Challenges in Global Health initiative P51 RR00165 to R.A., G.J.F. and R.R.A.; Yerkes National Primate Research Center base grant P51 RR00165; Emory CFAR grant P30 AI050409; and R24 RR16038 to David I. Watkins.

Author Contributions V.V. and K.T. contributed to the design of experiments, conducted analyses on T-cell responses, and contributed to manuscript preparation; S.H. performed analyses on T-cell phenotyping. T.H.V. performed analyses on viral escape. L.L. and A.P. performed analyses on humoral responses; L.C. performed the statistical analysis; G.S. supervised the analyses on viral escape and contributed to manuscript preparation; B.Z. and G.J.F. developed and provided the anti-human PD-1 blocking antibody, and contributed to the design of experiments and manuscript preparation. R.A. contributed to the concept, design of experiments and manuscript preparation. R.R.A. supervised the entire project, designed and coordinated the experiments, and contributed to manuscript preparation.

Author information

Author notes

    • Vijayakumar Velu
    •  & Kehmia Titanji

    These authors contributed equally to this work.

Affiliations

  1. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Vijayakumar Velu
    • , Kehmia Titanji
    • , Sajid Husain
    • , Annette Pladevega
    • , Lilin Lai
    • , Lakshmi Chennareddi
    • , Rafi Ahmed
    •  & Rama Rao Amara
  2. Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA

    • Vijayakumar Velu
    • , Kehmia Titanji
    • , Sajid Husain
    • , Annette Pladevega
    • , Lilin Lai
    • , Lakshmi Chennareddi
    •  & Rama Rao Amara
  3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Baogong Zhu
    •  & Gordon J. Freeman
  4. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Baogong Zhu
    •  & Gordon J. Freeman
  5. University of Pennsylvania School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Thomas H. Vanderford
    •  & Guido Silvestri

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Competing interests

G.J.F. has patents and receives patent royalties on the PD-1 pathway, and R.A. has patents on the PD-1 pathway.

Corresponding author

Correspondence to Rama Rao Amara.

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DOI

https://doi.org/10.1038/nature07662

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