PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression


Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells1,2,3,4, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice5. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load5. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: PD-1 is upregulated on HIV-specific CD8 T cells.
Figure 2: PD-1 expression is associated with HIV disease progression.
Figure 3: Blockade of the PD-1/PD-L1 pathway significantly increases expansion of tetramer + cells and frequency of HIV-specific, IFN-γ-producing CD8 T cells.
Figure 4: Effect of PD-1 expression on CD4 T cells.


  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

    Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999)

    CAS  Article  Google Scholar 

  3. 3

    Sharpe, A. H. & Freeman, G. J. The B7–CD28 superfamily. Nature Rev. Immunol. 2, 116–126 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Chen, L. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nature Rev. Immunol. 4, 336–347 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006; published online 28 December 2005)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Migueles, S. A. et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nature Immunol. 3, 1061–1068 (2002)

    CAS  Article  Google Scholar 

  7. 7

    Lichterfeld, M. et al. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J. Exp. Med. 200, 701–712 (2004)

    CAS  Article  Google Scholar 

  8. 8

    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)

    CAS  Article  Google Scholar 

  9. 9

    Kostense, S. et al. High viral burden in the presence of major HIV-specific CD8+ T cell expansions: evidence for impaired CTL effector function. Eur. J. Immunol. 31, 677–686 (2001)

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Appay, V. et al. HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Zhang, D. et al. Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood 101, 226–235 (2003)

    CAS  Article  Google Scholar 

  13. 13

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

    ADS  CAS  Article  Google Scholar 

  14. 14

    Kiepiela, P. et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432, 769–775 (2004)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Steiner, K. et al. Enhanced expression of CTLA-4 (CD152) on CD4+ T cells in HIV infection. Clin. Exp. Immunol. 115, 451–457 (1999)

    CAS  Article  Google Scholar 

  16. 16

    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)

    CAS  Article  Google Scholar 

  17. 17

    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 

  18. 18

    Loffredo, J. T. et al. Tat28–35SL8-specific CD8+ T lymphocytes are more effective than Gag181–189CM9-specific CD8+ T lymphocytes at suppressing simian immunodeficiency virus replication in a functional in vitro assay. J. Virol. 79, 14986–14991 (2005)

    CAS  Article  Google Scholar 

  19. 19

    Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Appay, V. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nature Med. 8, 379–385 (2002)

    CAS  Article  Google Scholar 

  21. 21

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

    CAS  Article  Google Scholar 

  22. 22

    Day, C. L. & Walker, B. D. Progress in defining CD4 helper cell responses in chronic viral infections. J. Exp. Med. 198, 1773–1777 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Trabattoni, D. et al. B7–H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. Blood 101, 2514–2520 (2003)

    CAS  Article  Google Scholar 

  24. 24

    Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Dorfman, D. M., Brown, J. A., Shahsafaei, A. & Freeman, G. J. 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)

    Article  Google Scholar 

  26. 26

    Brown, J. A. et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J. Immunol. 170, 1257–1266 (2003)

    CAS  Article  Google Scholar 

Download references


This work was supported by a Royal Society postdoctoral fellowship (C.L.D.), the Harvard University Center for AIDS Research (D.E.K. and B.D.W.), grants from the Doris Duke Charitable Foundation (B.D.W.), the NIH (B.D.W., G.J.F., R.A., P.J.R.G.), the Howard Hughes Medical Institute (B.D.W.); a grant from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative (G.J.F. and R.A.), a contract from the NIH (B.D.W.), and the Mark and Lisa Schwartz Foundation. We thank S. Chetty, N. Ismail, N. Mkhwanazi, K. Nair, A. Piechocka-Trocha, A. Rathod and M. Vanderstock for technical assistance.

Author information



Corresponding author

Correspondence to Bruce D. Walker.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This file contains Supplementary Figures 1–4 and Supplementary Table 1. These figures provide supporting data indicating that PD-1 expression is associated with functional impairment of HIV-specific CD8 T cells, and that PD-1 expression on HIV-specific CD8 T cells and total CD8 T cells is associated with viral load and absolute CD4 count. Supplementary Table 1 lists the MHC Class I tetramers used in this study. (PDF 1041 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Day, C., Kaufmann, D., Kiepiela, P. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006). https://doi.org/10.1038/nature05115

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing