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Posted: 27 Oct 2011
30 years in 30 weeks, 2006

Immunologists have known for some time that chronic infections, such as HIV infection, differ from acute infections. After prolonged exposure, the immune system becomes less reactive to the pathogen, a state known as “exhaustion”. Following up on studies performed in the mouse model of chronic infection, Walker et al. uncovered a molecular mechanism underlying immune exhaustion, which has opened the door to potential interventions that may help restore the immune system back to a more functional state.

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
Nature. 2006 Sep 21;443(7109):350-4. Epub 2006 Aug 20.
Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD.

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Commentary by Dr.Bruce Walker

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Dr. Bruce Walker
A major challenge in the HIV field has been to understand why the strength of virus-specific CD8 T cell responses has no relationship to viral load, and yet CD8 depletion studies indicate that these cells are critical for immune control.  And a major challenge in the field of immunology in general has been the rapid translation of advances in murine models to humans.  In late 2005, through a telephone conversation with Rafi Ahmed, we became aware of yet unpublished data in the mouse model of chronic infection.  His laboratory had shown that  in mice persistently infected with LCMV, T cells up-regulate a surface molecule termed PD-1, for programmed death-1, a negative immunoregulatory molecule that turned off CD8 T cell function.  The potential parallels with HIV were immediately obvious to us—perhaps persistent exposure to HIV was having a similar impact on CD8 T cell function in humans, and perhaps similar immune regulation was rendering CD4 T cells exhausted as well.

We immediately formed a collaboration, obtaining antibody to PD-1 from Gordon Freeman, and launched a series of studies.  Given that we were trying to determine a relationship between PD-1 expression and viral load, these were ideal experiments to conduct at the heart of the HIV epidemic in KwaZulu Natal, in South Africa.  The murine data were published in Nature in early 2006 (Barber et al., 2006), the first study to identify a molecular pathway contributing to T cell dysfunction in chronic viral infection.  By that time, we already had preliminary data from patients in South Africa showing that there was a negative association between viral load and PD-1 expression on HIV-specific CD8 T cells.  These results indicated that the mechanism of T cell dysfunction identified in mice was also present in humans.

Over the ensuing months, we expanded these studies and analyzed CD4 T cell responses to HIV as well.  These data resulted in a paper entitled ‘PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression’, wherein we demonstrate the critical and reversible role played by the inhibitory receptor PD-1 in HIV-specific CD8 and CD4 T cell exhaustion (Day et al., 2006).  By measuring expression of PD-1 on HIV-specific CD8 T cells in adults with chronic clade C HIV infection in the Sinikithemba Cohort in South Africa, we were able to finally link CD8 T cells to disease outcome.  We found that PD-1 expression is significantly upregulated on HIV-specific CD8 T cells, and its expression correlates with impaired HIV-specific CD8 T cell function as well as with predictors of HIV disease progression: positively with plasma viral load and inversely with CD4 T cell count.  Moreover, blockade of the PD-1 binding to its ligand PD-L1 augmented HIV-specific T cell function, just as had been seen in mice infected with LCMV.   Similar results were reported by two other groups (Petrovas et al., 2006; Trautmann et al., 2006), firmly establishing a role for PD-1 in CD8 T cell exhaustion.  On CD4 T cells PD-1 expression correlated positively with viral load and an inversely with CD4 T cell count, indicating that this pathway was of broader importance.  These findings were the first to identify a pathway of reversible T cell impairment that may serve as a potential target for enhancing the function of exhausted T cells in humans with chronic HIV infection. 

The impact of these murine and human findings extend far beyond the field of HIV: the role of PD-1 was also demonstrated in other important human chronic viral infections such as hepatitis B and C, as well as in persistent parasitic and bacterial infections.  Recent studies in SIV-infected macaques indicate enhanced T cell immunity and reduced plasma viral load following PD-1 blockade in vivo, thus providing further rationale for targeting the PD-1 pathway as a novel therapeutic approach in controlling HIV infection in humans. Carefully designed studies are required to determine the potential benefit of PD-1 blockade in HIV-infected individuals, as this molecule is also a regulator of immune responses in physiological conditions.  The first clinical trials of PD-1 blockade in HIV-infected individuals are now in the planning phase.  

Overall, these findings have stood the test of time, as they have served as a platform to launch numerous currently ongoing studies that are seeking to further define key molecules in the PD-1 signaling pathway, and to identify new immunoregulatory networks that contribute to T cell exhaustion in chronic infections. These studies have revealed a complex interplay of multiple immunoregulatory pathways that work together to influence the functional capacity of antigen-specific T cells and disease outcome. Further work will provide important insights into mechanisms of immune regulation in chronic infections, and focus potential therapeutic approaches to enhance immunity and improve disease outcome.

  • Barber, D.L., E.J. Wherry, D. Masopust, B. Zhu, J.P. Allison, A.H. Sharpe, G.J. Freeman, and R. Ahmed. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682-687.
  • Day, C.L., D.E. Kaufmann, P. Kiepiela, J.A. Brown, E.S. Moodley, S. Reddy, E.W. Mackey, J.D. Miller, A.J. Leslie, C. DePierres, Z. Mncube, J. Duraiswamy, B. Zhu, Q. Eichbaum, M. Altfeld, E.J. Wherry, H.M. Coovadia, P.J. Goulder, P. Klenerman, R. Ahmed, G.J. Freeman, and B.D. Walker. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350-354.
  • Petrovas, C., J.P. Casazza, J.M. Brenchley, D.A. Price, E. Gostick, W.C. Adams, M.L. Precopio, T. Schacker, M. Roederer, D.C. Douek, and R.A. Koup. 2006. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. The Journal of experimental medicine 203:2281-2292.
  • Trautmann, L., L. Janbazian, N. Chomont, E.A. Said, S. Gimmig, B. Bessette, M.R. Boulassel, E. Delwart, H. Sepulveda, R.S. Balderas, J.P. Routy, E.K. Haddad, and R.P. Sekaly. 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature medicine 12:1198-1202.

About the Author: Dr. Bruce Walker is a Professor of Medicine at Harvard Medical School, a Howard Hughes Medical Institute Investigator, and Director of the Ragon Institute of MGH, MIT and Harvard.

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