A Second Wind for T Cells

Abstract

One of the mysteries of human immunodeficiency virus (HIV) infection is why the cellular immune response fails to clear the infection (see Rowland-Jones and Dong). Noting recent research implicating up-regulation of the inhibitory cell surface receptor programmed death 1 (PD-1) and production of functionally impaired "exhausted" virus-specific T cells in chronic infection of mice with lymphocytic choriomeningitis virus (LCMV), Day et al . investigated the role of PD-1 signaling in HIV infection. In people with chronic, untreated HIV infection, PD-1 expression was increased in CD8 + T cells that specifically recognize HIV antigens. Increased PD-1 expression was associated with increased viral load and decreased CD4 + T cell count. Antiretroviral therapy, which decreased viral load (and antigen exposure), led to a decrease in PD-1 expression. There was an inverse relation between PD-1 expression and the proliferative response of HIV-specific T cells to HIV peptides, indicating greater functional exhaustion. Intriguingly, incubation of peripheral blood mononuclear cells with blocking antibodies directed against PD-1 ligands enhanced both the proliferative response to HIV peptides and interferon-γ production. Similarly, increased PD-1 expression on CD4 T + cells was associated with increased viral load and decreased CD4 + T cell count, and incubation with antibody against PD-1 ligand 1 enhanced proliferation in response to an HIV protein. Thus, the authors concluded that chronic HIV infection was associated with up-regulation of PD-1 on HIV-specific T cells, that this up-regulation was associated with impaired T cell function, and that blocking PD-1 activation might enhance the ability of T cells to control HIV. Trautmann et al . had similar findings and came to similar conclusions in a separate study. C. L. Day, 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. R. Goulder, P. Klenerman, R. Ahmed, G. J. Freeman, B. D. Walker, PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443 , 350-354 (2006). [PubMed] L. Trautmann, 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, R.-P. Sekaly, Upregulation of PD-1 expression on HIV-specific CD8 + T cells leads to reversible immune dysfunction. Nature Med. , published online 20 August 2006 (doi:10.1038/nm1482). [PubMed] S. Rowland-Jones, T. Dong, Tired T cells turn around. Nature 443 , 282-283 (2006). [PubMed]