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PURPOSE OF THE STUDIES. Recent evidence from a mouse model of chronic viral infection suggests a crucial role for the programmed death 1 (PD-1)/programmed death 1 ligand (PD-L1) signaling pathway in downregulating the functions of virus-specific CD8+ T cells. PD-1 is an inhibiting receptor that negatively regulates activated T cells, and it is markedly upregulated on the surface of “exhausted” virus-specific CD8+ T cells in mice. HIV similarly induces a virus-specific impairment of T-cell functions. The purpose of these 2 studies was to investigate the expression of PD-1 on HIV-specific T cell in patients infected with the virus.
STUDY POPULATION AND METHODS. Both studies evaluated subjects with HIV and healthy controls and compared PD-1 expression in these individuals on virus-specific T cells. A panel of MHC class I tetramers were used to identify HIV-specific CD8+ T cells. PD-1 expression was then measured on tetramer-positive cells. PD-1 expression was also analyzed on cytomegalovirus-specific, Epstein-Barr virus–specific, and vaccinia virus–specific CD8+ T cells from HIV-negative controls.
RESULTS. The findings in these studies were remarkably similar. PD-1 was significantly upregulated on HIV-specific T cells, and expression correlated with impaired HIV-specific CD8+ T-cell function as well as predictors of disease progression: HIV viral load, a reduced capacity for cytokine production, and decreased proliferation of HIV-specific CD8+ T cells. Cytomegalovirus-specific CD8+ T cells from the same donors did not upregulate PD-1 and seemed to maintain functional integrity. Blockade of the PD-1/PD-1L pathway result reversed immune dysfunction.
CONCLUSIONS. The PD-1/PD-1L pathway is associated with significant HIV-specific T-cell exhaustion. The accumulation of HIV-specific dysfunctional T cells in an infected host may prevent the renewal of a functionally competent HIV-specific CD8+ T-cell response.
REVIEWER COMMENTS. HIV has proven remarkably adept at inhibiting the very system that evolved to control it. Expression of a negative regulator of activated T cells, PD-1, is markedly increased on HIV-specific CD8+ T cells when HIV engages the T-cell receptor. Such T cells have been termed “exhausted” because they fail to respond as fully activated effector cytotoxic T cells. Surprisingly, blockade of PD-1 engagement with its ligand results in a restoration of T-cell function. This observation suggests a target for enhancing the function of exhausted T cells in HIV-infected individuals. However, much has to be learned about the importance of this pathway in the control of normal T-cell activation. T-cell activation seems to be an intrinsic component of HIV pathogenesis; therefore, blocking this activation may be useful. However, it would be potentially dangerous to be unable to turn off an activated immune response to a routine infection.
- Copyright © 2007 by the American Academy of Pediatrics