T cell exhaustion is characterized by a progressive, hierarchical

T cell exhaustion is characterized by a progressive, hierarchical diminishment of CD8 T cell effector function, including loss of cytotoxic function, antiviral cytokine production, and proliferative capacity.4 Cellular phenotype and function associated with this phenomenon Cyclopamine datasheet have long been observed in chronic HCV infection.5 However, this potential mechanism of viral persistence has been of increasing interest over

recent years, because the inhibitory ligands that mediate this phenomenon have been described, and importantly, the ability of blockade of these negative signals to reverse virus-specific T cell dysfunction has been demonstrated. One of the initial inhibitory ligands described as characterizing exhausted T cells was programmed death-1 (PD-1), an inhibitory receptor belonging to the CD28 superfamily. Initial demonstration of this relationship was in a murine model of chronic viral infection, where blockade of interactions of PD-1 with its ligands was shown to improve function of virus-specific CD8 T cells and reduce viral load.6 Subsequently, PD-1 has been shown to be highly expressed on exhausted T cells isolated from patients infected with human

immunodeficiency Dabrafenib clinical trial virus (HIV) or HCV.7-9 In the context of HIV, it has been demonstrated that in vitro blockade of PD-1 signaling increased the proliferative potential Protein kinase N1 and antiviral activity of HIV-specific CD8 T cells.7 In addition, PD-1 blockade in vivo in simian immunodeficiency virus–infected macaques led to an expansion of and enhanced

functionality of simian immunodeficiency virus–specific CD8 T cells, with improved survival.10 However, whereas in vitro blockade of PD-1 signaling in HCV infection has been shown to restore effector function to peripheral HCV-specific CD8 T cells, blockade appeared insufficient to restore CTL function of intrahepatic HCV-specific CD8 T cells expressing high levels of PD-1, suggesting that PD-1 blockade alone is not sufficient to significantly correct T cell exhaustion in the context of chronic HCV infection.11 In addition to PD-1, a number of other inhibitory ligands have now been described as being associated with virus-specific CD8 T cell dysfunction in chronic HCV infection. Killer cell lectin-like receptor G1 (KLRG1), or CD161, is expressed by virus-specific CD8 T cells with diminished proliferative potential and reduced expression of cytotoxic mediators.12 Cytotoxic T lymphocyte antigen 4 (CTLA-4), an inhibitor of T cell activation, has been shown to be up-regulated on T cells in HIV infection, where dysfunctional HIV-specific CD4 but not CD8 T cells express increased levels of this ligand, and its in vitro blockade leads to an improvement in CD4 T cell proliferation as well as function.

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