The direct effect of type I IFN on CD8+ T cells also occurs in other viral infections.23 Type I IFNs also promote IL-15 production, which is a CD8+ T-cell survival factor24 and plays a critical role in stimulating and maintaining memory CD8+ T cells.23 Type I IFN and IL-12 are also involved in memory CD8+ T-cell development.25 Whether dually functional vector influences HBV-specific CD8+ memory T-cell generation needs further investigation. CD8+ T cells play

a critical role in HBV clearance.3 Intrahepatic HBV-specific CD8+ T cells are required for rapid viral clearance during acute HBV infection. Several HBV-specific CD8+ T-cell cytokines, such as IFN-γ and TNF-α, are essential for suppressing HBV gene expression and replication.3 However, in CHB patients http://www.selleckchem.com/products/MK-2206.html the inhibitory PD-1 receptor is up-regulated on both peripheral blood selleck compound mononuclear cells (PBMCs) and intrahepatic lymphocytes,

particularly on HBV-specific CD8+ T cells, where PD-1 interaction with PD-L1 ligand on APCs results in functional suppression and apoptosis of CD8+ T cells.26 This loss of function is known as “T-cell exhaustion” that is common during persistent viral infection, including human immunodeficiency virus (HIV), HBV, and HCV infection. In the present study, we observed that immunotolerance in chronic HBV-carrier mice correlated with decreased hepatic CD8+ T-cell percentage and number (Fig. 1D), including IFN-γ+ and HBc-specific CD8+ T cells (Fig. 1F,G), as well as higher PD-1

expression (Fig. 1E) and augmented serum TGF-β and IL-10 (Fig. 1C). Treatment with ssRNA-shRNA dually functional vector reversed this immunotolerance. More important, CD8+ T cells were necessary for dual-vector-mediated HBV inhibition (Fig. 6A-C). In addition, NK cells may also be involved in dual-vector-mediated HBV inhibition, for NK cell-depletion partly attenuated dual-vector-mediated HBV suppression (Fig. 5A,B). Increasing data have shown that NK cells play an important role in clearance of HBV, especially Ureohydrolase in the early stage of infection. HBV persistence impairs NK cell function possibly by elevated TGF-β1 through down-regulation of NKG2D/DAP10 and 2B4/SAP expression.27 The dual-vector therapy might release the impairment of NK cell function by both reducing HBV load and arousing activation stimulated by increased type I IFN. The decreased TGF-β1 after dual-vector therapy may also contribute to restoring NK cell function. PRRs play critical roles in defense against invading pathogens by way of recognition of pathogen-associated molecular patterns (PAMPs). Therapeutic strategies that incorporate both PRR activation and target-gene silencing have promising potential to treat cancer and viral infections. Poeck et al.