In line with their transient reconstitution,

these populations continued to express high levels of CTLA-4 and Bim. The lack of reversal of their proapoptotic phenotype in the face of effective suppression of circulating HBV DNA may reflect the inability of antiviral therapy to adequately switch off intrahepatic production of covalently closed circular (cccDNA), manifested in high residual serum HBsAg levels. Patients in this study were only followed for a maximum of 18 months after the initiation of therapy; it will be important in future studies to assess whether there is more effective T-cell reprogramming in at least a subset of patients after more prolonged treatment. The lack of sustained off-treatment responses generally seen in CHB, accompanied by the ineffective T-cell reprogramming MLN2238 nmr that we observed, point to the need for Alisertib solubility dmso a more directed therapeutic approach. We therefore investigated the potential to rescue HBV-specific CD8 T cell responses in vitro, using the approach of mAbs blocking the CTLA-4 receptor already used in human cancer trials.16 The fact that this was able to increase the expansion of functional HBV-specific

responses in a number of patients supports a role for CTLA-4 in T-cell exhaustion in CHB. However, in some cases in the large cohort examined, a lack of detectable T-cell reconstitution upon CTLA-4 blockade is likely to reflect a dominant role for other coinhibitory pathways. This is supported by our data showing nonredundant roles for the CTLA-4 and PD-1 pathways in the T-cell tolerance of CHB, with a similar number of patients only responding to blockade of one or other pathway and some responding synergistically to dual blockade. Complementary roles for different coinhibitory pathways have been recently highlighted in the LCMV model,23 in HCV,9 and in HIV, where another coinhibitory molecule, Tim-3, was found to

be expressed on largely nonoverlapping T-cell populations to those expressing PD-1.24 It remains to be determined whether the contribution of different coinhibitors is stochastic or is predictable medchemexpress from the baseline expression of these receptors on HBV-specific T cells in different patients, such that the selection of blocking strategies could be individually tailored. Our findings suggest that whereas CTLA-4 may promote exhaustion of HBV-specific CD8, it may also serve as a brake on liver inflammation through its increased expression on CD8 of other specificities. Recent work has highlighted the critical role for CTLA-4-expressing antigen-specific effector T cells in regulating peripheral tolerance after secondary encounter with antigen in target tissues.15 Restoration of effective antiviral immunity through blockade of CTLA-4 may therefore be at the expense of control of collateral tissue damage, emphasizing the need for a targeted therapeutic approach.25 In summary, we demonstrate a contributory role for CTLA-4 in driving Bim-dependent apoptosis of the antiviral response in CHB.