Dysfunctional CD8؉ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8؉ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.Quantitative and qualitative impairments of virus-specific T cells are present in different chronic viral infections, in both humans and mice. The persistent exposure to viral antigens can lead to virus-specific T-cell deletion or to progressive functional impairment. Recent data show that these exhausted T cells hyperexpress the programmed death 1 (PD-1) molecule (8,14,19,23) and that blocking the engagement of PD-1 with its ligand (PD-L1) leads to an enhancement of the antiviral functions of these T cells (1,7,23,30,32). The characterization of the functional defects of virus-specific T cells in patients with chronic hepatitis B virus (HBV) infection, a condition that affects 350 million people worldwide, is still largely incomplete and often based on an oversimplified dichotomy between patients who control acute infection and subjects with established chronicity. While it is well documented that patients who succeed in resolving HBV infection express a vigorous and functionally efficient HBV-specific T-cell response (9,12,13,15,21,29), the degree of HBV-specific T-cell impairments which affect chronically infected patients has so far been only partially analyzed with small groups of patients by using a limited set of well-characterized HLA-A2-restricted epitopes (3,18,21,25,27,28,34) or by focusing mainly on HLA class II-restricted responses targeting HBV structural antigens (9, 11-13, 17, 26, 31).To overcome these limitations, we performed a longitudinal study of HBV-specific T-cell responses by using pools of overlapping peptide...
