Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection

Abstract

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...

Effects of antiviral therapy on the cellular immune response in patients with chronic hepatitis B

“…The independent effect of the length of HBV DNA suppression on specific immune response, found in this study, was partly in accordance with previous studies (16,17). It is widely hypothesized that the T-cell function exhaustion of CHB patients occurs because of the prolonged exposure of T cells to high quantities of viral antigens and that T-cell resting from antigenic stimulation is a crucial requirement for restoration of a functional antiviral T-cell response (3,5,9,18). In this study, the results demonstrated a negative correlation between HBV-DNA levels and HBV-specific CTL responses in untreated CHB patients.…”

“…The permanent suppression of HBV replication following treatment requires a robust acquired immune response against the HBV core and envelope antigens (5). There is evidence that antiviral therapy alters the balance between host immunity and viral replication, enabling weakened virus-specific immune responses to strengthen, broaden, and possibly control the infection, probably due to the decreased HBV antigen levels allowing the recovery of the T-cell response (6)(7)(8)(9). This mechanism may be important in contributing to complete recovery from CHB.…”

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

“…6,39,40 We made a similar observation when incubating total splenocytes isolated from wild-type (WT), but not PD-L1 knockout (KO) mice with anti-PD-L1 antibody (Figure 3a; compare lanes 1–2 and 3–4 in Figure 3b), thus demonstrating antibody specificity. However, co-culture of WT splenocytes with WT adipocytes significantly dampened the anti-PD-L1 antibody effect on CD8 + IFNγ + T cells (compare lanes 1–2 and 5–6 in Figure 3b).…”

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

“…5 Increasing evidence demonstrates that upregulation of the PD-1 inhibitory receptor mediates HIV-specific CD8 1 T-cell functional exhaustion and CD8 1 T cell is apoptosis-sensitive, resulting in an impairment of CD8 1 T cell's ability to control virus replication. [6][7][8][9] Involvement of the PD-1 pathway has also been shown during hepatitis B and C virus infection [10][11][12][13] with PD-L1 expression demonstrated in situ on a wide variety of solid tumors including pancreas, lung, ovarian and bladder tumors. [14][15][16][17][18] Studies relating PD-L1 expression on tumors to disease outcome show that PD-L1 expression strongly correlates with unfavorable prognosis in kidney, bladder, gastric and pancreatic cancer.…”