Background & Aims: Recent studies have shown that programmed death 1 (PD-1) expression can impair virus-specific CD8 T-cell responses during chronic viral infection, including hepatitis B virus (HBV). This study aimed to characterize the PD-1 expression during acute hepatitis B (AHB) and further address whether and how the PD-1-mediated pathway balances antiviral immunity versus immunopathology, possibly contributing to disease progression. Methods: Peripheral and intrahepatic PD-1 expression was investigated longitudinally in 23 human HLA-A2-positive patients with acute hepatitis B. Four patients with HBV-related acute liver failure, 13 patients with chronic hepatitis B, and 9 healthy individuals were enrolled as controls. Flow cytometric, immunohistochemical, and immunofunctional assays were performed to analyze the impact of PD-1 expression. Results: PD-1 expression was significantly up-regulated on HBV-specific CD8 T cells in the early phase of acute HBV infection, and successful viral clearance correlated with a subsequent decrease in PD-1 expression. Blocking the PD-1-mediated pathway in vitro enhanced HBV-specific CD8 T-cell proliferation and inflammatory cytokine production, while reducing interleukin-10 production and apoptosis, confirming the essential role of PD-1 in tempering the T-cell response during the acute phase of infection. In contrast, delayed PD-1 expression on HBV-specific CD8 T cells was associated with acute liver failure. Conclusions: PD-1 up-regulation may efficiently mitigate pathogenic CD8 T-cell responses and liver damage, correlating with disease progression of acute HBV infection. This study therefore shows how this negative signaling pathway functions in such early HBV infection, which will be important for better clinical management, prognosis, and new HBV treatments.
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