298 SUSTAINED VIROLOGIC RESPONSE IN HIGH VIRAEMIC GENOTYPE-1 HCV INFECTION CORRELATES WITH PERIPHERAL HCV-SPECIFIC CYTOTOXIC RESPONSE RESTORATION

Abstract

Background and Aims: Programmed cell death-1 receptor (PD-1) plays pivotal roles in regulating host immune responses. This study aimed to characterize PD-1 expression in patients with HBVrelated acute-on-chronic liver failure (ACLF) and further evaluate its prognostic significance and functions associated with the disease progression. Methods: Sixty-four patients with HBV-related ACLF (Early, n = 23; Intermediate, n = 21; Late, n = 20) and twenty healthy controls (HC) were enrolled in this study. Flow cytometric, immunohistochemical and functional analyses were employed in the study. Results: Our study found that the expression of PD-1 on circulating CD8T cells was significantly upregulated in ACLF patients from early, intermediate to late stage. Both immunohistochemical staining and flow cytometric analyses revealed a further enhanced PD-1-expression in the liver compared with its counterparts in the peripheral blood in ALCF patients. Moreover, we found the expression of PD-L1, the ligand for PD-1, was also greatly enhanced on the hepatocytes. Correlation analysis with the clinical parameters showed that the expression of PD-1 on CD8T cells positively correlated with MELD Score (model for endstage liver disease) and aspartate aminotransferase (AST), and negatively correlated with prothrombin activity (PTA). Notably, longitudinal study showed that there were gradually decreased PD1-expressions on CD8T cells in patients with improved prognosis, compared with sustained or even increased expressions in those with poor prognosis. Furthermore, the expression of several common g-chain cytokines, including IL-2, IL-7 and IL-15, were greatly upregulated in the liver of ACLF patients, which would contribute to the upregulation of PD-1 on CD8T cell. To evaluate the function of PD-1 on CD8T cells, the in-vitro assays showed that blocking PD-L1 could revitalize the abilities of CD8T cells in cytokine-secretion and proliferation. Conclusions: PD-1 upregulation could mitigate pathogenic CD8Tcell responses, whereas sustained overexpression of PD-1 on CD8T cells is associated with poor prognosis, indicating an uncontrollable immune injury in the liver of ACLF patients. Therefore, PD-1 expression on CD8-T cells could serve as a potential prognostic marker for patients with HBV-related ACLF, which would be valuable for better clinical management and new therapy development.