Dysfunction of hepatitis B virus-specific CD8 T cells depends on viral load and is partially regulated by PD-1:PD-L1 interaction in a mouse model of persistent infection (P6123)

Abstract

Abstract The levels of functional impairment of CD8 T cells in chronic hepatitis B patients are correlated with viral loads, where the mechanisms underlying this dysfunction remain unclear. Taking advantage of a mouse model of chronic HBV infection mediated by adeno-associated viral vectors carrying HBV genome (AAV/HBV), we demonstrated that the function of HBV-specific CD8 T cells lost gradually during persistent infection with high viral load of AAV/HBV and was irreversible with therapeutic vaccination, while infection with low viral load resulted in a less extent of functional impairment, which was restored after vaccination. Consistently, CD8 T cells expressed increasing levels of inhibitory receptors in a viral load-dependent manner, especially programmed death 1 (PD-1). Furthermore, in PD-L1 KO mice infected with AAV/HBV, the levels of viral antigen decreased, concomitant with more potent function of specific CD8 T cells. However, the reduction maintained only in KO mice with low viral load, whereas the antigen levels rebounded in those infected with high load, suggesting the roles of other factors beyond PD-1:PD-L1 signaling pathway in regulating immune tolerance in chronic hepatitis B infection. Collectively, our data indicate that the viral load-dependent dysfunction of CD8 T cells induced in chronic HBV infection is partially regulated by inhibitory signal via PD-1, and blocking PD-1:PD-L1 alone may not be sufficient to rescue the immunity against persistent HBV infection.