Robust virus-specific CD8⁺ T cell responses are required for the clearance of hepatitis B virus (HBV). However, the factors that determine the magnitude of HBV-specific CD8⁺ T cell responses are poorly understood. To examine the impact of genetic variations of HBV on HBV-specific CD8⁺ T cell responses, we introduced three HBV clones (Aa_IND [Aa], C_JPN22 [C22], and D_IND60 [D60]) that express various amounts of HBV antigens into the livers of C57BL/6 (B6) (H-2b) mice and B10.D2 (H-2d) mice. In B6 mice, clone C22 barely induced HBV-specific CD8⁺ T cell responses and persisted the longest, while clone D60 elicited strong HBV-specific CD8⁺ T cell responses and was rapidly cleared. These differences between HBV clones largely diminished in H-2d mice. Interestingly, the magnitude of HBV-specific CD8⁺ T cell responses in B6 mice was associated with the HB core antigen expression level during the early phase of HBV transduction. Surprisingly, robust HBV-specific CD8⁺ T cell responses to clone C22 were induced in interferon-α/β receptor-deficient (IFN-αβR^–/–) (H-2b) mice. The induction of HBV-specific CD8⁺ T cell responses to C22 in IFN-αβR^–/– mice reflects enhanced HBV antigen expression because the suppression of antigen expression by HBV-specific small interfering RNA (siRNA) attenuated HBV-specific T cell responses in IFN-αβR^–/– mice and prolonged HBV expression. Collectively, these results suggest that HBV genetic variation and type I interferon signaling determine the magnitude of HBV-specific CD8⁺ T cell responses by regulating the initial antigen expression levels.

IMPORTANCE Hepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8⁺ T cell responses are required for the clearance of HBV. However, the relative contributions of genetic variation and innate immune responses to the induction of HBV-specific CD8⁺ T cell responses are not fully understood. In this study, we discovered that different clearance rates between HBV clones after hydrodynamic transduction were associated with the magnitude of HBV-specific CD8⁺ T cell responses and initial HB core antigen expression. Surprisingly, type I interferon signaling negatively regulated HBV-specific CD8⁺ T cell responses by reducing early HBV antigen expression. These results show that the magnitude of the HBV-specific CD8⁺ T cell response is regulated primarily by the initial antigen expression level.