Hepatitis B virus core antigen determines viral persistence in a C57BL/6 mouse model

• DOI: 10.1073/pnas.1004762107
• Publication Date: 2010-05-04T02:02:58Z
• Authors: Yi-Jiun Lin; Li-Rung Huang; Hung-Chih Yang; Horng-Tay Tzeng; Ping-Ning Hsu; Hui-Lin Wu; Pei-Jer Chen; Ding-Shinn Chen
• Keywords: Male; 0303 health sciences; Blotting, Northern; Hepatitis B; Virus Replication; Hepatitis B Core Antigens; 3. Good health; Mice, Inbred C57BL; Blotting, Southern; Interferon-gamma; Mice; 03 medical and health sciences; Liver; Animals; Amino Acid Sequence; Sequence Deletion

We recently developed a mouse model of hepatitis B virus (HBV) persistence, in which a single i.v. hydrodynamic injection of HBV DNA to C57BL/6 mice allows HBV replication and induces a partial immune response, so that about 20–30% of the mice carry HBV for more than 6 months. The model was used to identify the viral antigen crucial for HBV persistence. We knocked out individual HBV genes by introducing a premature termination codon to the HBV core, HBeAg, HBx, and polymerase ORFs. The specific-gene-deficient HBV mutants were hydrodynamically injected into mice and the HBV profiles of the mice were monitored. About 90% of the mice that received the HBcAg-mutated HBV plasmid exhibited high levels of hepatitis B surface antigenemia and maintained HBsAg expression for more than 6 months after injection. To map the region of HBcAg essential for viral clearance, we constructed a set of serial HBcAg deletion mutants for hydrodynamic injection. We localized the essential region of HBcAg to the carboxyl terminus, specifically to the 10 terminal amino acids (HBcAg176–185). The majority of mice receiving this HBV mutant DNA did not elicit a proper HBcAg-specific IFN-γ response and expressed HBV virions for 6 months. These results indicate that the immune response triggered in mice by HBcAg during exposure to HBV is important in determining HBV persistence.