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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 20; pp. 9340 - 9345
• Main Authors: Lin, Yi-Jiun, Huang, Li-Rung, Yang, Hung-Chih, Tzeng, Horng-Tay, Hsu, Ping-Ning, Wu, Hui-Lin, Chen, Pei-Jer, Chen, Ding-Shinn
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.05.2010; National Acad Sciences
• Subjects: Amino Acid Sequence; Amino acids; Animals; Antigens; Biological Sciences; Blotting, Northern; Blotting, Southern; Chronic hepatitis; Deoxyribonucleic acid; DNA; Genes; Hepatitis; Hepatitis antigens; Hepatitis B; Hepatitis B - genetics; Hepatitis B - immunology; Hepatitis B - virology; Hepatitis B Core Antigens - genetics; Hepatitis B Core Antigens - immunology; Hepatitis B Core Antigens - metabolism; Hepatitis B virus; Hydrodynamics; Infections; Interferon-gamma - immunology; Liver; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mutation; Plasmids; Rodents; Sequence Deletion; Virus Replication - genetics; Virus Replication - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1004762107

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.