The present situation and prospect of research on HBeAg-negative mouse model

Abstract

Hepatitis B virus (HBV) infection is one of the important causes of global liver disease. There are about 250 million patients infected with hepatitis B virus in the world. Chronic HBV infection will lead to liver fibrosis, liver cirrhosis (LC) and even hepatocellular carcinoma (HCC). HBV is a partially double-stranded circular 3.2 kb DNA virus containing four overlapping open reading frames that encode HBsAg, HBeAg, HBcAg, HBV polymerase and HBx protein, respectively. Once HBV particles interacting with sodium taurocholate cotransporting polypeptide (NTCP) on the cell membrane, the nucleocapsid is released into cytoplasm. Subsequently, relaxed circular DNA (rcDNA) is converted to covalently closed circular DNA (cccDNA) in the nucleus, then forms stable minichromosome in the existence of histone and nonhistone proteins. The nucleocapsid can either assemble with viral envelope and released as mature HBV particles or transport back to the nucleus to refill the cccDNA pool. HBV cccDNA serves as a template for viral mRNA synthesis. Persistence of cccDNA is the major course that HBV is hard to eliminate and relapses after drug withdrawal. Though current approved drugs have made huge progress in suppressing viral replication, completely eliminating HBV remains a challenge. The natural history of chronic hepatitis B (CHB) may go through four phases, including the immune tolerant, the immune clearance, the inactive or non-replicative and the re-activation or immune escape phases. During the first two phases the patient is hepatitis B e antigen (HBeAg) positive. On the contrary, during the last two phases the patient is HBeAg-negative. Most infected patients that are HBeAg-negative is usually associated with HBV gene dual mutations of ntA1762T/G1764A and mutation of ntG1896A leading to reduce or HBeAg-negative in basic core promoter (BCP) and PreC region, respectively. The prevalence of HBeAg-negative patients is likely to vary across geographic areas. In recent years, HBeAg-negative patients are increasing globally. Compared with HBeAg-positive patients, HBeAg-negative patients have the following clinic characteristics: More complex course of disease, lower sustained response rate to antiviral drugs and more likely to develop into end-stage liver disease. The mechanism research and drug treatment on HBeAg-negative infection are seriously hampered by the absence of ideal animal model: Simple and efficient transduction method, long-term cccDNA, and model animal with normal immunological function. So far, there have been numerous studies on mouse models of CHB, but few reports about HBeAg-negative mouse models. It is of great significance to study disease mechanisms and develop therapeutic drugs of HBeAg-negative CHB infection using HBeAg-negative CHB mouse model with cccDNA and normal immunological function. In this paper, we have briefly reviewed the research status and application prospect of the model.