Precise analysis of the effect of basal core promoter/precore mutations on the main phenotype of chronic hepatitis B in mouse models

High replication and mutation rates of hepatitis B virus (HBV) often lead to reduced or suppressed hepatitis B e antigen expression. The most common mutations are genomic variations in the basal core promoter (BCP) and pre‐core (PC) regions. However, the effect of BCP/PC mutations on HBV phenotype i...

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Bibliographic Details
Published in:Journal of medical virology 2020-12, Vol.92 (12), p.3412-3419
Main Authors: Liu, Yang, Zhao, Zhong Hua, Lv, Xiao Qin, Tang, Yu Wei, Cao, Min, Xiang, Qin, Wu, Yue, Zhang, Hua Tang, Lai, Guo Qi
Format: Article
Language:English
Subjects:
Alanine
Alanine transaminase
Alanine Transaminase - blood
Animal models
Animals
Antigens
basal core promoter
cccsDNA
chronic hepatitis B
Chronic infection
Deoxyribonucleic acid
Disease Models, Animal
DNA
DNA, Viral - blood
DNA, Viral - genetics
Gene expression
Genomics
Genotype & phenotype
Hepatitis
Hepatitis B
Hepatitis B e antigen
Hepatitis B e Antigens - blood
Hepatitis B e Antigens - genetics
Hepatitis B surface antigen
Hepatitis B Surface Antigens - blood
Hepatitis B Surface Antigens - genetics
Hepatitis B virus - genetics
Hepatitis B, Chronic - genetics
Hepatitis B, Chronic - virology
Immune response
Injection
Interferon
Interleukin-10 - genetics
Interleukin-4 - genetics
Interleukins
Male
Medical treatment
Mice
Microprocessors
Mouse devices
Mutation
Mutation rates
Phenotype
Phenotypes
pre‐core mutations
Promoter Regions, Genetic
Replication
Transfection
Virology
Viruses
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Summary:High replication and mutation rates of hepatitis B virus (HBV) often lead to reduced or suppressed hepatitis B e antigen expression. The most common mutations are genomic variations in the basal core promoter (BCP) and pre‐core (PC) regions. However, the effect of BCP/PC mutations on HBV phenotype in vivo remains unclear. We compared and analyzed BCP/PC mutations and BCP/PC reverse mutations in mouse models. In addition to terminating the expression of HBeAg, BCP/PC mutations also resulted in a significant decrease in HBsAg, HBV DNA, and cccDNA in the early stage, and an obvious increase in serum alanine aminotransferase throughout the transfection period. In both groups, serum HBV DNA was positively correlated with intracellular HBV DNA and cccDNA. Further, we found that interleukin‐4 (IL‐4) and L‐10 levels were significantly lower in the BCP/PC(M) group than in the BCP/PC(R) group at 4 weeks post‐injection. However, IL‐1β was significantly lower in the BCP/PC(M) group than in the BCP/PC(R) group at 26 weeks post‐injection. In summary, we precisely analyzed the effect of BCP/PC mutations on the phenotype in vivo, which is important to evaluating disease progression and treatment responses of variable chronic hepatitis B patients. Highlights BCP/PC(M) and BCP/PC(R) chronic hepatitis B mouse models were established successfully by injecting two kinds of cccDNA. The HBV markers, including HBsAg, HBeAg, HBcAg, HBV DNA, and cccDNA in serum and/or in the liver could persist for at least 26 weeks. BCP/PC mutations resulted in a decrease in HBsAg, HBV DNA, cccDNA in the early stage, and an increase in serum ALT throughout the transfection period. HBV DNA in the serum could better respond to viral replication and cccDNA status in vivo. BCP/PC mutations contributed to an inefficient immune response in the late stages of chronic infection.
ISSN:0146-6615
1096-9071
DOI:10.1002/jmv.26025