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Comparison of envelope and precore/core variants of hepatitis B virus (HBV) during chronic HBV infection
M Takayanagi1, S Kakumu, T Ishikawa
1Third Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Insights
Active hepatitis B virus (HBV) infection promotes viral gene mutations, particularly in the pre-S/S and pre-C/C regions. Defective HBV strains are often selected after hepatitis B e antigen (HBeAg) loss, suggesting immune selection of viral mutants.
Area of Science:
- Virology
- Hepatology
- Molecular Biology
Background:
- Chronic hepatitis B virus (HBV) infection is a global health concern.
- Understanding HBV genetic variability during chronic infection is crucial for disease management.
Purpose of the Study:
- To analyze genetic variations in pre-C/C and pre-S/S coding genes of HBV in chronic carriers.
- To investigate the relationship between hepatitis activity, HBeAg status, and HBV genetic mutations.
Main Methods:
- Analysis of serial serum samples from four chronic HBV carriers over 4-5 years.
- Polymerase chain reaction (PCR) amplification, cloning, and sequencing of HBV pre-C/C and pre-S/S genes (subtype adr).
- Comparison of amino acid divergence rates between patients with chronic active hepatitis and asymptomatic carriers.
Main Results:
- Patients with chronic active hepatitis showed significantly higher amino acid divergence rates in pre-C/C and pre-S/S regions compared to asymptomatic carriers.
- Deletions in the C and pre-S1 genes were observed in patients after becoming negative for hepatitis B e antigen (HBeAg).
- The pre-S/S region exhibited greater divergence than the pre-C/C region in both patient groups.
Conclusions:
- Active hepatitis induces significant variation in HBV genes, with defective viruses often selected after HBeAg disappearance.
- Patients with active liver disease harbor more viral mutant clones, suggesting immune selection plays a role in viral evolution.
- Genetic mutations in HBV may be linked to disease progression and persistence in chronic carriers.
Abstract:
We analyzed entire pre-C/C and pre-S/S coding genes of hepatitis B virus (HBV) in serial serum samples from four chronic HBV carriers with 4-5 years of follow-up. Two patients with chronic active hepatitis became seronegative for HB e antigen (HBeAg), but the hepatitis did not subside, while the other two were persistent asymptomatic carriers with normal aminotransferase values. DNAs amplified by PCR were cloned and sequenced (subtype adr). After HBeAg became negative, one patient had 96-183 bp deletions in 4/6 clones for C gene. In addition, both patients had 129-183 bp deletions in 3/6 and 2/5 clones for pre-S1 gene, respectively. Divergence rate of deduced amino acid for both pre-C/C and pre-S/S regions from the adr subtype was significantly higher in patients with chronic hepatitis than in asymptomatic carriers. Furthermore, the divergence rate for pre-S/S region was usually greater in asymptomatic carriers as well as chronic hepatitis patients compared with that for pre-C/C region. However, no significant difference was found in the rate of amino acid divergence for the entire HBV genes between the serial samples in all patients studied here. These results suggest that active hepatitis induces variation of HBV gene and defective virus is often selected along with the disappearance of HBeAg. In addition, the fact that patients with active liver disease possess greater numbers of mutant clones than asymptomatic carriers suggests that viral mutants are being immune-selected.