Heterogeneity of hepatitis B virus (HBV) core gene in a patient with HBV-associated cirrhosis and serum negativity for anti-HBc

Abstract

Aims: We describe here the case of a patient suffering from severe chronic hepatitis B associated with an unusual hepatitis B virus serology: HBsAg and HBeAg were both positive while anti-HBc was negative by radioimmunoassay.

Methods: A very sensitive anti-HBc ELISA (IMx CORE) was performed and was able to detect anti-HBc sporadically throughout the clinical course. Molecular characterization of hepatitis B virus strains in this patient enabled us to explain this particular serological and clinical pattern of hepatitis B virus infection.

Results: Hepatitis B virus genotype determined by size polymorphism of the core gene and the pre-S region was found to be D/E and consistent with the results of serological subtyping (HBV ayw2-4). DNA sequence analysis of the pre-C/C region showed the presence of significant nucleotide changes. In association with a wild type hepatitis B virus strain, we could detect at least four hepatitis B virus variants with nucleotide deletions leading to a frameshift in the core gene. According to the position of the mutations, these hepatitis B virus core variants are expected to be defective for B-cell epitopes and TH-cell epitopes.

Conclusions: These mutations explain the low level production of anti-HBc antibody. It is noteworthy that the absence of detectable anti-HBc in serum was associated with severe liver damage, suggesting that the deficient humoral response to HBcAg was not accompanied by a cellular immune tolerance to HBc/eAg, the supposed target for cytotoxic T-cell lysis.