Hepatitis B Virus e Antigen Variants

Abstract

More than 300 million people worldwide are chronically infected with hepatitis B virus (HBV). Considering the very short generation time for a virus, and the high error rate associated with the reverse transcription step of HBV replication, decades of HBV infection are probably equivalent to million years of human evolution. The most important selective force during the natural course of HBV infection appears to be the immune response. The development of anti-HBe antibody in hepatitis B patients usually correlates with reduction of HBV viremia. As a consequence, escape mutants of anti-HBe are selected. The core promoter mutants express less HBe antigen (HBeAg) through transcriptional down regulation, while precore mutants express truncated products. We recently identified additional mutations that modulate HBeAg translation initiation, proteolytic cleavage, and secondary structure maintenance through a disulfide bond. The core promoter mutants have been associated with the development of fulminant hepatitis during acute infection and liver cancer during chronic infection. Consistent with their enhanced pathogenicity, core promoter mutants were found to replicate at up to 10-fold higher levels in transfected human hepatoma cells than the wild-type virus. Moreover, some core promoter mutants are impaired in virion secretion due to missense mutations in the envelope gene. These virological properties may help explain enhanced pathogenicity of core promoter mutants in vivo.

Figure 1

Disappearance of HBeAg and rise of anti-HBe is associated with decline in viremia titer and replacement of wild-type HBV by the core promoter mutants and/or precore mutants. However, the core promoter mutants become prevalent even before the rise of anti-HBe.

Figure 2

Expression of core protein and HBeAg. Core protein is translated from pregenomic mRNA, using the ATG codon at 1901 as initiation site. HBeAg is translated from the precore mRNA, using ATG at 1814. The primary translation product is cleaved at the N-terminus by the signal peptidase and in the C-terminus by a basic endopeptidase before secretion into the blood stream. The G1896A nonsense mutation in the precore region specifically prevents translation of HBeAg.

Figure 3

Expression of three co-terminal envelope proteins of the HBV through three in-frame ATG codons and two subgenomic RNA species: 2.4 kb and 2.1 kb transcripts. The 2.4 kb RNA produces the large envelope protein, while the 2.1 kb RNA has heterogeneous 5' ends to allow the expression of middle or small envelope protein. Both large and small envelope proteins have glycosylated and nonglycosylated versions, while the middle protein has monoglycosylated and doubly glycosylated forms.