title: Impact of viral genotypes and naturally occurring mutations on biological properties of hepatitis B virus.
abstract: Hepatitis B patients worldwide are infected with different viral genotypes. Within the same individual the dominant viral species evolves over the course of chronic infection to generate viral variants or mutants. The mutations, often selected by the host immune response or antiviral therapy, are sometimes restricted by viral genotypes. We are interested in characterizing mutations that affect the expression of hepatitis B e-antigen (HBeAg), a protein with a large effect on duration of infection and severity of liver diseases. HBeAg is encoded by the precore region in addition to the core gene. Core promoter mutations reduce HBeAg expression at the transcriptional level. We found that the hot spot mutations (A1762T/G1764A) only mildly reduced HBeAg expression and enhanced genome replication, while incorporation of additional core promoter mutations intensified both phenotypes. At the step of translation, a G1896A nonsense mutation in the precore region abolishes HBeAg expression. We first reportedthat the G1896A mutation rarely occurred in genotype A. Subsequent studies by others established the role of polymorphism at nucleotide 1858, rather than genotype, as the determinant for the G1896A mutation. Conversion of the precore/core protein to HBeAg requires proteolytic removal of both the amino and carboxy termini, and a (151)RRGR(154) motif has been implicated as the carboxy terminal cleavage site. In this regard, genotype A is unique in possessing a dipeptide insertion that expands the motif into (151)RRDRGR(156). We found that genotype A is cleaved primarily at R156, generating a mature HBeAg that is two amino acids longer than HBeAg from other genotypes. There are different avenues whereby HBeAg expression or its antigenicity can be modulated by viral genotype and naturally occurring mutations.
authors.affiliation: Liver Research Center, Rhode Island Hospital, Brown University, Providence, Rhode Island, USA.
authors.forename: Shuping
authors.initials: S
authors.lastname: Tong