SUBTYPES, GENOTYPES AND MOLECULAR EPIDEMIOLOGY OF THE HEPATITIS-B VIRUS AS REFLECTED BY SEQUENCE VARIABILITY OF THE S-GENE

The serologic heterogeneity of the hepatitis B virus (HBV) has been es tablished from immunodiffusion experiments for a long time. Four serot ypes called subtypes of the hepatitis B surface antigen (HBsAg) have b een defined by two mutually exclusive determinant pairs, d/y and w/r, and a common determinant a. These subtypes are adw, ayw, adr and ayu. By subdivision of the four major subtypes in the mid-70s, nine differe nt subtypes were identified. Sequencing of viral genomes has now becom e a major goal of descriptive virology, and sequence data is now used to trace routes of infection, to reconstruct the phylogenetic history of viruses and two delimit genetic subtypes. A genetic classification based on the comparison of complete genomes has defined four genomic g roups of HBV, later referred upon as genotypes, which were designated with A-D. However, the interrelation of the nine subtypes to the genot ypes, the possible presence of more than four human HBV genotypes as w ell as their global geographical prevalence remained to be determined. By sequencing the S-gene of HBV the molecular basis was assessed for the serological variations of HBsAg within the major four subtypes. Th ereby, also two new genotypes of HBV designated with E and F were iden tified. Complete genomic sequencing of E and F strains confirmed their status as new genotypes. The F genotype was found to diverge from oth er HBV genomes sequenced by 14%, thus being the most divergent HBV gen ome so far characterized. When the worldwide molecular epidemiology of HBV based on the variability of the S-gene was defined, the E and F s trains seemed to originate in aboriginal populations of Africa and the New World, respectively. They shared a unque substitution at residue 140 in the second immunodominant loop of their encoded surface antigen when compared to the vaccine strain. Future research will establish w hether this substitution may predispose to a vaccine escape mutant at residue 141, that now has been reported to occur in conjunction with t he 140 substitution.