Subtypes, Genotypes and Molecular Epidemiology of the Hepatitis B Virus as Reflected by Sequence Variability of the S-Gene

Abstract

The serologic heterogeneity of the hepatitis B virus (HBV) has been established from immunodiffusion experiments for a long time. Four serotypes called subtypes of the hepatitis B surface antigen (HBsAg) have been defined by two mutually exclusive determinant pairs, d/y and w/r, and a common determinant a. These subtypes are adw, ayw, adr and ayr. By subdivision of the four major subtypes in the mid-70s, nine different subtypes were identified. Sequencing of viral genomes has now become 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 groups of HBV, later referred upon as genotypes, which were designated with A-D. However, the interrelation of the nine subtypes to the genotypes, the possible presence of more than four human HBV genotypes as well 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. Thereby, also two new genotypes of HBV designated with E and F were identified. Complete genomic sequencing of E and F strains confirmed their status as new genotypes. The F genotype was found to diverge from other HBV genomes sequenced by 14%, thus being the most divergent HBV genome so far characterized. When the worldwide molecular epidemiology of HBV based on the variability of the S-gene was defined, the E and F strains 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 whether this substitution may predispose to a vaccine escape mutant at residue 141, that now has been reported to occur in conjunction with the 140 substitution.

A unique segment of the hepatitis B virus group A genotype identified in isolates from South Africa.

“…For example, adr is confined to the East, ayw2 predominates in the Mediterranean region and adw4 is found only in the Pacific region. Serotype adw2 predominates in Northern Europe and sub-Saharan Africa, but its prevalence declines moving from East Africa towards Central and West Africa and is accompanied by a corresponding increase in the unique African serotype, ayw4 (Magnius & Norder, 1995). Of HBV serotypes in South Africa, 97n7 % were previously reported to be serotype adw2, with the remaining 2n3 % being ayw (Courouce!…”

“…Several of the genotypic groups are serotypically heterogeneous : group C contains adw, adr and ayr ; both groups A and B contain serotype adw and ayw1 ; and group D contains serotypes ayw2, ayw3 and ayw4. In addition, the genotypic groups are also themselves geographically arranged (Magnius & Norder, 1995) : adw2 clusters into group A in the West but into groups B and C in the East ; ayw1 also occurs in group A in the West, but is confined to group B in the East ; group A is seldom found in the East, whereas group C is limited to the East ; group E is limited to parts of East, Central and West Africa and group F to the Pacific (Magnius & Norder, 1995). Little is known about the HBV genotypes that occur in southern Africa.…”

Virological outcomes in patients infected chronically with hepatitis B virus genotype A in comparison with genotypes B and C

“…Of the eight genotypes of HBV, E, and F are local, and confined to Central Africa and Central/South America, respectively [Magnius and Norder, 1995;Miyakawa and Mizokami, 2003]. Genotype H is genetically close to F and distributes in Central America [Arauz-Ruiz et al, 2002].…”

“…Due to their uneven geographical distribution, however, only two HBV genotypes prevail in most countries; the United States is the only exception with seven (A-G) genotypes [Chu et al, 2003;Westland et al, 2003]. Thus, genotypes A and D are common in Europe and India, while genotypes B and C are frequent in Asia [Magnius and Norder, 1995;Miyakawa and Mizokami, 2003]. Therefore, comparison has been restricted between patients infected with genotypes A and D, as well as those with B and C [Zhang et al, 1996;Mayerat et al, 1999;Kao et al, 2000;Orito et al, 2001;Chu et al, 2002;Thakur et al, 2002].…”

Identification and functional studies of HLA-A0201 restricted CTL epitopes in the X protein of hepatitis B virus

“…Sequence variation of the HBV genome is associated with the virus infection and immune evasion. HBV sequence data are used to trace down routes of infection, reconstruct the phylogenetic history of viruses, and develop anti-virus strategies (Magnius and Norder, 1995). Hepatitis B surface antigen (HBsAg) has five major subtype determinants termed a, d, y, w, and r, which have primarily epidemiologic significance.…”