Nature of the Virus

The hepatitis B virion is a 42 nm particle comprising an electron-dense nucleocapsid or core (HBcAg) 27 nm in diameter, surrounded by an outer envelope of the surface protein (HBsAg) embedded in membraneous lipid derived from the host cell (Figure 6.2). The surface antigen, originally referred to as Australia antigen, is produced in excess by the infected hepatocytes and is secreted in the form of 22 nm particles and tubular structures of the same diameter.

The nucleocapsid of the virion consists of the viral genome surrounded by the core antigen. The genome, which is approximately 3.2kilobases in length, has an unusual structure and is composed of two linear strands of DNA held in a circular configuration by base-pairing at the 5' ends. One of the strands is incomplete and the 3' end is associated with a DNA polymerase which is able to complete that strand in the presence of deoxynucleoside triphosphates (Figure 6.3).

The genomes of many isolates of HBV have been cloned and the complete nucleotide sequences determined. Analysis of the coding potential of the genome reveals four open reading frames (ORFs) which are conserved between all of these isolates, but there is some

Figure 6.3 The molecular structure of the genome of hepatitis B virus

variation in sequence of up to 12% of nucleotides. The first ORF encodes the various forms of the surface protein. The core ORF has two in-phase initiation codons. The 'precore' region is highly conserved, has the properties of a signal sequence and is responsible for the secretion of HBeAg. The third ORF, which is the largest and overlaps the other three, encodes the viral polymerase. The fourth ORF was designated 'x' because the function of its small gene product was not known initially; however, 'x' has now been demonstrated to be a transcrip-tional transactivator, and may enhance the expression of other viral proteins.

Surface Antigen Epitopes

There is a variation in the epitopes presented on the surface of the virions and subviral 22 nm particles so that there are several subtypes of HBV which differ in their geographical distribution. All isolates of the virus share a common epitope, a, a domain of the major surface protein which is believed to protrude as a double loop from the surface of the particle. Two other pairs of mutually exclusive antigenic determinants, d or y and w or r, are also present on the major surface protein. These variations have been correlated with single nucleotide changes in the surface ORF which lead to variation in single amino acids in the protein. Four principal subtypes of HBV are recog nised: adw, adr, ayw and ayr. Subtype adw predominates in northern Europe, the Americas and Australasia and also is found in Africa and Asia. Subtype ayw is found in the Mediterranean region, eastern Europe, northern and western Africa, the Near East and the Indian subcontinent. In the Far East, adr predominates but the rarer ayr may occasionally be found in Japan and Papua New Guinea. Other less common variants exist as a result of subdivision of the principal antigenic determinants. More recently, subtyping has been carried out by DNA sequencing of the surface antigen gene, and at least six genotypes, A-F, which differ by more than 8% in the protein sequence, have been identified. Subtyping is mainly of epidemiological or phylogenetic significance.

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