Although HBV has a circular DNA genome that is partially double stranded, it replicates by means of an RNA intermediate. The process is catalyzed by a translation product of the polymerase open reading frame that has reverse transcriptase activity. The enzyme is found in association with the virion and achieves a high rate of nucleotide misincorporation during transcription because such enzymes lack proofreading activity. The virus is remarkable for its efficient use of nucleic acid because the genome is only 3.2 kb long and yet it encodes four groups of proteins and their regulatory elements (1). This is achieved in some regions by reading the sequence through different frames to direct the synthesis of distinct proteins from the same genetic material. Only a few of the mutations that occur during the normal replication cycle therefore permit the entry of a new virus to the pool for natural selection. Nevertheless, patients with chronic hepatitis have been shown to have viruses with different sequences cocirculating, and some regions of the genome are poorly conserved between different isolates (2).

The existence of patients with evidence of HBV replication but no evidence of liver disease, both in the early phase of acute infection (3) and in some chronic infections (4), has led to the suggestion that the virus is not directly cytopathic but that it is the immune response to infected liver cells that causes the hepatitis (5). The development of polymerase chain reaction (PCR) sequencing techniques has allowed us to determine whether sequence variation occurs under host selection and offers an explanation for the variable outcome of HBV infection.