WHOLE GENOME ANALYSIS OF HEPATITIS-B VIRUS FROM 4 CASES OF FULMINANT-HEPATITIS - GENETIC-VARIABILITY AND ITS POTENTIAL ROLE IN DISEASE PATHOGENICITY

The precore stop-codon variant of hepatitis B virus (HBV) has been ass ociated with fulminant hepatitis but is also found in patients with pe rsistent infection and chronic hepatitis, We have examined the possibi lity that the severe outcome of infection in patients with fulminant d isease may be a result of additional genomic variation. We sequenced t he entire HBV genome from three patients of Greek and one patient of C hinese origin with fulminant hepatitis, and from two patients with hep atitis B e antigen (HBeAg) positive chronic infection from the same re gions, using direct sequencing of amplified viral DNA, Three of the fu lminant cases were infected with the precore stop-codon variant (HBeAg negative) and the fourth with the wild-type (HBeAg positive) virus. W e compared sequences from our four fulminant isolates, and an addition al fulminant isolate reported by others, with HBeAg positive carriers from the same regions and 12 published HBV genomes. There was a higher number of nucleotide and amino-acid substitutions throughout the HBV genome in the precore variant fulminant sequences than in the wild typ e. A cluster of mutations previously identified in the X region (126-1 32) in sequences reported in Japanese patients and encompassing the En hancer II-Core Promoter region (1751-1768), were not found in our pati ents. We conclude that although there are no changes common to all seq uences of HBV isolates from fulminant cases, some of these changes are in recognized cis-acting regulatory elements, whilst others are in th e immediate vicinity of such elements. The effect of these mutations o n viral genome transcription must now be determined.