A PRES MUTATION ISOLATED FROM A PATIENT WITH CHRONIC HEPATITIS-B INFECTION LEADS TO VIRUS RETENTION AND MISASSEMBLY

A preS mutation derived from a patient with chronic hepatitis B virus (HBV) infection who had HBV reinfection with fibrosing cholestatic hep atitis after orthotopic liver transplantation was characterized. Seque nce analysis of the HBV genome revealed two deletions and a point muta tion in the regulatory CCAAT element of the S promoter. To investigate the particular preS mutation for replication competence and viral ass embly in functional experiments, the mutant preS region was introduced into a replication competent HBV plasmid. Functional studies were per formed by transfecting this plasmid into hepatoma cells. Analysis of t he mutant HBV strain revealed an inverse ratio of S-gene products in c omparison to wild-type HBV that leads to intracellular viral retention . An atypical intracellular distribution of HBV proteins and an enhanc ed nuclear localization of HBV DNA was also detected. Additionally, a major fraction of the extracellular viral particles was malformed. The association of intracellular accumulation of viral proteins with cirr hosis and fibrosing cholestatic hepatitis has been described recently. In this study, we show that the particular preS mutation accounted fo r the viral retention, which may have contributed to a more progressiv e form of liver disease found in this HBV-positive patient after liver transplantation.