A dominant hepatitis B virus population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis

There is increasing evidence that certain pathogenic hepatitis B virus (HBV ) variants may play a role in the pathogenesis of fulminant hepatitis (FHB) . Recently, we isolated from a patient with fulminant recurrent hepatitis B after liver transplantation variants with enhanced replication competence and a possible defect in viral particle secretion. Both viral features may have contributed to the severity of the disease. The aim of this study was to prove the secretion defect of these variants, to analyze the consequence s , and to identify the responsible viral mutations. The variant genomes an d appropriate wild-type/variant hybrid genomes were functionally characteri zed after transfection in human hepatoma cells. Two cloned genomes and the polymerase chain reaction (PCR)-amplified mixture of full-length genomes sh owed a block in viral particle secretion. This was caused by a combination of amino acid changes in the S-protein including the mutation G145R frequen tly emerging after hyperimmunoglobulin treatment. The mutations induced ret ention of the surface proteins in an endoplasmic reticulum (ER)-like compar tment, but no intracellular accumulation. These data provide evidence for t he in vivo existence of a dominant HBV population with a severe defect in v iral particle secretion caused by mutations in the S-gene. This viral pheno type in combination with the enhanced replication competence may have contr ibuted to the fulminant clinical course of the infection.