BIOLOGIC PROPERTIES OF HEPATITIS-B VIRAL GENOMES WITH MUTATIONS IN THE PRECORE PROMOTER AND PRECORE OPEN READING FRAME

It is now well recognized that mutations in the hepatitis B virus (HBV ) genome occur during the natural course of chronic viral infection. R egions of the viral genome that are frequently affected by such mutati ons, rearrangements, and/or deletions generally involve the precore pr omoter, precore, and core as well as the preS gene regions. However, l ittle is known regarding the biologic consequences of these mutations on the functional properties of the variant viral strains with respect to effects on viral replication. In this study, we investigated the f unctional significance of precore promoter and precore gene mutations that reduce or abolish the synthesis of hepatitis B e antigen (HBeAg). We found that precore promoter mutations diminished the expression of HBeAg but did not affect the synthesis of pregenomic RNA. However, th ese precore mutations were associated with a modest increase in HBV re plication. In contrast, a naturally occurring mutant that carries a te rmination codon in position 28 of the precore open reading frame demon strated increased encapsidation of pregenomic mRNA into nucleocapsid p articles. Consequently, this variant viral strain demonstrated a subst antial increase in the level of viral replication compared to ''wild-t ype'' HBV and other precore promoter mutant viral strains. These studi es suggest that substitutions in the precore promoter and precore gene not only alter the synthesis of HBeAg but also affect the level of vi ral replication. (C) 1997 Academic Press.