USE OF DOMINANT-NEGATIVE MUTANTS OF THE HEPADNAVIRAL CORE PROTEIN AS ANTIVIRAL AGENTS

Chronic hepatitis B virus (HBV) infection is a major cause of acute an d chronic liver diseases. We have recently described HBV and woodchuck hepatitis virus (WHV) dominant negative (DN) core mutants that were c apable of inhibiting wild-type viral replication by 95%. These mutants may represent a potent class of antiviral agents that act as ''intrac ellular immunogens.'' To facilitate their potential use in animal mode l systems, we now have studied the duck HBV (DHBV) and placed the DN m utant constructs in recombinant retroviral and adenoviral expression v ectors. Transient expression of the DHBV molecular equivalent of the W HV and HBV DN constructs inhibited wild-type DHBV replication by 98%. Recombinant retroviral and adenoviral vectors containing the HBV and D HBV DN complementary DNAs (cDNAs) were used to transiently and stably transduce hepatoma derived cell Lines constitutively expressing replic ating wild-type virus. These investigations show that the DN core muta nts were powerful inhibitors of HBV and DHBV replication when delivere d intracellularly and appear as promising antiviral agents for gene th erapy of persistent viral infection of the liver.