HBV genotypes A1 and A2 have distinct replication phenotypes due to polymorphisms in the HBV X gene

HBV is a leading cause of liver disease worldwide. HBV genotypes have distinct geographical distributions, routes of transmission, virological features and clinical characteristics. HBV subtypes A1 and A2, despite being classified within one genotype, appear to have distinct virologic and clinical features. Whether such differences among the diverse HBV genotypes resulting from the virus or host has not been established mostly because of limitations in cell culture tools and models. Here we establish and apply infectious in vitro and in vivo systems to study the virological behaviors and treatment responses of HBV A1 and A2. The surprising and intriguing finding of subtype A2 having a higher replication phenotype because of polymorphisms in the HBx gene provides the first indication that sequence variations, specifically in HBx gene here and possibly elsewhere on the genome, may underpin the diverse clinical phenotypes of HBV infections. This study underscores the value of this platform in investigating HBV biology and the need to study genotype-phenotype differences among the diverse HBV genotypes that may offer unique insight into functions of viral proteins and regulatory elements.