Based on the diversity of nucleotide sequences of cloned hepatitis B virus DNA genomes, we have predicted possible replication of genetic variants of human hepatitis B virus. This prediction is exemplified by studies of a chronic carrier of HBsAgladw2, who lacked anti-HBc but carried exceedingly high levels of hepatitis B virus DNA in serum. Molecular characterization of a number of clones revealed a restriction map that deviated significantly from the typical pattern of the adw2 subtype, especially around the EcoRI site commonly used as a reference point. Mutations appearing consistently in the precore and core regions included (a) mutation in the precore region resulting in a termination codon after the initiation codon, (b) mutation of the core initiation codon and (c) an inframe insert of 36 nucleotides in the precore region with a new initiation site for the core protein.
The 36-nucleotide insertion resulted in a new core protein with 12 extra amino acids at its amino-terminal end. A few scattered point mutations were clustered in the amino-terminal half of the core gene. Although the core protein of this hepatitis B virus variant carried immunologically detectable HBcAg, the absence of a humoral immune response to HBcAg could have been caused by previous infection with human immunodeficiency virus. This naturally occurring human hepatitis B vitiny~ variant replicated efficiently without expressing the precore region, confirming previous observations made @f the artificial mutants of duck hepatitis B virus. (HEPATOLYGY 1990;11:271-276.) , I Hepatottopic DNA (hepadna) viruses are widely distributed in humdns, woodchucks, Beechy ground squirrels and Pekin dutks (I). The prototype hepatitis B viruses (HBVs) are envelwed DNA viruses consisting of an outer lipid coat bearing JIpsAg. The inner nucleocapsid contains the HBcAg, t%k Viral genome and the DNA polymerase/reverse transcriptase. Nucleotide sequence analysis of cloned HBV DNA has shown that