Infectious hepatitis B virus variant defective in pre-S2 protein expression in a chronic carrier.
All human hepatitis B viruses characterized so far express three envelope proteins, pre-S1, pre-S2, and HBs, which are believed to function as binding proteins for the cellular receptor, as targets for immune-mediated virus elimination, and in virion morphogenesis and secretion. Here we report the characterization of infectious HBV variant genomes that are unable to express a pre-S2 protein and which were derived from serum of a highly viremic chronic carrier. Direct sequencing of the amplified pre-S region and sequencing of 50 cloned amplified pre-S DNA fragments revealed that in all molecules, in addition to numerous nucleotide changes, there were deletions of the pre-S2 translation initiation codon and three codons 54 nucleotides downstream thereof. No pre-S2 protein and altered pre-S1 proteins were found in the serum of the patient. Cloned infectious HBV DNA genomes having the pre-S region substituted by the variant pre-S region were replication competent in cultured hepatoblastoma cells. Morphologically normal virions were efficiently secreted and were infectious for primary human hepatocyte cultures. These data demonstrate that HBV devoid of pre-S2 protein can occur in vivo as a dominant or exclusive virus population and that expression of the pre-S2 protein is not essential for HBV replication, virion morphogenesis, secretion, or in vitro infectivity.
Fernholz
D
D
Max-Planck-Institut für Biochemie, Martinsried/München, Germany.
Galle
P R
PR
Stemler
M
M
Brunetto
M
M
Bonino
F
F
Will
H
H
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002353:Carrier State; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015967:Gene Expression Regulation, Viral; D014644:Genetic Variation; D016679:Genome, Viral; D006509:Hepatitis B / Q000235:genetics*; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis* / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000737:chemistry / Q000235:genetics* / Q000254:growth & development / Q000648:ultrastructure; D006521:Hepatitis, Chronic / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000382:microbiology; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011498:Protein Precursors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014766:Viremia; D014779:Virus Replication
D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D011498:Protein Precursors