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Journal of Virology, March 2008, p. 2250-2264, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.02155-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hepatitis B Surface Antigen Levels and Sequences of Natural Hepatitis B Virus Variants Influence the Assembly and Secretion of Hepatitis D Virus

Department of Medical Research and Education,¹ Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,⁵ Institutes of Clinical Medicine,² Microbiology and Immunology,⁴ Faculty of Internal Medicine, National Yang-Ming University, Taipei, Taiwan,⁶ Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan³

Received 2 October 2007/ Accepted 12 December 2007

Various domains of hepatitis B surface antigen (HBsAg) are essential for the assembly and secretion of hepatitis D virus (HDV). This study investigated the influences of the levels and sequences of HBsAg of naturally occurring HBV variants on the assembly and secretion of HDV. Six hepatitis B virus (HBV)-producing plasmids (three genotype B and three genotype C) and six HBsAg expression plasmids that expressed various HBsAg levels were constructed from the sera of HDV-infected patients. These plasmids were cotransfected with six expression plasmids of HDV of genotype 1, 2, or 4 into the Huh-7 hepatoma cell line. Serum HBsAg and HBV DNA levels were correlated with HDV RNA levels and outcomes of chronic hepatitis D (CHD) patients. The secretion of genotype 1, 2, or 4 HDV generally correlated with HBsAg levels but not with HBV genotypes or HBV DNA levels. Swapping and residue mutagenesis experiments of HBsAg-coding sequences revealed that the residue Pro-62 in the cytosolic domain-I affects the assembly and secretion of genotype 2 and 4 HDV and not those of genotype 1. The pre-S2 N-terminal deletion HBV mutant adversely affects secretion of the three HDV genotypes. In patients, serum HDV RNA levels correlated with HBsAg levels but not with HBV DNA levels. Viremia of HDV or HBV correlated with poor outcomes. In conclusion, the assembly and secretion of HDV were influenced by the amounts and sequences of HBsAg. For an effective treatment of CHD, reduction of HBsAg production in addition to the suppression of HBV and HDV replication might be crucial.

Published ahead of print on 19 December 2007.