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J. Virol. doi:10.1128/JVI.02341-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

In Vitro Study of the Effects of Precore and Lamivudine Resistant Mutations on HBV Replication

Department of Microbiology and Immunology, and Department of Pathology, Milton S. Hershey Medical Center, The Penn State College of Medicine, Hershey, Pennsylvania 17033, and Victorian Infectious Disease Reference Laboratory, North Melbourne, Victoria, Australia

^* To whom correspondence should be addressed. Email: hisom{at}psu.edu.

	Abstract

Understanding the consequences of mutation in the hepatitis B virus (HBV) genome on HBV replication is critical for treating chronic HBV infection. In this study, HBV replication in HepG2 cells initiated by transduction with precore (PC), rtM204I, or wild type (wt) HBV recombinant baculoviruses was compared. The pattern and magnitude of HBV replication when initiated by a PC HBV recombinant baculovirus were similar to what was observed for wt HBV throughout the time course examined. In contrast, when the rtM204I mutation was introduced into wt HBV, by day 10 p.i. the levels of intra- and extracellular HBV DNA were markedly reduced compared to wt HBV. Although the rtM204I mutation reduced production of HBV replicative intermediates, no effect on the levels of covalently closed circular DNA or HBV transcripts was observed at late time points. Co-infection studies with different ratios of wt and rtM204I baculovirus showed that rtM204I did not produce a product that inhibited HBV replication. However, the combination of wt and rtM204I yielded HBV DNA levels at late time points greater than wt alone, suggesting that wt polymerase may function in trans to boost rtM204I replication. We conclude that the rtM204I mutation generates a polymerase that is not only resistant to lamivudine but also replicates nucleic acids to lower levels in vitro.