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Journal of Virology, March 2007, p. 2656-2662, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02020-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Enhancement of Hepatitis B Virus Replication by the Regulatory X Protein In Vitro and In Vivo{triangledown}

Victor V. Keasler, Amanda J. Hodgson, Charles R. Madden, and Betty L. Slagle*

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030-3411

Received 15 September 2006/ Accepted 12 December 2006

The 3.2-kb hepatitis B virus (HBV) genome encodes a single regulatory protein termed HBx. While multiple functions have been identified for HBx in cell culture, its role in virus replication remains undefined. In the present study, we combined an HBV plasmid-based replication assay with the hydrodynamic tail vein injection model to investigate the function(s) of HBx in vivo. Using a greater-than-unit-length HBV plasmid DNA construct (payw1.2) and a similar construct with a stop codon at position 7 of the HBx open reading frame (payw1.2*7), we showed that HBV replication in transfected HepG2 cells was reduced 65% in the absence of HBx. These plasmids were next introduced into the livers of outbred ICR mice via hydrodynamic tail vein injection. At the peak of virus replication, at 4 days postinjection, intrahepatic markers of HBV replication were reduced 72% to 83% in mice injected with HBx-deficient payw1.2*7 compared to those measured in mice receiving wild-type payw1.2. A second plasmid encoding HBx was able to restore virus replication from payw1.2*7 to wild-type levels. Finally, viremia was monitored over the course of acute virus replication, and at 4 days postinjection, it was reduced by nearly 2 logs in the absence of HBx. These studies establish that the role for HBx in virus replication previously shown in transfected HepG2 cells is also apparent in the mouse liver within the context of acute hepatitis. Importantly, the function of HBx can now be studied in an in vivo setting that more closely approximates the cellular environment for HBV replication.

* Corresponding author. Mailing address: Department of Molecular Virology and Microbiology, Baylor College of Medicine, BCM-385 One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-3006. Fax: (713) 798-5075. E-mail: bslagle{at}bcm.edu.

{triangledown} Published ahead of print on 20 December 2006.

Journal of Virology, March 2007, p. 2656-2662, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02020-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Clippinger, A. J., Gearhart, T. L., Bouchard, M. J. (2009). Hepatitis B Virus X Protein Modulates Apoptosis in Primary Rat Hepatocytes by Regulating both NF-{kappa}B and the Mitochondrial Permeability Transition Pore. J. Virol. 83: 4718-4731 [Abstract] [Full Text]  
  • Cha, M.-Y., Ryu, D.-K., Jung, H.-S., Chang, H.-E., Ryu, W.-S. (2009). Stimulation of hepatitis B virus genome replication by HBx is linked to both nuclear and cytoplasmic HBx expression. J. Gen. Virol. 90: 978-986 [Abstract] [Full Text]  
  • Hodgson, A. J., Keasler, V. V., Slagle, B. L. (2008). Premature Cell Cycle Entry Induced by Hepatitis B Virus Regulatory HBx Protein during Compensatory Liver Regeneration. Cancer Res. 68: 10341-10348 [Abstract] [Full Text]  
  • Clippinger, A. J., Bouchard, M. J. (2008). Hepatitis B Virus HBx Protein Localizes to Mitochondria in Primary Rat Hepatocytes and Modulates Mitochondrial Membrane Potential. J. Virol. 82: 6798-6811 [Abstract] [Full Text]  
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