Hepadnaviruses can cause chronic, productive, infections, associated with both progressive liver damage and the accumulation of aberrant, integrated forms of viral DNA. Both events appear to be co-factors in the development of hepatocellular carcinoma, which occurs with high frequency in chronically-infected individuals. The productive phase of hepadnavirus infections is apparently maintained solely by the transcriptional activity of a covalently-closed, circular (CCC) viral DNA found at low copy number in the nucleus of infected hepatocytes. Effective antiviral chemotherapies to eliminate this species, by ending virus production, should not only stop further liver damage but, also, substantially reduce the life-time risk of liver cancer. The possibility of devising such virus-specific therapies is encouraged by a recent report that, in duck hepatocyte tissue culture, hepadnavirus CCC DNA is synthesized via a virus-specified mechanism, involving reverse transcription of a viral RNA, and not by host-specific, semi-conservation replication. A detailed understanding of this process, including its role and significance in in vivo virus replication will, therefore, be a major goal of our investigations. The process of formation and of maintenance of CCC viral DNA in chronic, hepadnavirus infections will be studied, primary, in the context of both in vivo and in vitro infections by duck hepatits virus. Questions to be addressed will include: (1) What are the roles of viral and cellular proteins in the conversion of virion, relaxed circular, partially double- stranded DNA to CCC DNA? (2) How is CCC DNA maintained during chronic, hepatocellular infections? (3) What is the detailed molecular mechanism of viral DNA synthesis during chronic infections? Towards these goals, we have identified major events in hepadnaviral DNA synthesis and developed the first detailed model for this process, obtained preliminary evidence that CCC DNA can accumulate, in vitro, via an intracellular route, identified a number of drugs that appear to be useful for characterization of the hepadnavirus life cycle, and established a system for in vitro infection of primary woodchuck hepatocytes with woodchuck hepatitis virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018641-12
Application #
2060745
Study Section
Virology Study Section (VR)
Project Start
1982-09-01
Project End
1995-03-31
Budget Start
1993-08-01
Budget End
1995-03-31
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Institute for Cancer Research
Department
Type
DUNS #
872612445
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Cai, Dawei; Mills, Courtney; Yu, Wenquan et al. (2012) Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation. Antimicrob Agents Chemother 56:4277-88
Mason, William S; Liu, Chen; Aldrich, Carol E et al. (2010) Clonal expansion of normal-appearing human hepatocytes during chronic hepatitis B virus infection. J Virol 84:8308-15
Mason, William S; Low, Huey-Chi; Xu, Chunxiao et al. (2009) Detection of clonally expanded hepatocytes in chimpanzees with chronic hepatitis B virus infection. J Virol 83:8396-408
Mason, William S; Xu, Chunxiao; Low, Huey Chi et al. (2009) The amount of hepatocyte turnover that occurred during resolution of transient hepadnavirus infections was lower when virus replication was inhibited with entecavir. J Virol 83:1778-89
Mason, W S; Litwin, S; Xu, C et al. (2007) Hepatocyte turnover in transient and chronic hepadnavirus infections. J Viral Hepat 14 Suppl 1:22-8
Xu, Chunxiao; Yamamoto, Toshiki; Zhou, Tianlun et al. (2007) The liver of woodchucks chronically infected with the woodchuck hepatitis virus contains foci of virus core antigen-negative hepatocytes with both altered and normal morphology. Virology 359:283-94
Guo, Haitao; Mason, William S; Aldrich, Carol E et al. (2005) Identification and characterization of avihepadnaviruses isolated from exotic anseriformes maintained in captivity. J Virol 79:2729-42
Yamamoto, Toshiki; Litwin, Samuel; Zhou, Tianlun et al. (2002) Mutations of the woodchuck hepatitis virus polymerase gene that confer resistance to lamivudine and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil. J Virol 76:1213-23
Zhu, Y; Yamamoto, T; Cullen, J et al. (2001) Kinetics of hepadnavirus loss from the liver during inhibition of viral DNA synthesis. J Virol 75:311-22
Zhou, T; Saputelli, J; Aldrich, C E et al. (1999) Emergence of drug-resistant populations of woodchuck hepatitis virus in woodchucks treated with the antiviral nucleoside lamivudine. Antimicrob Agents Chemother 43:1947-54

Showing the most recent 10 out of 45 publications