Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus
Open accessAbstract
The template for synthesis of hepadnaviral RNAs is a covalently closed circular (ccc) DNA located in the nucleus of the infected hepatocyte. Hepatocytes are normally long-lived and nondividing, and antiviral therapies in chronically infected individuals face the problem of eliminating not only the replicative forms of viral DNA found in the cytoplasm but also the cccDNA from the nucleus. Because cccDNA does not replicate semiconservatively, it is not an obvious target for antiviral therapy. However, elimination of cccDNA might be facilitated if its half-life were short in comparison to the generation time of hepatocytes and if new cccDNA formation were effectively blocked. We have therefore measured cccDNA levels in woodchuck hepatocyte cultures following in vitro infection with woodchuck hepatitis virus and treatment with inhibitors of viral DNA synthesis. The viral reverse transcriptase inhibitors lamivudine (3TC) [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine), FTC (5-fluoro-2',3'-dideoxy-3'-thiacytidine) and ddC (2',3'-dideoxycytidine) were added to the cultures beginning at 4 days postinfection. Treatment for up to 36 days with 3TC reduced the amount of cccDNA in the cultures not more than twofold compared to that of an untreated control. Treatment with ddC for 36 days and with FTC for 12 days resulted in effects similar to that of treatment with 3TC. Moreover, the declines in cccDNA appeared to reflect the loss of hepatocytes from the cultures rather than of cccDNA from hepatocytes. These results emphasize the important role of the longevity of the infected hepatocytes in the persistence of an infection.
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NA alone has little or no effect on the elimination of replicative templates of HBV, the cccDNA, despite effective suppression of HBV replication by inhibiting viral reverse transcriptase.
“It is clear now that NA alone has little or no effect on the elimination of replicative templates of hepatitis B virus (HBV), the covalently closed circular DNA (cccDNA), despite its effective suppression of HBV replication by inhibiting viral reverse transcriptase.1,2”
From The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo (2014) · cites this paper as [2]
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- Authors
- Moraleda, G., Saputelli, J., Aldrich, C. E., Averett, D., Condreay, L., & Mason, W. S.
- Affiliations
- Fox Chase Cancer Center (US)
- ORCID
- Condreay, L
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 1997-12
- Volume
- 71
- Issue
- 12
- Pages
- 9392-9399
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC230243
- OpenAlex
- W2141460271
- Cited by
- 263
- References
- 32
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 11 · 2017: 8 · 2016: 11 · 2015: 15 · 2014: 10 · 2013: 8 · 2012: 5
- FWCI
- 9.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca057425-03)
- National Cancer Institute (CA-57425, CA40737)
- National Institute of Allergy and Infectious Diseases (AI-18641, R01AI018641)
- Topics
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- woodchuck hepatitis virus, covalently closed circular DNA, antiviral therapy, reverse transcriptase inhibitors, lamivudine, adefovir, zalcitabine, hepatocyte culture, chronic viral infection, viral persistence, hepadnaviruses
- MeSH terms
- Emtricitabine, Animals, Antiviral Agents, Cells, Cultured, DNA, Circular, DNA, Viral, Liver, Marmota, Virus Replication, Zalcitabine, Hepatitis B Virus, Woodchuck, Reverse Transcriptase Inhibitors, Lamivudine, Rats
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