Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients
Knowledge of factors regulating transcriptional activity of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in understanding mechanisms of viral decay and how these processes are thwarted in chronically HBV-infected patients. Liver biopsies from 119 treatment-naive chronical...
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Published in | Gastroenterology (New York, N.Y. 1943) Vol. 133; no. 3; p. 843 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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United States
01.09.2007
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Abstract | Knowledge of factors regulating transcriptional activity of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in understanding mechanisms of viral decay and how these processes are thwarted in chronically HBV-infected patients.
Liver biopsies from 119 treatment-naive chronically infected patients (42 HBeAg-positive and 77 HBeAg-negative) were determined for HBV transcriptional and replicative activity.
Significantly lower median serum HBV DNA (-4 log), intrahepatic HBV DNA (-2 log), and cccDNA (-1 log) amounts were measured in HBeAg-negative versus HBeAg-positive patients. Despite a good correlation found between intrahepatic amounts of progeny virions and serum HBV DNA in all patients, cccDNA levels did not correlate with serum titers in HBeAg-negative individuals. Analysis of HBV RNA transcripts showed that impaired virion productivity in HBeAg-negative individuals was due to lower steady-state levels of pregenomic RNA produced per cccDNA. Interestingly, preS/S RNA levels and serum HBsAg concentrations did not differ between HBeAg-positive and HBeAg-negative patients when normalized for cccDNA contents, showing that subviral particle production was not impaired in HBeAg-negative patients and correlated with cccDNA levels. Although the majority of HBeAg-negative individuals harbored cccDNA with common precore and/or basal core promoter mutations, occurrence of these variants was not responsible for reduced viral replication. Instead, replacement of wild-type cccDNA with core promoter mutants reestablished high virion productivity.
Lower viremia in HBeAg-negative individuals is not only due to lower cccDNA content but also to impaired virion productivity, which can arise without emergence of HBeAg variants and without affecting HBsAg production. |
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AbstractList | Knowledge of factors regulating transcriptional activity of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in understanding mechanisms of viral decay and how these processes are thwarted in chronically HBV-infected patients.
Liver biopsies from 119 treatment-naive chronically infected patients (42 HBeAg-positive and 77 HBeAg-negative) were determined for HBV transcriptional and replicative activity.
Significantly lower median serum HBV DNA (-4 log), intrahepatic HBV DNA (-2 log), and cccDNA (-1 log) amounts were measured in HBeAg-negative versus HBeAg-positive patients. Despite a good correlation found between intrahepatic amounts of progeny virions and serum HBV DNA in all patients, cccDNA levels did not correlate with serum titers in HBeAg-negative individuals. Analysis of HBV RNA transcripts showed that impaired virion productivity in HBeAg-negative individuals was due to lower steady-state levels of pregenomic RNA produced per cccDNA. Interestingly, preS/S RNA levels and serum HBsAg concentrations did not differ between HBeAg-positive and HBeAg-negative patients when normalized for cccDNA contents, showing that subviral particle production was not impaired in HBeAg-negative patients and correlated with cccDNA levels. Although the majority of HBeAg-negative individuals harbored cccDNA with common precore and/or basal core promoter mutations, occurrence of these variants was not responsible for reduced viral replication. Instead, replacement of wild-type cccDNA with core promoter mutants reestablished high virion productivity.
Lower viremia in HBeAg-negative individuals is not only due to lower cccDNA content but also to impaired virion productivity, which can arise without emergence of HBeAg variants and without affecting HBsAg production. |
Author | Petersen, Joerg Wachtler, Paul Jacob, Anna Lutgehetmann, Marc Murray, John M Dandri, Maura Volz, Tassilo Quaas, Alexander |
Author_xml | – sequence: 1 givenname: Tassilo surname: Volz fullname: Volz, Tassilo organization: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany – sequence: 2 givenname: Marc surname: Lutgehetmann fullname: Lutgehetmann, Marc – sequence: 3 givenname: Paul surname: Wachtler fullname: Wachtler, Paul – sequence: 4 givenname: Anna surname: Jacob fullname: Jacob, Anna – sequence: 5 givenname: Alexander surname: Quaas fullname: Quaas, Alexander – sequence: 6 givenname: John M surname: Murray fullname: Murray, John M – sequence: 7 givenname: Maura surname: Dandri fullname: Dandri, Maura – sequence: 8 givenname: Joerg surname: Petersen fullname: Petersen, Joerg |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17854594$$D View this record in MEDLINE/PubMed |
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SubjectTerms | Adult Biopsy Case-Control Studies DNA, Viral - blood Female Genotype Hepacivirus - genetics Hepacivirus - physiology Hepatitis B - blood Hepatitis B - immunology Hepatitis B e Antigens - blood Humans Liver - pathology Liver - virology Male Middle Aged Mutation - genetics RNA, Viral - blood Viral Core Proteins - genetics Viremia - blood Viremia - etiology Viremia - immunology Virus Replication - physiology |
Title | Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients |
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