title: Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Liver biopsies from 119 treatment-naive chronically infected patients (42 HBeAg-positive and 77 HBeAg-negative) were determined for HBV transcriptional and replicative activity.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tassilo
authors.initials: T
authors.lastname: Volz
authors.forename: Marc
authors.initials: M
authors.lastname: Lutgehetmann
authors.forename: Paul
authors.initials: P
authors.lastname: Wachtler
authors.forename: Anna
authors.initials: A
authors.lastname: Jacob
authors.forename: Alexander
authors.initials: A
authors.lastname: Quaas
authors.forename: John M
authors.initials: JM
authors.lastname: Murray
authors.forename: Maura
authors.initials: M
authors.lastname: Dandri
authors.forename: Joerg
authors.initials: J
authors.lastname: Petersen
mesh_terms: D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D004279:DNA, Viral / Q000097:blood; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D006509:Hepatitis B / Q000097:blood* / Q000276:immunology; D006513:Hepatitis B e Antigens / Q000097:blood*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D012367:RNA, Viral / Q000097:blood; D014758:Viral Core Proteins / Q000235:genetics; D014766:Viremia / Q000097:blood / Q000209:etiology* / Q000276:immunology; D014779:Virus Replication / Q000502:physiology*
chemical_list: D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D012367:RNA, Viral; D014758:Viral Core Proteins