Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients.
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.
Volz
Tassilo
T
Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Lutgehetmann
Marc
M
Wachtler
Paul
P
Jacob
Anna
A
Quaas
Alexander
A
Murray
John M
JM
Dandri
Maura
M
Petersen
Joerg
J
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*
D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D012367:RNA, Viral; D014758:Viral Core Proteins