Impaired intrahepatic hepatitis B virus productivity contributes to low viremia in most HBeAg-negative patients

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 133; no. 3; p. 843
• Main Authors: Volz, Tassilo, Lutgehetmann, Marc, Wachtler, Paul, Jacob, Anna, Quaas, Alexander, Murray, John M, Dandri, Maura, Petersen, Joerg
• Format: Journal Article
• Language: English
• Published: United States 01.09.2007
• Subjects: 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
• ISSN: 0016-5085
• DOI: 10.1053/j.gastro.2007.06.057

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.