Journal Article Epublish 1 citation
PubMed: 39898797 DOI: 10.1172/JCI184243
Transcription of hepatitis B surface antigen shifts from cccDNA to integrated HBV DNA during treatment.
J Clin Invest 135(6)
Authors: Maraake Taddese, Tanner Grudda, Giulia Belluccini, Mark Anderson, Gavin Cloherty, Hyon S Hwang, Monika Mani, Che-Min Lo, Naomi Esrig, Mark S Sulkowski, Richard K Sterling, Yang Zhang, Ruy M Ribeiro, David L Thomas, Chloe L Thio, Ashwin Balagopal
Affiliations
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
- Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
- Abbott Diagnostics, Abbott Park, Illinois, USA.
- Divison of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA.
- Division of Gastrointestinal and Hepatic Pathology, Joint Pathology Center, Silver Spring, Maryland, USA.
Abstract
The cornerstone of functional cure for chronic hepatitis B (CHB) is hepatitis B surface antigen (HBsAg) loss from blood. HBsAg is encoded by covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome (iDNA). Nucleos(t)ide analogs (NUCs), the mainstay of CHB treatment, rarely lead to HBsAg loss, which we hypothesized was due to continued iDNA transcription despite decreased cccDNA transcription. To test this, we applied a multiplex droplet digital PCR that identifies the dominant source of HBsAg mRNAs to 3,436 single cells from paired liver biopsies obtained from 10 people with CHB and HIV receiving NUCs. With increased NUC duration, cells producing HBsAg mRNAs shifted their transcription from chiefly cccDNA to chiefly iDNA. This shift was due to both a reduction in the number of cccDNA-containing cells and diminished cccDNA-derived transcription per cell; furthermore, it correlated with reduced detection of proteins deriving from cccDNA but not iDNA. Despite this shift in the primary source of HBsAg, rare cells remained with detectable cccDNA-derived transcription, suggesting a source for maintaining the replication cycle. Functional cure must address both iDNA and residual cccDNA transcription. Further research is required to understand the significance of HBsAg when chiefly derived from iDNA.
MeSH
Hepatitis B Surface Antigens, Cells, Antigens, Surface, Therapeutics, Hepatitis B, Dna, Hepatitis