Kinetics of Intrahepatic Covalently Closed Circular DNA and Serum Hepatitis B Surface Antigen During Antiviral Therapy for Chronic Hepatitis B: Lessons From Experimental and Clinical Studies  Fabien Zoulim, MD, PhD, Barbara Testoni, PhD, Fanny Lebossé, MD  Clinical Gastroenterology and Hepatology  Volume 11, Issue 8, Pages 1011-1013 (August 2013) DOI: 10.1016/j.cgh.2013.04.010 Copyright © 2013 AGA Institute Terms and Conditions

Figure 1 HBsAg synthesis and cccDNA dynamics during HBV infection. HBsAg is produced from cccDNA and HBV sequences integrated in the host genome. Then, HBs is secreted as a component of complete virions, as well as filamentous and spherical particles. NUC-based treatment interferes with viral polymerase activity and recycling of newly synthesized relaxed, circular, partially double-stranded DNA (rcDNA) into the cell nucleus, ultimately affecting both virion productivity and cccDNA pool amplification. Viral cccDNA is organized as a minichromosome and its transcriptional activity is regulated epigenetically, which in turn may affect HBsAg expression levels. IFN-based treatments favor the recruitment of negative regulators, determining a cccDNA silenced chromatin status, not permissive to active transcription and expression of viral proteins. When the liver is subjected to injury/regeneration cycles, hepatocyte turnover contributes to the dilution of cccDNA content, but it does not affect HBV-integration events, which continue to represent a potential source of HBsAg production. ESCRT, endosomal sorting complexes required for transport; DNMT, DNA methyl-transferase; HAT, histone acetyl-transferase; HBc, HBV Core protein; HBx, HBV X protein; HDAC, histone deacetylase; HMT, histone methyl-transferase; HP1, heterochromatin protein 1; MeCP2, methyl CpG binding protein 2; mRNA, messenger RNA; MVB, multi-vesicular bodies; PCAF, p300/CREB-binding protein-associated factor; Sirt1, human Silent Information Regulator, sirtuin; Suv39, Histone H3-K9 Methyltransferase ESET; TF, transcription factor. Clinical Gastroenterology and Hepatology 2013 11, 1011-1013DOI: (10.1016/j.cgh.2013.04.010) Copyright © 2013 AGA Institute Terms and Conditions