Volume 68, Issue 3, Pages 386-388 (March 2018) Inhibition of hepatitis B virus gene expression: A step towards functional cure  Fabien Zoulim  Journal of Hepatology  Volume 68, Issue 3, Pages 386-388 (March 2018) DOI: 10.1016/j.jhep.2017.11.036 Copyright © 2017 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Key obstacles to be overcome to attain HBV cure (adapted from Testoni et al.6). cccDNA viral minichromosome persistence and transcriptional activity are at the basis of HBV replication and antigen production. HBV DNA integration in the host genome is not supposed to contribute to virion production, but there are several lines of evidence that HBsAg may also originate from integrated sequences. During chronic infection, there is a progressive impairment in HBV specific T cell function, due to multiple mechanisms, including prolonged exposure to secreted HBV antigens, a deficient activation of innate immune cells and defective antigen presentation by infected cells, and the restoration of a tolerogenic environment in the infected liver, due to immune-modulatory cells and secretion of tolerogenic molecules. To decrease HBsAg levels and potentially restore innate and adaptive immunity, several paths can be followed: i) targeting cccDNA through elimination or silencing its transcriptional activity; ii) targeting viral transcripts via antisense oligonucleotides or small interfering RNAs; iii) interfering with envelope protein processing and half-life in the blood. cccDNA, covalently closed circular DNA; DC, dendritic cell; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; IL-10, interleukin-10; NK, natural killer; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand-1; pgRNA, pregenomic RNA; rcDNA, relaxed circular DNA; TGFβ, transforming growth factor-β. Journal of Hepatology 2018 68, 386-388DOI: (10.1016/j.jhep.2017.11.036) Copyright © 2017 European Association for the Study of the Liver Terms and Conditions