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New Insights into Hepatitis D Virus Persistence: the Role of Interferon Response and Implications for Upcoming Novel Therapies
J Hepatol. 2020 Dec 1;S0168-8278(20)33819-8. doi: 10.1016/j.jhep.2020.11.032.Online ahead of print.
Zhenfeng Zhang1, Stephan Urban2
1Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
2Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany;; German Center for Infection Research (DZIF) - Heidelberg Partner Site, Heidelberg, Germany;. Electronic address: Stephan.Urban@med.uni-heidelberg.de.
Chronic hepatitis D (CHD), a global health problem, manifests as the most severe form of viral hepatitis. The causative agent, hepatitis D virus (HDV), is the smallest known human virus replicating its circular single-stranded RNA genome in the nucleus of hepatocytes. HDV requires hepatitis B virus (HBV) encoded envelope proteins for dissemination and de novo cell entry. However, HDV can also spread through cell division. Following NTCP-mediated entry into hepatocytes, replicative intermediates of HDV-RNA are sensed by the pattern recognition receptor MDA5 resulting in IFN-β/λ induction. This IFN response strongly suppresses cell-division-mediated spread of HDV genomes, however only marginally affects HDV RNA replication in already infected, resting hepatocytes. In patients, mono-therapy with IFN-α/λ shows efficacy but rarely results in HDV clearance. Recent molecular insights into key determinants of HDV persistence, and the accelerated development of specifically acting antivirals interfering with the replication cycle, opens promising new therapeutic perspectives. In this review, we shortly summarize our knowledge on replication/persistence of HDV and the newly discovered HDV-like agents, the interplay of HDV with IFN response and its consequences for persistence. Finally, we discuss the possible role of IFNs in combination with upcoming new therapies aiming at HDV cure.