Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2020; 26(21): 2781-2791
Published online Jun 7, 2020. doi: 10.3748/wjg.v26.i21.2781
Innate immune recognition and modulation in hepatitis D virus infection
Stephanie Jung, Sebastian Maximilian Altstetter, Ulrike Protzer
Stephanie Jung, Sebastian Maximilian Altstetter, Ulrike Protzer, Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich D-81675, Germany
Ulrike Protzer, German Center for Infection Research (DZIF), Munich Partner Site, Munich D-81675, Germany
Author contributions: Jung S, Altstetter SM and Protzer U contributed to the writing and revising of the manuscript.
Supported by German Research Foundation, No. TRR 179.
Conflict-of-interest statement: The authors declare no conflict of interests concerning the content of this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Ulrike Protzer, MD, Director, Professor, Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, German Center for Infection Research (DZIF), Munich Partner Site, Trogerstrasse 30, Munich D-81675, Germany.
Received: December 29, 2019
Peer-review started: December 29, 2019
First decision: January 19, 2020
Revised: March 30, 2020
Accepted: May 23, 2020
Article in press: May 23, 2020
Published online: June 7, 2020

Hepatitis D virus (HDV) is a global health threat with more than 15 million humans affected. Current treatment options are largely unsatisfactory leaving chronically infected humans at high risk to develop liver cirrhosis and hepatocellular carcinoma. HDV is the only human satellite virus known. It encodes only two proteins, and requires Hepatitis B virus (HBV) envelope protein expression for productive virion release and spread of the infection. How HDV could evolve and why HBV was selected as a helper virus remains unknown. Since the discovery of Na+-taurocholate co-transporting polypeptide as the essential uptake receptor for HBV and HDV, we are beginning to understand the interactions of HDV and the immune system. While HBV is mostly regarded a stealth virus, that escapes innate immune recognition, HBV-HDV coinfection is characterized by a strong innate immune response. Cytoplasmic RNA sensor melanoma differentiation antigen 5 has been reported to recognize HDV RNA replication and activate innate immunity. Innate immunity, however, seems not to impair HDV replication while it inhibits HBV. In this review, we describe what is known up-to-date about the interplay between HBV as a helper and HDV’s immune evasion strategy and identify where additional research is required.

Keywords: Hepatitis D virus, Hepatitis B virus, Innate immunity, Pathogen-associated molecular pattern molecules, Immune evasion, Immunosuppression

Core tip: Hepatitis D virus (HDV) is the only known human satellite virus requiring hepatitis B virus (HBV) coinfection for productive viral release. However, it was recently shown that HDV can be disseminated by viruses other than HBV in experimental setups, so it remains unexplained why HDV chose HBV as a helper virus. As HDV might possibly profit from HBV mediated immunosuppression, we first focus on recent findings on HDV recognition by the innate immune system. Later on, we summarize partially controversial data on immunomodulatory mechanisms of both, HBV and HDV.