Hepatitis D (HDV) is a viral hepatitis caused by hepatitis D virus (HDV) infection, often occurring as a co-infection or superinfection with hepatitis B virus (HBV). Approximately 90% of chronic hepatitis B patients who become co-infected with HDV develop chronic hepatitis, increasing the risk of adverse outcomes such as liver failure, cirrhosis, and liver cancer. Due to the historical underestimation of HDV prevalence and disease burden, it has not received the attention it deserves. Hepatitis E virus (HEV) infection is a major cause of acute hepatitis globally, with no specific antiviral drugs available.
At the 58th Annual Meeting of the European Association for the Study of the Liver (EASL 2023) and the EASL Congress 2023, three new research abstracts from Dr. Wenshi Wang’s team at the Jiangsu Provincial Key Laboratory of Immunology and Metabolism, Xuzhou Medical University, have been selected. Hepatology Digest presents the latest research developments in the fields of hepatitis D and hepatitis E.
Tracing the Origin and Evolution Dynamics of Hepatitis D Virus
Chronic HDV infection can lead to the most severe viral hepatitis. Although discovered over 40 years ago, the origin and evolution of HDV remain unclear. As a satellite virus of HBV, it is poorly understood whether there is shared evolution and migration between HDV and HBV. This study aims to map the geographic and temporal dynamics of HDV’s evolution.
The study found that the origin time and rapid spread period of HDV were distant on the timeline. Specifically, HDV can be traced back to 1280 in the human population, evolving into eight genotypes between 1810 and 1920. In contrast, HBV can be traced back to 23,700 years ago, evolving into eight genotypes about 1,100 years ago. Additionally, HDV originated in South America, mainly spreading globally through Central Asia, while HBV originated in Europe, primarily spreading through Africa and East Asia. Both viruses had distinct temporal and geographical transmission routes. Despite this, HDV showed significant geographical isolation characteristics. Adaptation to HBV genotypes and human lineages contributed to HDV evolution and branching.
In conclusion,This study reveals the origin and evolutionary process of HDV. HDV and HBV have different geographical and temporal origins, indicating no shared evolution and migration. However, HDV’s genetic diversity is driven by multiple factors, including HBV genotypes and human lineages. This study provides insights into the unique distribution characteristics of HDV worldwide.This research won “EASL Congress 2023 – Full Bursary Award” and “EASL Congress 2023 – Best Poster Presentation Award.”
Regulation of HDV Lifecycle and Response to Lonafarnib by Different Genotypes of L-HDAg C-Terminal Region
HDV belongs to the Hepatitis D virus family and is a spherical, icosahedral, RNA virus with a diameter of about 36 nm. It has eight genotypes, each with distinct lifecycle dynamics. HDV’s replication cycle includes various stages, with different therapeutic targets. This study explores the role of the C-terminal region of L-HDAg in the HDV lifecycle and its response to Lonafarnib treatment.
They constructed constructs expressing chimeric or mutated L-HDAg and an HDV reverse-complementation system to study the role of the C-terminal region of L-HDAg in HDV replication and virus assembly in detail.
Despite significant differences in the C-terminal regions of L-HDAg among HDV genotypes 1-8, they had similar effects on inhibiting HDV replication and supporting virus assembly. Specific residues, including proline and hydrophobic residues, and the prenylation site in the C-terminus supported HDV envelopment. Conversely, the prenylation site, rather than proline and hydrophobic residues, contributed to the trans-repressive function of L-HDAg. This finding explains Lonafarnib’s dual mode of action on HDV: blocking virus particle assembly and promoting intracellular HDV replication. These actions specifically target L-HDAg of HDV, avoiding off-target effects on host prenylation proteins.
In conclusion,The different C-terminal regions of L-HDAg themselves are not the potential reasons for the distinct dynamics of HDV genotypes 1-8. During HDV envelopment, the prenylation site and hydrophobic residues in L-HDAg may interact hydrophobically with the hydrophobic C-terminus of S-HBsAg, while proline may extend the C-terminus of L-HDAg to promote protein-protein interactions. These findings provide insights into the unique lifecycle of HDV and guide the clinical application of Lonafarnib.This research won “EASL Congress 2023 – Full Bursary Award.”
miR-26a Targets USP15 to Suppress Hepatitis E Virus Replication via Enhanced RIG-I-Mediated Type I Interferon Response
Hepatitis E virus (HEV) is an RNA virus belonging to the Hepatitis E family and is a major cause of acute viral hepatitis worldwide. Currently, there are no specific antiviral drugs for HEV. Small non-coding RNAs play a role in the host’s natural antiviral response and could serve as a new strategy against HEV. However, the critical miRNAs that regulate the HEV lifecycle remain unclear.
The study used dual-luciferase reporter gene assays to measure IFN-β promoter activity and real-time quantitative PCR (qRT-PCR) to measure IFN-β, interferon-stimulated genes (ISGs), USP15 mRNA levels, or HEV RNA levels. Protein levels of USP15, RIG-I, IRF3, and HEV ORF2 were validated using immunoblotting or immunofluorescence assays. Co-immunoprecipitation and immunoblotting analysis determined the interaction or ubiquitination level between USP15 and key elements of the IFN signaling pathway.
It found that miR-26a inhibits HEV replication by specifically suppressing USP15 expression. Molecular mechanisms revealed that USP15 interacts directly with Retinoic Acid-Inducible Gene I (RIG-I), deubiquitinating K63-linked RIG-I, thereby negatively regulating type I interferon (IFN) signaling. Conversely, miR-26a enhances RIG-I K63 ubiquitination by downregulating USP15, leading to increased type I IFN antiviral responses and anti-HEV activity. Interestingly, the activation of the type I IFN response can inhibit miR-26a expression, serving as an intrinsic negative feedback loop to maintain balanced activation signals.
In conclusion,This study identified a new anti-HEV miRNA and elucidated its antiviral mechanism. miR-26a may serve as a potential antiviral drug against HEV infection.
Xuzhou Medical University
TAG: EASL2023;Vioce of China;HDV;HEV
