Advanced Stem Cell Model Enhances Understanding of Hepatitis D Virus Mechanisms

Hepatitis D virus (HDV), a significant contributor to severe liver inflammation, affects approximately 12 million people globally, according to World Health Organization estimates. Despite its impact, treatment options remain limited. Researchers from TWINCORE, the Center for Experimental and Clinical Infection Research in Hannover, have innovated a stem cell-based infection model to study HDV, providing new insights into its biology and potential therapeutic targets.

This novel model utilizes stem cell-derived liver cells that closely mimic primary liver cells, offering a more accurate environment to investigate HDV infection compared to traditional liver cell lines. Dr. Arnaud Carpentier, an expert in stem cell infection models at TWINCORE, emphasized the model's realism, which could facilitate a better understanding of how the virus interacts with liver tissue.

HDV is unique as a satellite virus relying on hepatitis B virus (HBV) components to form its protective shell. Its dependence on HBV explains why vaccines targeting hepatitis B also confer protection against HDV. Currently, treatments are mainly limited to interferon-alpha and Hepcludex, a drug that blocks HDV entry into liver cells. However, Hepcludex does not prevent the virus from spreading during cell division, highlighting the need for new antiviral strategies.

Using the stem cell-based system, the team conducted single-cell sequencing to analyze gene activity during infection. This analysis revealed two distinct cell populations: one with active viral replication and another where the virus was unable to reproduce. A key difference between these groups was the expression of the gene IRF1 (Interferon Regulatory Factor 1), which plays a crucial role in cellular immune response.

Frauke Lange, a doctoral researcher at the institute and first author of the study, explained that overexpression of IRF1 inhibits HDV infection and prevents its spread during cell division — a step not targeted by current therapies like Hepcludex. IRF1 regulates 101 downstream genes, and Lange's team aims to identify which of these contribute to its antiviral effects. Their findings open new avenues for developing combination therapies that could complement existing treatments.

Overall, this research underscores the value of stem cell-based infection models in virology and offers promising directions for future HDV therapies. As the team continues their work, these insights may lead to more effective interventions against this severe form of viral hepatitis.