Hepatitis B patient-derived virus exhibits replication step-dependent resistance to Interferon in a chronic in-vitro infection model

Overview

Chronic Hepatitis B virus (HBV) infection affects 300 million people worldwide, with no existing cure. The first-line treatment is interferon (IFN), an antiviral cytokine. However, clinical IFN therapy only reduces HBV DNA levels in 25% of patients, suggesting that some exhibit resistance to IFN. Genotype, viral load, and other factors are hypothesized to influence this resistance. Conversely, research studies show that IFN treatment consistently reduces both HBV DNA and viral protein levels. To investigate the contradiction between clinical and laboratory research findings, infectious virions of varying genotypes and propagation methods were cultured using a highly physiologically relevant model: humanized liver chimeric mice-derived human hepatocytes (HLCM-HHs). To examine IFN’s direct effects, HBV-infected HLCM-HHs were treated with IFN-alpha and IFN-beta for 10 days, and pre-genomic HBV RNA, extracellular HBV surface antigens, and HBV DNA levels were measured. The results revealed resistance to exogenous IFN among patient-derived inocula, despite induction of IFN-response genes in all inocula. Then, to validate these findings, HLCM-HH's were coinfected with Hepatitis Delta Virus (HDV), a satellite virus of HBV that induces the IFN response. HDV coinfection reinforced previous results: HBV DNA levels were not affected when treated with three genotypes of patient-derived inocula, despite IFN-response gene induction in all six. The patient-resistant samples differed in genotype between these experiments, implying that in-vitro HBV resistance to IFN is genotype-independent. Ultimately, this study establishes a correlation between HBV DNA and HBsAg reduction among patient inocula regardless of genotype, elucidating novel mechanisms of IFN resistance for improvement of clinical IFN therapy.

Awards (2)

Category Award: HM
Sponsored Award: Senior Division Biochemistry/Molecular Biology Award

Competition history

CSEF 2023 Biochemistry/ Molecular Biology · Entry S0508

Resources

Related projects

JSHS · 2023