期刊
GUT
卷 69, 期 1, 页码 158-167出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2018-317065
关键词
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资金
- Inserm
- University of Strasbourg
- European Union [671231, 667273]
- Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS) [15/1099]
- French Cancer Agency (ARC) [IHU201301187]
- LabEx [ANR-10-LA B-28]
- French National Research Agency as part of the Investments for the Future (Investissements d'Avenir) programme
- ANRS fellowship [ECTZ50121]
Objective Hepatitis D virus (HDV) is a circular RNA virus coinfecting hepatocytes with hepatitis B virus. Chronic hepatitis D results in severe liver disease and an increased risk of liver cancer. Efficient therapeutic approaches against HDV are absent. Design Here, we combined an RNAi loss-of-function and small molecule screen to uncover host-dependency factors for HDV infection. Results Functional screening unravelled the hypoxia-inducible factor (HIF)-signalling and insulin-resistance pathways, RNA polymerase II, glycosaminoglycan biosynthesis and the pyrimidine metabolism as virus-hepatocyte dependency networks. Validation studies in primary human hepatocytes identified the carbamoyl-phosphatesynthetase 2, aspartate transcarbamylase and dihydroorotase (CAD) enzyme and estrogen receptor alpha (encoded by ESR1) as key host factors for HDV life cycle. Mechanistic studies revealed that the two host factors are required for viral replication. Inhibition studies using N-(phosphonoacetyl)-L-aspartic acid and fulvestrant, specific CAD and ESR1 inhibitors, respectively, uncovered their impact as antiviral targets. Conclusion The discovery of HDV host-dependency factors elucidates the pathogenesis of viral disease biology and opens therapeutic strategies for HDV cure.
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