Combined small molecule and loss-of-function screen uncovers estrogen receptor alpha and CAD as host factors for HDV infection and antiviral targets. Issue 1 (4th March 2019)

• Record Type: Journal Article
• Authors: Verrier, Eloi R; Weiss, Amélie; Bach, Charlotte; Heydmann, Laura; Turon-Lagot, Vincent; Kopp, Arnaud; El Saghire, Houssein; Crouchet, Emilie; Pessaux, Patrick; Garcia, Thomas; Pale, Patrick; Zeisel, Mirjam B; Sureau, Camille; Schuster, Catherine; Brino, Laurent; Baumert, Thomas F
• Is Part Of: Gut. Volume 69:Issue 1(2020)
• Page Start: 158
• Page End: 167
• Publication Date: 2019-03-04
• Subjects: antiviral therapy -- hepatitis D -- screening -- liver; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-317065
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.