RT Journal Article
SR Electronic
T1 Combined small molecule and loss-of-function screen uncovers estrogen receptor alpha and CAD as host factors for HDV infection and antiviral targets
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 158
OP 167
DO 10.1136/gutjnl-2018-317065
VO 69
IS 1
A1 Eloi R Verrier
A1 Amélie Weiss
A1 Charlotte Bach
A1 Laura Heydmann
A1 Vincent Turon-Lagot
A1 Arnaud Kopp
A1 Houssein El Saghire
A1 Emilie Crouchet
A1 Patrick Pessaux
A1 Thomas Garcia
A1 Patrick Pale
A1 Mirjam B Zeisel
A1 Camille Sureau
A1 Catherine Schuster
A1 Laurent Brino
A1 Thomas F Baumert
YR 2020
UL http://gut.bmj.com/content/69/1/158.abstract
AB 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.