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Gut. 2019 Mar 4. pii: gutjnl-2018-317065. doi: 10.1136/gutjnl-2018-317065. [Epub ahead of print]

Combined small molecule and loss-of-function screen uncovers estrogen receptor alpha and CAD as host factors for HDV infection and antiviral targets.

Author information

1
Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, F-67000 Strasbourg, France.
2
IGBMC, Plateforme de Criblage Haut-débit, UMR7104 CNRS U1258 Inserm, Illkirch, France.
3
Institut Hospitalo-universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
4
Laboratoire de Synthèse, Réactivité Organiques et Catalyse, Institut de Chimie, UMR 7177 CNRS, Université de Strasbourg, Strasbourg, France.
5
INTS, Laboratoire de Virologie Moléculaire, Paris, France.
6
Institut Universitaire de France, Paris, France.

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.

KEYWORDS:

antiviral therapy; hepatitis D; liver; screening

PMID:
30833451
DOI:
10.1136/gutjnl-2018-317065

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