Combined small molecule and loss-of-function screen uncovers estrogen receptor alpha and CAD as host factors for HDV infection and antiviral targets.
Gut
; 69(1): 158-167, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-30833451
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácido Fosfonoacéticos
/
Pirimidinas
/
Aspartato Carbamoiltransferase
/
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)
/
Ácido Aspártico
/
Hepatite D Crônica
/
Receptor alfa de Estrogênio
/
Di-Hidro-Orotase
/
Fulvestranto
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Gut
Ano de publicação:
2020
Tipo de documento:
Article