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Cell-based CccDNA Reporter Assay Combined with Functional Genomics Identifies YBX1 as HBV CccDNA Host Factor and Antiviral Candidate Target
Eloi R. Verrier
Gaëtan Ligat
Laura Heydmann
Katharina Dörnbrack
Julija Miller
Anne Maglott-Roth
Frank Jühling
Houssein El Saghire
Margaux J Heuschkel
Naoto Fujiwara
Sen-Yung Hsieh
Yujin Hoshida
David E. Root
Emanuele Felli
Patrick Pessaux
Atish Mukherji
Laurent Mailly
Catherine Schuster
Laurent Brino
Michael Nassal
Thomas Baumert
出版
Universität
, 2023
URL
http://books.google.com.hk/books?id=iZ8u0AEACAAJ&hl=&source=gbs_api
註釋
Abstract: Objectives Chronic hepatitis B virus (HBV) infection is a leading cause of liver disease and hepatocellular carcinoma. A key feature of HBV replication is the synthesis of the covalently close circular (ccc)DNA, not targeted by current treatments and whose elimination would be crucial for viral cure. To date, little is known about cccDNA formation. One major challenge to address this urgent question is the absence of robust models for the study of cccDNA biology.
Design We established a cell-based HBV cccDNA reporter assay and performed a loss-of-function screen targeting 239 genes encoding the human DNA damage response machinery.
Results Overcoming the limitations of current models, the reporter assay enables to quantity cccDNA levels using a robust ELISA as a readout. A loss-of-function screen identified 27 candidate cccDNA host factors, including Y box binding protein 1 (YBX1), a DNA binding protein regulating transcription and translation. Validation studies in authentic infection models revealed a robust decrease in HBV cccDNA levels following silencing, providing proof-of-concept for the importance of YBX1 in the early steps of the HBV life cycle. In patients, YBX1 expression robustly correlates with both HBV load and liver disease progression.
Conclusion Our cell-based reporter assay enables the discovery of HBV cccDNA host factors including YBX1 and is suitable for the characterisation of cccDNA-related host factors, antiviral targets and compounds