Abstract
Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Here, we perform a genome-wide gain-of-function screen using a poorly permissive hepatoma cell line to uncover host factors enhancing HBV infection. Validation studies in primary human hepatocytes identified CDKN2C as an important host factor for HBV replication. CDKN2C is overexpressed in highly permissive cells and HBV-infected patients. Mechanistic studies show a role for CDKN2C in inducing cell cycle G1 arrest through inhibition of CDK4/6 associated with the upregulation of HBV transcription enhancers. A correlation between CDKN2C expression and disease progression in HBV-infected patients suggests a role in HBV-induced liver disease. Taken together, we identify a previously undiscovered clinically relevant HBV host factor, allowing the development of improved infectious model systems for drug discovery and the study of the HBV life cycle.
Highlights
Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide
The capsid delivers the viral genome to the nucleus, where HBV relaxed circular DNA is converted into episomal covalently closed circular DNA, in a process thought to be mediated by host DNA repair enzymes, such as tyrosyl-DNAphosphodiesterase 29 and DNA Polymerase kappa[10]
The closed circular DNA (cccDNA) is the reservoir for viral persistence and serves as a template for all viral transcripts. cccDNA levels are not affected by the nucleot(s)ide analogs (NUCs)-based treatments targeting the viral reverse transcriptase, which converts viral pregenomic RNA into de novo genomic DNA, within newly formed nucleocapsids prior to virion budding[11]
Summary
Chronic HBV infection is a major cause of liver disease and cancer worldwide. Approaches for cure are lacking, and the knowledge of virus-host interactions is still limited. Available drugs for the treatment of chronic HBV infection, such as NUCs, are direct-acting antivirals and allow the suppression of viral replication, but viral cure is rarely achieved. Innovative therapeutic strategies, such as host-targeting agents (HTAs), have emerged as novel candidates for the treatment of viral infections, including hepatotropic viruses[12,13,14,15]. NTCP-overexpressing Huh[7] cells remain poorly permissive to HBV infection but support infection by hepatitis D virus (HDV), an HBV-satellite virus carrying HBV envelope proteins[16] This suggests that after HBV entry, additional key factors are still limiting in these cells. We expect that the identification of these previously undiscovered HBV factors will facilitate the development of improved infectious cell culture systems for the identification of innovative antiviral molecules
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