A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production

A hallmark of chronic hepatitis B virus (CHB) infection is the presence of high circulating levels of non-infectious small lipid HBV surface antigen ( HBsAg) vesicles. Although rare, sustained HBsAgloss is the idealized endpoint of any CHB therapy. A novel small molecule RG7834 has been previously reported to inhibit HBsAgexpression by targeting terminal nucleotidyltransferaseprotein 4A and 4B (TENT4A and TENT4B). In this study, we describe a genome-wide CRISPRscreen to identify other potential novel host factorsrequired for HBsAgexpression and to gain further insights into the mechanism of RG7834. We report more than 60 genes involved in regulating HBsAgand identified novel factors involved in RG7834 activity, including a zinc fingerCCHC-type containing 14 (ZCCHC14) protein. We show that ZCCHC14, together with TENT4A/B, stabilizes HBsAgexpression through HBV RNA tailing, providing a potential new therapeutic target to achieve functional cure in CHB patients.