Hepatitis B Virus DNA Polymerase Restrains Viral Replication Through the CREB1/HOXA Distal Transcript Antisense RNA Homeobox A13 Axis

Abstract

LncRNAs have been associated with infection and hepatitis B virus (HBV)‐related diseases, though the underlying mechanisms remain unclear. We obtained HBV‐HCC lncRNA profiles by deep sequencing and found HOTTIP to be significantly upregulated. RT‐qPCR indicated that HOTTIP is highly expressed in HBV‐positive hepatoma tissue and induced by HBV in vitro. Virological experiments showed that HOTTIP significantly suppresses the generation of hepatitis B viral surface antigen (HBsAg), hepatitis B viral e antigen (HBeAg) and HBV replication. HOXA13, a downstream factor of HOTTIP, was found to bind to HBV Enh I/Xp to repress the production of HBV pregenome RNA (pgRNA) and total RNA as well as HBV replication, suggesting that HOXA13 mediates HOTTIP‐induced suppression of HBV replication. More interestingly, HBV DNA pol binds to and stabilizes CREB1 mRNA to facilitate translation of the protein, which in turn binds to the regulatory element of HOTTIP to promote its expression. Conclusion Our findings demonstrate that HBV DNA pol attenuates HBV replication via activation of the CREB1‐HOTTIP‐HOXA13 axis. These findings shed light on the mechanism by which HBV restrains replication to contribute to persistent infection.