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

Abstract

Long noncoding RNAs (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 HOXA distal transcript antisense RNA (HOTTIP) to be significantly up-regulated. 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, hepatitis B viral e antigen and HBV replication. Homeobox A13 (HOXA13), a downstream factor of HOTTIP, was found to bind to HBV enhancer I and X promotor 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 polymerase (DNA pol) binds to and stabilizes cAMP-responsive element-binding protein 1 (CREB1) mRNA to facilitate translation of the protein, which, in turn, binds to the regulatory element of HOTTIP to promote its expression. Our findings demonstrate that HBV DNA pol attenuates HBV replication through activation of the CREB1-HOTTIP-HOXA13 axis. These findings shed light on the mechanism by which HBV restrains replication to contribute to persistent infection.