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World J Gastroenterol. Jul 7, 2014; 20(25): 7993-8004
Published online Jul 7, 2014. doi: 10.3748/wjg.v20.i25.7993
Prospects for inhibiting the post-transcriptional regulation of gene expression in hepatitis B virus
Augustine Chen, Nattanan Panjaworayan T-Thienprasert, Chris M Brown
Augustine Chen, Centre for Translational Cancer Research, Department of Biochemistry, University of Otago, 710 Cumberland St, Dunedin 9054, New Zealand
Nattanan Panjaworayan T-Thienprasert, Department of Biochemistry, Faculty of Science, Kasetsart University, Ladyaow Chatuchak, Bangkok 10900, Thailand
Chris M Brown, Department of Biochemistry and Webster Centre for Infectious diseases, University of Otago, 710 Cumberland St, Dunedin 9054, New Zealand
Author contributions: All authors contributed equally to writing this review.
Supported by Thailand Research Fund and the Commission on Higher Education Fund grant (to Nattanan Panjaworayan T-Thienprasert), No. MRG5680051; and NZ Health Research Council Grant 05/195 (to Augustine Chen and Chris M Brown)
Correspondence to: Chris M Brown, PhD, Department of Biochemistry and Webster Centre for Infectious diseases, University of Otago, 710 Cumberland St, Dunedin 9054, New Zealand. chris.brown@otago.ac.nz
Telephone: +64-3-4795201 Fax: +64-3-4797866
Received: October 25, 2013
Revised: January 19, 2014
Accepted: April 8, 2014
Published online: July 7, 2014
Processing time: 251 Days and 4.7 Hours
Abstract

There is a continuing need for novel antivirals to treat hepatitis B virus (HBV) infection, as it remains a major health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral lifecycle. In this review, we consider the steps in which HBV RNAs are processed, exported from the nucleus and translated. These are often overlooked steps in the HBV life-cycle. HBV, like retroviruses, incorporates a number of unusual steps in these processes, which use a combination of viral and host cellular machinery. Some of these unusual steps deserve a closer scrutiny. They may provide alternative targets to existing antiviral therapies, which are associated with increasing drug resistance. The RNA post-transcriptional regulatory element identified 20 years ago promotes nucleocytoplasmic export of all unspliced HBV RNAs. There is evidence that inhibition of this step is part of the antiviral action of interferon. Similarly, the structured RNA epsilon element situated at the 5’ end of the polycistronic HBV pregenomic RNA also performs key roles during HBV replication. The pregenomic RNA, which is the template for translation of both the viral core and polymerase proteins, is also encapsidated and used in replication. This complex process, regulated at the epsilon element, also presents an attractive antiviral target. These RNA elements that mediate and regulate gene expression are highly conserved and could be targeted using novel strategies employing RNAi, miRNAs or aptamers. Such approaches targeting these functionally constrained genomic regions should avoid escape mutations. Therefore understanding these regulatory elements, along with providing potential targets, may also facilitate the development of other new classes of antiviral drugs.

Keywords: Hepatitis B virus; Translational control; Antiviral; Nuclear export; Post-transcriptional control; Nucleocytoplasmic export

Core tip: This review presents an outline of what is known about post-transcriptional regulation of gene expression in hepatitis B virus, a virus that infects over 200 million people worldwide. These steps may be targeted by novel antivirals, or be considered when characterising new antivirals derived from screening natural or synthetic products.