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World J Gastroenterol. Oct 28, 2014; 20(40): 14589-14597
Published online Oct 28, 2014. doi: 10.3748/wjg.v20.i40.14589
Hepatitis D virus infection, replication and cross-talk with the hepatitis B virus
Chi-Ruei Huang, Szecheng John Lo
Chi-Ruei Huang, Szecheng John Lo, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan
Chi-Ruei Huang, Szecheng John Lo, Department and Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
Szecheng John Lo, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
Author contributions: Huang CR and Lo SJ both wrote the main text of this review article.
Supported by Grants (CMRPD-1C0811) from Chang Gung Memorial Hospital, the National Science Council and the National Health Research Institute to Lo SJ
Correspondence to: Szecheng John Lo, PhD, Department of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Taoyuan 333, Taiwan. losj@mail.cgu.edu.tw
Telephone: +886-3-2118800-3295 Fax: +886-3-2118392
Received: October 28, 2013
Revised: May 12, 2014
Accepted: June 20, 2014
Published online: October 28, 2014
Abstract

Viral hepatitis remains a worldwide public health problem. The hepatitis D virus (HDV) must either coinfect or superinfect with the hepatitis B virus (HBV). HDV contains a small RNA genome (approximately 1.7 kb) with a single open reading frame (ORF) and requires HBV supplying surface antigens (HBsAgs) to assemble a new HDV virion. During HDV replication, two isoforms of a delta antigen, a small delta antigen (SDAg) and a large delta antigen (LDAg), are produced from the same ORF of the HDV genome. The SDAg is required for HDV replication, whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA. Various clinical outcomes of HBV/HDV dual infection have been reported, but the molecular interaction between HBV and HDV is poorly understood, especially regarding how HBV and HDV compete with HBsAgs for assembling virions. In this paper, we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export. Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications (PTMs), including acetylation, phosphorylation, and isoprenylation, we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling, LDAg PTMs, and nuclear export mechanisms in this review.

Keywords: Hepatitis B virus, Hepatitis D virus, Posttranslational modification, Endoplasmic reticulum stress, Nuclear export

Core tip: Hepatitis D virus (HDV) is a defective virus that depends on hepatitis B virus (HBV) to supply envelope proteins (HBsAgs) for assembling a new virion. The association of the clinical severity of hepatitis with HDV genotypes (HDV-1 to 8) has been reported, but the mechanism is unknown. Whether the combinations of HBV genotypes (A to H) with HDV genotypes cause varying clinical outcomes remains to be explored. This review focuses on HDV replication, the cross-talk between HDV and HBV, and the endoplasmic reticulum (ER) stress induced by HBsAgs in the ER which results in the promotion of large delta antigen export from the nucleus to interact with HBsAgs.