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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 28, 2016; 22(24): 5467-5478
Published online Jun 28, 2016. doi: 10.3748/wjg.v22.i24.5467
X region mutations of hepatitis B virus related to clinical severity
Hong Kim, Seoung-Ae Lee, Bum-Joon Kim
Hong Kim, Seoung-Ae Lee, Bum-Joon Kim, Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Chongno-gu, Seoul 110-799, South Korea
Author contributions: Kim BJ conceived this research and participated in its design and coordination; Kim H and Lee SA analyzed and interpreted the data; Kim BJ and Kim H wrote this manuscript; Kim H and Lee SA reviewed the manuscript; All authors approved the final manuscript.
Supported by National Research Foundation grant of Ministry of Science, ICT and Future Planning, South Korea, No. NRF-2015R1C1A1A02037267; and Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, South Korea, No. HI14C0955.
Conflict-of-interest statement: No conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Bum-Joon Kim, PhD, Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul 110-799, South Korea.
Telephone: + 82-2-7408316 Fax: + 82-2-7430881
Received: March 24, 2016
Peer-review started: March 25, 2016
First decision: May 12, 2016
Revised: May 17, 2016
Accepted: June 2, 2016
Article in press: June 2, 2016
Published online: June 28, 2016

Chronic hepatitis B virus (HBV) infection remains a major health problem, with more than 240 million people chronically infected worldwide and potentially 650000 deaths per year due to advanced liver diseases including liver cirrhosis and hepatocellular carcinoma (HCC). HBV-X protein (HBx) contributes to the biology and pathogenesis of HBV via stimulating virus replication or altering host gene expression related to HCC. The HBV X region contains only 465 bp encoding the 16.5 kDa HBx protein, which also contains several critical cis-elements such as enhancer II, the core promoter and the microRNA-binding region. Thus, mutations in this region may affect not only the HBx open reading frame but also the overlapped cis-elements. Recently, several types of HBx mutations significantly associated with clinical severity have been described, although the functional mechanism in most of these cases remains unsolved. This review article will mainly focus on the HBx mutations proven to be significantly related to clinical severity via epidemiological studies.

Keywords: Hepatitis B virus infection, Hepatitis B virus-X protein mutation, Hepatocellular carcinoma, Clinical severity

Core tip: Of hepatitis B virus (HBV)-X protein (HBx) mutations related to clinical severity, the A1762T/G1764A BCP mutation is one of the most frequently encountered HBx mutations and plays a significant role in liver disease progression in chronic patients with HBV infections. It also further contributes to disease progression by inducing mutations of other HBx mutations related to clinical severity, such as G1386A/C (V5M/L), C1653T (H94Y), T1753V (I127V) and HBx C-terminal deletion or insertion. Moreover, T1753V (I127L,T,N,S) and C1653T (H94Y) mutations in the enhancer II/BCP region and A1383C, G1386A/C (V5M/L) and C1485T (P38S) in the negative regulation domain are significantly related to severe types of liver diseases, including hepatocellular carcinoma. Furthermore, deletions or insertions affecting the C-terminal region of HBx may also contribute to the severity of the clinical outcome in chronic patients. In addition, our recent study indicated that a novel mutation type (X8Del) composed of an 8-bp deletion in the C-terminal region of the HBx could contribute to occult HBV infection in vaccinated Korean individuals via a reduced secretion of HBsAg and virions. Therefore, several distinct types of HBx mutations may contribute to HBV pathogenesis by regulating HBV replication or host genes related to cell homeostasis.