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X region mutations of hepatitis B virus related to clinical severity

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World Journal of Gastroenterology 2016年第24期22卷 5467-5478页

作者： 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

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.

关键词： Hepatitis B virus infection Hepatitis B virus-X protein mutation Hepatocellular carcinoma Clinical severity

Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression

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World Journal of Gastroenterology 2018年第16期24卷 1708-1724页

作者： Yu-Min Choi So-Young Lee bum-joon kim Department of Microbiology and Immunology Biomedical Sciences Liver Research Institute and Cancer Research Institute Seoul National University College of Medicine

The annual number of deaths caused by hepatitis B virus(HBV)-related disease, including cirrhosis and hepatocellular carcinoma(HCC), is estimated as 887000. The reported prevalence of HBV reverse transcriptase(RT) mutation prior to treatment is varied and the impact of preexisting mutations on the treatment of na?ve patients remains controversial, and primarily depends on geographic factors, HBV genotypes, HBe Ag serostatus, HBV viral loads, disease progression, intergenotypic recombination and co-infection with HIV. Different sensitivity of detection methodology used could also affect their prevalence results. Several genotype-dependent HBV RT positions that can affect the emergence of drug resistance have also been reported. Eight mutations in RT(rtL80I, rtD134N, rtN139K/T/H, rtY141F, rtM204I/V, rtF221Y, rtI224V, and rtM309K) are significantly associated with HCC progression. HBe Ag-negative status, low viral load, and genotype C infection are significantly related to a higher frequency and prevalence of preexisting RT mutations. Preexisting mutations are most frequently found in the A-B interdomain of RT which overlaps with the HBs Ag "a" determinant region, mutations of which can lead to simultaneous viral immune escape. In conclusion, the presence of baseline RT mutations can affect drug treatment outcomes and disease progression in HBVinfected populations via modulation of viral fitness and host-immune responses.

关键词： polymerase hepatocellular carcinoma reverse transcriptase preexisting mutations hepatitis B virus

Precore/core region mutations of hepatitis B virus related to clinical severity

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World Journal of Gastroenterology 2016年第17期22卷 4287-4296页

作者： Hong kim Seoung-Ae Lee Seung Yeon Do bum-joon kim Department of Biomedical Sciences Microbiology and Immunology Liver Research Institute and Cancer Research Institute College of Medicine Seoul National University

Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem, with more than 350 million chronically infected people worldwide and over 1 million annual deaths due to cirrhosis and liver cancer. HBV mutations are primarily generated due both to a lack of proofreading capacity by HBV polymerase and to host immune pressure, which is a very important factor for predicting disease progression and therapeutic outcomes. Several types of HBV precore/core (preC/C) mutations have been described to date. The host immune response against T cells drives mutation in the preC/C region. Specifically, preC/C mutations in the MHC class II restricted region are more common than in other regions and are significantly related to hepatocellular carcinoma. Certain mutations, including preC G1896A, are also significantly related to HBeAg-negative chronic infection. This review article mainly focuses on the HBV preC/C mutations that are related to disease severity and on the HBeAg serostatus of chronically infected patients.

关键词： Hepatitis B virus infection Precore/core mutations Hepatocellular carcinoma HBeAg serostatus Disease severity

Induction of endoplasmic reticulum-derived oxidative stress by an occult infection related S surface antigen variant

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World Journal of Gastroenterology 2015年第22期21卷 6872-6883页

作者： In-Kyung Lee Seoung-Ae Lee Hong kim You-Sub Won bum-joon kim Department of Microbiology and Immunology Liver Research Institute Cancer Research Institute and SNUMRCCollege of Medicine Seoul National University

AIM: To investigate the mechanism of endoplasmic reticulum(ER) stress induction by an occult infection related hepatitis B virus S surface antigen(HBsAg)***: We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western ***: Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant upregulated ER stress-related proteins and induced reactive oxygen species(ROS) compared to the wildtype via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins(HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the upregulation of caspase proteins(caspase 6, 9 and 12).Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS ***: Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.

关键词： Endoplasmic reticulum oxidative stress Hepatitis B virus KD variant Colocalization Reactive oxidative species Apoptotic cell death

Sex disparity in viral load, inflammation and liver damage in transgenic mice carrying full hepatitis B virus genome with the W4P mutation in the preS1 region

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World Journal of Gastroenterology 2018年第10期24卷 1084-1092页

作者： Seoung-Ae Lee So-Young Lee Yu-Min Choi Hong kim bum-joon kim Department of Microbiology and Immunology Biomedical Sciences Liver Research Institute and Cancer Research Institute Seoul National University College of Medicine

AIM To study sex disparity in susceptibility to hepatocellular carcinoma(HCC), we created a transgenic mouse model that expressed the full hepatitis B virus(HBV) genome with the W4P *** Transgenic mice were generated by transferring the p HY92-1.1 x-HBV-full genome plasmid(genotype A2) into C57 Bl/6 N mice. We compared serum levels of hepatitis B surface antigen(HBs Ag), interleukin(IL)-6, and the liver enzymes alanine aminotransferase(ALT) and aspartate transaminase(AST), as well as liver histopathological features in male and female transgenic(W4PTG) mice and in nontransgenic littermates of 10 mo of age. RESULTS W4PTG males exhibited more pronounced hepatomegaly, significantly increased granule generation in liver tissue, elevated HBs Ag expression in the liver and serum, and higher serum ALT and IL-6 levels compared to W4PTG females or littermate control groups. CONCLUSION Together, our data indicate that the W4 P mutation in pre S1 may contribute to sex disparity in susceptibility to HCC by causing increased HBV virion replication and enhanced IL-6-mediated inflammation in male individuals. Additionally, our transgenic mouse model that expresses full HBV genome with the W4 P mutation in pre S1 could be effectively used for the studies of the progression of liver diseases, including HCC.

关键词： Hepatitis B virus W4P mutation of preS1 transgenic mice Hepatocellular carcinoma

Locked nucleic acid real-time polymerase chain reaction method identifying two polymorphisms of hepatitis B virus genotype C2 infections,rt269L and rt269I

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World Journal of Gastroenterology 2023年第11期29卷 1721-1734页

作者： Kijeong kim Yu-Min Choi Dong Hyun kim Junghwa Jang Won Hyeok Choe bum-joon kim Department of Microbiology College of MedicineChung-Ang UniversitySeoul 06974South Korea Department of Microbiology and Immunology College of MedicineSeoul National UniversitySeoul 03080South Korea Department of Internal Medicine Konkuk University School of MedicineSeoul 05030South Korea Department of Biomedical Sciences College of MedicineSeoul National UniversitySeoul 03080South Korea Liver Research Institute College of MedicineSeoul National UniversitySeoul 03080South Korea Seoul National University Medical Research Center Seoul 03080South Korea

BACKGROUND The presence of two distinct hepatitis B virus(HBV)Pol RT polymorphisms,rt269L and rt269I,could contribute to the unique clinical or virological phenotype of HBV genotype ***,a simple and sensitive method capable of identifying both types in chronic hepatitis B(CHB)patients infected with genotype C2 should be *** To develop a novel simple and sensitive locked nucleic acid(LNA)-real timepolymerase chain reaction(RT-PCR)method capable of identifying two rt269 types in CHB genotype C2 *** We designed proper primer and probe sets for LNA-RT-PCR for the separation of rt269 *** synthesized DNAs of the wild type and variant forms,melting temperature analysis,detection sensitivity,and endpoint genotyping for LNA-RT-PCR were *** developed LNA-RT-PCR method was applied to a total of 94 CHB patients of genotype C2 for the identification of two rt269 polymorphisms,and these results were compared with those obtained by a direct sequencing *** The LNA-RT-PCR method could identify two rt269L and rt269I polymorphisms of three genotypes,two rt269L types[‘L1’(WT)and‘L2’]and one rt269I type(‘I’)in single(63 samples,72.4%)or mixed forms(24 samples,27.6%)in 87(92.6%sensitivity)of 94 samples from Korean CHB *** the results were compared with those obtained by the direct sequencing protocol,the LNA-RT-PCR method showed the same results in all but one of 87 positive detected samples(98.9%specificity).CONCLUSION The newly developed LNA-RT-PCR method could identify two rt269 polymorphisms,rt269L and rt269I,in CHB patients with genotype C2 *** method could be effectively used for the understanding of disease progression in genotype C2 endemic areas.

关键词： Hepatitis B virus Genotype C2 Polymerase rt269 Locked nucleic acid-real time-polymerase chain reaction Chronic hepatitis B

Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-na?ve Korean patients infected with genotype C2

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World Journal of Gastroenterology 2017年第23期23卷 4222-4232页

作者： Ji-Eun kim So-Young Lee Hong kim Ki-Jeong kim Won-Hyeok Choe bum-joon kim Department of Biomedical Sciences Microbiology and Immunologyand Liver Research InstituteSeoul National University College of Medicine Department of Microbiology School of MedicineJoong-Ang University Department of Internal Medicine Konkuk University School of Medicine

AIM To report naturally occurring mutations in the reverse transcriptase region(RT) of hepatitis B virus(HBV) polymerase from treatment na?ve Korean chronic patients infected with genotype *** Here, full-length HBV reverse transcriptase RT sequences were amplified and sequenced from 131 treatment na?ve Korean patients chronically infected with hepatitis B genotype C2. The patients had two distinct clinical statuses: 59 patients with chronic hepatitis(CH) and 72 patients with hepatocellular carcinoma(HCC). The deduced amino acids(AAs) at42 previously reported potential nucleos(t)ide analog resistance(NAr) mutation positions in the RT region were analyzed. RESULTS Potential NAr mutations involving 24 positions were found in 79 of the 131 patients(60.3%). Notably, AA substitutions at 2 positions(rt184 and rt204) involved in primary drug resistance and at 2 positions(rt80 and rt180) that functioned as secondary/compensatory mutations were detected in 10 patients(1 CH patient and 9 HCC patients) and 7 patients(1 CH and 6 HCC patients), respectively. The overall mutation frequencies in the HCC patients(3.17%, 96/3024 mutations) were significantly higher than the frequencies in the CH patients(2.09%, 52/2478 mutations)(P = 0.003). In addition, a total of 3 NAr positions, rt80, rt139 and rt204 were found to be significantly related to HCC from treatment na?ve Korean patients. CONCLUSION Our data showed that naturally occurring NAr mutations in South Korea might contribute to liver disease progression(particularly HCC generation) in chronic patients with genotype C2 infections.

关键词： Hepatitis B virus Polymerase Reverse transcriptase Potential nucleos(t)ide analog resistance Chronic hepatitis Hepatocellular carcinoma

Tenofovir is a more suitable treatment than entecavir for chronic hepatitis B patients carrying naturally occurring rtM204I mutations

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World Journal of Gastroenterology 2019年第33期25卷 4985-4998页

作者： Won Hyeok Choe Kijeong kim So-Young Lee Yu-Min Choi So Young Kwon Jeong Han kim bum-joon kim Department of Internal Medicine Konkuk University School of MedicineSeoul 05030South Korea Department of Microbiology College of MedicineChung-Ang UniversitySeoul 06974South Korea Department of Biomedical Sciences Microbiology and ImmunologyLiver Research InstituteCancer Research Institute and SNUMRCCollege of MedicineSeoul National UniversitySeoul 03080South Korea

BACKGROUND Hepatitis B virus(HBV) DNA polymerase mutations usually occur to long term use of nucleos(t)ide analogues(NAs), but they can occur spontaneously in treatment-na?ve chronic hepatitis B(CHB) patients. The naturally occurring HBV DNA polymerase mutations might complicate antiviral therapy with NAs,leading to the generation of drug-resistant viral mutants and disease *** most common substitutions are known to be YMDD-motif mutations, but their prevalence and the influence on antiviral therapy is *** To investigate prevalence of the naturally occurring rtM204I mutations in treatment-na?ve CHB genotype C2 patients and their influence on antiviral *** A total of 410 treatment-na?ve CHB patients infected with HBV genotype C2 strains were enrolled in this retrospective study. Among the 410 patients, 232 were treated with NAs for at least 12 mo. Significant fibrosis was defined as fibrosis-4 index > 3.25 or aspartate aminotransferase to platelet ratio index > *** viral response(CVR) during NAs was defined as undetectable serum HBV DNA(< 24 IU/m L). The rtM204I variants were analyzed by a newly developed locked nucleotide probe(LNA probe) based real-time PCR(LNA-RTPCR) *** The LNA-RT-PCR could discriminate rtM204I mutant-type(17 patients, 4.2%)from rt M204 wild-type(386 patients, 95.8%) in 403 of 410 patients(98.3%sensitivity). Multivariate analysis showed that naturally occurring rtM204I variants were more frequently detected in patients with significant fibrosis [oddratio(OR) 3.397, 95% confidence-interval(CI) 1.119-10.319, P = 0.031]. Of 232 patients receiving NAs, multivariate analysis revealed that achievement of CVR was reversely associated with naturally occurring rtM204I variants prior to NAs treatment(OR 0.014, 95%CI 0.002-0.096, P < 0.001). Almost patients receiving tenofovir achieved CVR at 12 mo of tenofovir, irrespective of pre-existence of naturally occurring rtM204I mutations(CVR rates: patients with

关键词： Chronic hepatitis B Entecavir Hepatitis B virus Liver fibrosis Mutation Tenofovir

Three-dimensional Analysis of Prestressed Concrete Offshore Wind Turbine Structure Under Environmental and 5-MW Turbine Loads

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Journal of Marine Science and Application 2018年第4期17卷 625-637页

作者： bum-joon kim Pasin Plodpradit Ki-Du kim Hyun-Gi kim Department of Civil and Environmental Plant Engineering Konkuk University Department of Energy Plant Engineering Catholic Kwangdong University

A concrete gravity base structure may not be suitable for offshore weak soil because of its heavy weight. Therefore, a conceptual model for a concrete offshore wind turbine structure suitable for weak soils is proposed. The proposed model is composed of a prestressed concrete(PSC) supported by a pile foundation. For a three-dimensional analysis of the large concrete structure, wave pressures based on the diffraction wave theory are developed using a three-dimensional solid finite element method. Static and dynamic analyses were performed to achieve the conceptual model of a PSC structure subjected to ocean environmental loads and a 5-MW turbine load on southwest coast in Korea. From the analysis, the maximum displacement and stresses of the proposed model did not exceed the allowable values from design standard, and the first mode of natural frequency of the structure was in a safe range to avoid resonance. The proposed model has enough structural stability to withstand external loads, and it is expected to be used in locations suitable for concrete gravity structures.

关键词： Prestressed concrete offshore wind turbine structure Morison equation Diffraction theory Static analysis Natural frequency analysis