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Precore mutation enhances viral replication to facilitate persistent infection especially in HBeAg-negative patients

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Virologica Sinica 2024年第2期39卷 319-330页

作者： Guixin Li Danli Yang Xin Liu Ting Zhang Hui Liu Jun Zou Zimeng Xu Xiangmei Chen Lizhong Dai Hongsong Chen fengmin lu Peking University People's Hospital Peking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijing International Cooperation Base for Science and Technology on NAFLD DiagnosisBeijing100044China Department of Microbiology and Infectious Disease Center School of Basic Medical SciencesPeking UniversityBeijing100191China Baruch S.Blumberg Institute DoylestownPA18901USA Shenzhen Sanyuansheng Biotechnology Co. LtdShenzhen518000China Precision Medicine Center of Zhengzhou University Academy of Medical SciencesZhengzhou UniversityZhengzhou450001China Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine Sansure Biotech Co.LtdChangsha410205China

Naturally occurred precore(PC,G1896A)and/or basal core promoter(BCP,A1762T/G1764A)mutations are prevalent in chronic HBV-infected patients,especially those under HBeAg-negative ***,the replicative capacity of HBV with PC/BCP mutations remains ***,meta-analysis showed that,only under HBeAg-negative status,the serum HBV DNA load in patients with PC mutation was 7.41-fold higher than those without the *** PC mutation alone and BCPþPC mutations promoted HBV replication in cell and hydrodynamic injection mouse *** human hepatocyte chimeric mouse model,BCPþPC mutations led to elevated replicative capacity and intrahepatic core protein ***,preC RNA harboring PC mutation could serve as mRNA to express core and P proteins,and such pgRNA-like function favored the maintenance of cccDNA pool under HBeAg-negative ***,BCPþPC mutations induced more extensive and severe human hepatocyte damage as well as activated endoplasmic reticulum stress and TNF signaling pathway in livers of chimeric *** study indicates that HBeAg-negative patients should be monitored on HBV mutations regularly and are expected to receive early antiviral treatment to prevent disease progression.

关键词： Hepatitis B virus Precore mutation Basal core promoter mutations Endoplasmic reticulum stress

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乙型肝炎病毒RNA的转录后调控机制及抗病毒策略

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中华肝脏病杂志 2024年第5期32卷 474-480页

作者：李德瑶陆丹娟曲晨箫张婷刘佳鲁凤民陈香梅北京大学基础医学院病原生物学系暨感染病研究中心北京100191 北京大学人民医院肝病研究所北京100044

慢性乙型肝炎病毒(HBV)感染是全球持续关注的重大公共健康问题之一。由于对HBV生命周期的认识还不够充分,目前尚缺乏有效治愈慢性乙型肝炎的药物。在HBV复制过程中,共价闭合环状DNA作为病毒复制的模板,可转录产生长度为3.5、2.4、2.1 k... 详细信息

慢性乙型肝炎病毒(HBV)感染是全球持续关注的重大公共健康问题之一。由于对HBV生命周期的认识还不够充分,目前尚缺乏有效治愈慢性乙型肝炎的药物。在HBV复制过程中,共价闭合环状DNA作为病毒复制的模板,可转录产生长度为3.5、2.4、2.1 kb以及0.7 kb的5种病毒RNA,分别翻译产生HBeAg、core蛋白、聚合酶(P)蛋白、HBsAg和HBx蛋白。其中,3.5 kb的前基因组RNA(pgRNA)也是病毒逆转录的模板,P蛋白可识别并结合pgRNA上的衣壳组装信号,启动衣壳组装和逆转录。近年来研究发现,HBV RNA的剪接、核输出、稳定性、翻译以及pgRNA衣壳化等过程均受到宿主细胞内的转录后调控网络调控,并依赖HBV RNA结构中独特的转录后调节元件。现对HBV RNA的转录后调控机制及其在HBV抗病毒治疗药物研究中的应用进行综述,以期为靶向HBV RNA的新药研发提供新思路。

关键词：慢性乙型肝炎乙型肝炎病毒转录后调控抗病毒治疗

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Severe acute hepatitis in children with unknown aetiology,etiology analysis and the next action

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Virologica Sinica 2022年第5期37卷 778-782页

作者： Yuan Gao Leijie Wang Lin Wang fengmin lu The Fourth Department of Hepatology Beijing Youan HospitalCapital Medical UniversityBeijing100069China Department of Microbiology&Infectious Disease Center School of Basic Medical SciencesPeking University Health Science CenterBeijing100191China Hepatology Institute Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasePeking University People's HospitalBeijing100044China

On April 5,2022,United Kingdom(UK)reported 10 cases of severe acute hepatitis with unknown cause among children under 10 years *** initial symptoms of these cases could date back to March 2022.A rapidly increasing number of cases lasted for a month and the growth seems to be slightly slowing down in *** of May 27,2022,the total number of children with acute hepatitis in UK reached to 222(UKHSA,2022a).European Union and European Economic Area reported 305 cases across 17 countries and none as epidemiologically linked as of May 31,2022(ECDC-WHO,2022).

关键词： acute etiology hepatitis

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RNA binding protein TIAR modulates HBV replication by tipping the balance of pgRNA translation

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4889-4902页

作者： Ting Zhang Huiling Zheng Danjuan lu Guiwen Guan Deyao Li Jing Zhang Shuhong Liu Jingmin Zhao Ju-Tao Guo fengmin lu Xiangmei Chen Department of Microbiology and Infectious Disease Center School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Department of Pathology and Hepatology The Ffth Medical Center of Chinese PLA General HospitalBeijing 100039China Department of Experimental Therapeutics Baruch S.Blumberg InstituteDoylestownPA 18902USA Bejing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases Peking University Hepatology InstitutePeking University People's HospitalBeijing 100044China

The pregenomic RNA(pgRNA)of hepatitis B virus(HBV)serves not only as a bicistronic message RNA to translate core protein(Cp)and DNA polymerase(Pol),but also as the template for reverse transcriptional replication of viral DNA upon packaging into *** it is well known that pgRNA translates much more Cp than Pol,the molecular mechanism underlying the regulation of Cp and Pol translation efficiency from pgRNA remains elusive.

关键词： translate template translation

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Simulation of Multilayer Silicon Thin Films Growth on Si(111) Surface

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Journal of Rare Earths 2006年第Z1期24卷 23-25页

作者： Wu fengmin lu Hangjun Institute of Condensed Matter Physics Zhejiang Normal University Jinhua 321004 China Institute of Condensed Matter Physics Zhejiang Normal University Jinhua 321004 China

The homoepitaxial growth of multilayer Si thin film on Si(111) surfaces was simulated by Monte Carlo (MC) method with realistic growth model and physical parameters. Special emphasis was placed on revealing the influence of the Ehrlich-Schwoebel (ES) barrier on the growth modes and morphologies. It is evident that there exists the ES barrier during multilayer Si thin film growth on Si (111) surface, which is deduced from the incomplete layer-by-layer growth process in the realistic experiments. The ES barrier EB=0.1～0.125 eV is estimated from the three-dimensional (3D) MC simulation and compared with the experimental results.

关键词： silicon homoepitaxy KMC simulation ES barrier

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Morphology transition in a heteroepitaxial system: Co/Cu(111)

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Rare Metals 2006年第Z1期25卷 540-543页

作者： WU fengmin lu Hangjun FANG Yunzhang Department of Physics Zhejiang Normal University Jinhua 321004 China Department of Physics Zhejiang Normal University Jinhua 321004 China Department of Physics Zhejiang Normal University Jinhua 321004 China

The initial stages of multilayer Co thin film grown on Cu(111) surface were simulated by means of kinetic Monte Carlo (KMC) method, where the realistic growth model and physical parameters were presented. The effects of edge diffusion along the islands and mass transport between interlayers were included in the simulation model. Emphasis was placed on revealing the transition of growth morphology in heteroepitaxial Co/Cu(111) system with the changing of surface temperature. The simulation results show that the dendritic islands form at low temperature (T=210 K), while compact islands grow at room temperature (RT). The Volmer-Webber (three-dimensional, 3D) growth mode is presented due to the relative higher Ehrlich-Schwoebel (ES) barrier. Our simulation results are in good agreement with the real scanning tunneling microscopy (STM) experiments.

关键词： heteroepitaxy morphology transition KMC simulation ES barrier

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Use of serum Golgi protein 73 for screening chronic hepatitis B virus infection patients needing antiviral therapy in the community

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Chinese Medical Journal 2022年第22期135卷 2741-2743页

作者： Jinwei Duan Xiajie Wen Huai Wang Weixin Chen Pei Gao Qianli Yuan Han Zheng Yanna Liu Jiang Wu Jie Wang Mingjie Yao fengmin lu Department of Epidemiology and Biostatistics College of Public HealthZhengzhou UniversityZhengzhouHenan 450001China Department of Microbiology and Infectious Disease Center School of Basic Medical SciencePeking University Health Science CenterBeijing 100191China Department of Immunization Beijing Centers for Disease Prevention and ControlBeijing Centers for Disease Preventive Medical ResearchBeijing 100013China Department of Anatomy and Embryology School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China

Chronic hepatitis B virus (HBV) infection is a major global public health problem. Approximately 887,000 people die of HBV infection-related diseases annually, with cirrhosis and hepatocellular carcinoma (HCC) being the principal causes of mortality.[1] Timely antiviral therapy greatly reduces the risks of cirrhosis and HCC. However, unfortunately, of those patients who are eligible for antiviral treatment, only 25% of patients in clinic settings and 12% of those in community settings obtain timely antiviral therapy.[2] Therefore, reliable means of identifying patients with chronic HBV infection that require antiviral therapy are necessary, particularly for use in the community.

关键词： patients infection mortality

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Relationship between the Level of Serum Golgi Protein 73 and the Risk of Short-term Death in Patients with ALD-ACLF

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Journal of Clinical and Translational Hepatology 2022年第3期10卷 449-457页

作者： Jingjing Tong Mingjie Yao Xiuying Mu Leijie Wang Xiajie Wen Xingran Zhai Xiang Xu Yu Wang Jing Chen Xiangwei Zhai Chongdan Guan fengmin lu Jinhua Hu Chinese PLA Medical School BeijingChina Senior Department of Hepatology the Fifth Medical Center of PLA General HospitalBeijingChina Department of Anatomy and Embryology School of Basic Medical SciencesPeking University Health Science CenterBeijingChina Peking University 302 Clinical Medical School BeijingChina Department of Microbiology&Infectious Disease Center School of Basic Medical SciencesPeking University Health Science CenterBeijingChina

Background and Aims:As a hepatocellular carcinoma biomarker,serum Golgi protein 73(GP73)is reportedly related to ***-on-chronic liver failure(ACLF)is characterized by severe systemic *** this study,we aimed to explore the association between the GP73 level and short-term mortality in patients with alcohol-associated liver disease-related ACLF(ALD-ACLF).Methods:This retrospective cohort study involved 126 Chinese adults with *** serum GP73 level was measured using enzymelinked immunosorbent *** were followed-up for 90 d and outcomes were *** were analyzed using multivariate Cox regression and piecewise linear regression *** predictive value of GP73 and classic models for the short-term prognosis of participants were evaluated and compared using receiver operating characteristic ***:The serum GP73 level was independently associated with an increased mortality risk in patients with *** with the lowest tertile,the highest serum GP73 level predisposed patients with ALD-ACLF to a higher mortality risk in the fully adjusted model[at 28 days:hazard ratio(HR):4.29(0.99–18.54),p=0.0511;at 90 days:HR:3.52(1.15–10.79),p=0.0276].Further analysis revealed a positive linear ***73 significantly improved the accuracy of the Child-Turcotte-Pugh score,model for end-stage liver disease score,and model for end-stage liver diseasesodium score in predicting short-time prognosis of patients with ***:The serum GP73 level is a significant predictor of the subsequent risk of death in patients with ***73 improved the predictive value of classic prognostic scores.

关键词： Golgi protein 73(GP73) Alcohol-associated liver disease Acuteon-chronic liver failure(ACLF) Prognosis Retrospective cohort study

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Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos（t）ide analogs

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Frontiers of Medicine 2017年第4期11卷 502-508页

作者： fengmin lu Jie Wang Xiangmei Chen Dongping Xu Ningshao Xia State Key Laboratory of Natural and Biomimetic Drugs Department of Microbiology & Infectious Disease Center School of Basic Medical Sciences Peking University Health Science Center Beijing 100191 China Institute of Infectious Diseases Beijing 302 Hospital Beijing 100039 China State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics School of Public Health Xiamen UniversityXiamen 361102 China

Although the efficacy of nucleos（t）ide analogue （NA） has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus （HBV） are integrated into the Hfe cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA （cccDNA）, particularly among patients receiving NA therapy. Therefore, the concept of virological response is redefined as persistent loss of serum HBV DNA and HBV RNA. In contrast to hepatitis B surface antigen （HBsAg） that can originate from either the cccDNA or the integrated HBV DNA fragment, serum HBV RNA, with pregenomic RNA origination, can only be transcribed from cccDNA. Therefore, the loss of serum HBV RNA would likely be a promising predicator for safe drug discontinuation. The clinical status of consistent loss of serum HBV RNA accompanied with low serum HBsAg levels might be implicated as a ＂para-functional cure,＂ a status nearly close to the functional cure of chronic hepatitis B, to distinguish the ＂functional cure＂ characterized as serum HBsAg loss with or without anti-HBs seroconversion.

关键词： chronic hepatitis B serum HBV RNA nucleos(t)ide analogs virological response para-functional cure

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An unbalanced PD-L1/CD86 ratio in CD14^＋＋CD16^＋ monocytes is correlated with HCV viremia during chronic HCV infection

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Cellular & Molecular Immunology 2014年第3期11卷 294-304页

作者： Jiajia Zheng Hua Liang Chunhui Xu Qiang Xu Ting Zhang Tao Shen fengmin lu Department of Microbiology Peking University Health Science Center Beijing China Department of Laboratory Medicine Peking University Third Hospital Beijing China State Key Laboratory for infectious Disease Prevention and Control National Center for AIDS/STD Control and Prevention China CDC Beijing China Center of Infectious Diseases Peking University Beijing China These authors contributed equally to this work

Circulating monocyte subsets with distinct functions play important roles in hepatitis C virus （HCV） infection. However, the mechanisms have not been well studied. In this study, we analyzed the distributions and phenotypic characteristics of three circulating monocyte subsets--CD14^＋＋CD16^-, CD14^＋＋CD16^＋ and CD14^＋＋mCD16^——in chronic HCV-infected patients, HCV spontaneous resolvers and healthy controls, and we evaluated the possible link between HCV viremia and disease progression. Our results indicated that the frequency of the CD 14^＋＋CD 16^＋ monocyte subset was decreased, and negatively correlated with HCV RNA and core antigen levels during chronic HCV infection. PD-L1 expression and the PD-L1/CD86 ratio in CD14^＋＋CD16^＋ monocytes were higher during chronic HCV infection than in spontaneous HCV resolvers and healthy controls. The PD-L1/CD86 ratio positively correlated with HCV viral load and core antigen levels. Finally, PD-L1 was significantly increased, while cytokine secretions were dramatically decreased upon Toll-like receptor （TLR） ligand binding and HCV JFH-lstimulation. These findings indicates the compromised immune status of the CD14^＋＋CD16^＋ monocytes during chronic HCV infection and provides new insights into the specific role of the CD14^＋＋CD16^＋ monocytes and their significance in chronic HCV infection.

关键词： core antigen hepatitis C virus monocytes PD-L1/CD86 viral load

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