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Zhao Q, Liu H, Tang L, Wang F, Tolufashe G, Chang J, Guo JT. Mechanism of interferon alpha therapy for chronic hepatitis B and potential approaches to improve its therapeutic efficacy. Antiviral Res 2024; 221:105782. [PMID: 38110058 DOI: 10.1016/j.antiviral.2023.105782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Hepatitis B virus (HBV) chronically infects 296 million people worldwide and causes more than 820,000 deaths annually due to cirrhosis and hepatocellular carcinoma. Current standard-of-care medications for chronic hepatitis B (CHB) include nucleos(t)ide analogue (NA) viral DNA polymerase inhibitors and pegylated interferon alpha (PEG-IFN-α). NAs can efficiently suppress viral replication and improve liver pathology, but not eliminate or inactivate HBV covalently closed circular DNA (cccDNA). CCC DNA is the most stable HBV replication intermediate that exists as a minichromosome in the nucleus of infected hepatocyte to transcribe viral RNA and support viral protein translation and genome replication. Consequentially, a finite duration of NA therapy rarely achieves a sustained off-treatment suppression of viral replication and life-long NA treatment is most likely required. On the contrary, PEG-IFN-α has the benefit of finite treatment duration and achieves HBsAg seroclearance, the indication of durable immune control of HBV replication and functional cure of CHB, in approximately 5% of treated patients. However, the low antiviral efficacy and poor tolerability limit its use. Understanding how IFN-α suppresses HBV replication and regulates antiviral immune responses will help rational optimization of IFN therapy and development of novel immune modulators to improve the rate of functional cure. This review article highlights mechanistic insight on IFN control of HBV infection and recent progress in development of novel IFN regimens, small molecule IFN mimetics and combination therapy of PEG-IFN-α with new direct-acting antivirals and therapeutic vaccines to facilitate the functional cure of CHB.
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Affiliation(s)
- Qiong Zhao
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Hui Liu
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Liudi Tang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Fuxuan Wang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | | | - Jinhong Chang
- Baruch S. Blumberg Institute, Doylestown, PA, United States
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, PA, United States.
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2
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Zheng K, Shen Y, Xia X, Song Y, Zhang AM. Genetic polymorphisms in the IFNL4, MxA, and MxB genes were associated with biochemical index of chronic HBV patients from Yunnan, China. PeerJ 2022; 10:e13353. [PMID: 35505682 PMCID: PMC9057288 DOI: 10.7717/peerj.13353] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 04/07/2022] [Indexed: 01/15/2023] Open
Abstract
Hepatitis B virus (HBV) infection causes Hepatitis B, which is one of the most common causes of hepatocellular carcinoma (HCC). The single nucleotide polymorphisms (SNPs) of the host immune genes could impact HBV infection, viral clearance, and treatment effect. However, the contradictory roles of several studies suggest further analysis of various populations. The whole blood and biochemical indexes of 448 HBV patients and matched controls were collected from the Yunnan population to investigate the genetic roles of IFNL4 and the downstream genes (MxA and MxB). The genotypes, alleles, and haplotypes frequencies of the seven SNPs (rs11322783, rs117648444, rs2071430, rs17000900, rs9982944, rs408825, and rs2838029) from the HBV patients and controls were analyzed. However, no association was identified between the SNPs and HBV infection. Then, biochemical index levels were evaluated among the HBV patients with different genotypes of the seven SNPs. The results indicated that the liver function index levels (including alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), and albumin (ALB)) were influenced by the genotypes of the SNPs in HBV patients. Moreover, when the HBV patients were divided into HBsAg-positive and -negative groups, the association between the SNP genotypes and the biochemical indexes still existed. In addition, although the genetic polymorphisms in the IFNL4, MxA, and MxB genes were not significantly associated with HBV infection in the Yunnan population, these genes could indirectly influence disease progression by associating with the biochemical index levels of Yunnan HBV patients.
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Affiliation(s)
- Kexi Zheng
- Kunming University of Science and Technology, Kunming, China
| | - Yunsong Shen
- Kunming Angel Women’s & Children’s Hospital, Kunming, China
| | - Xueshan Xia
- Kunming University of Science and Technology, Kunming, China
| | - Yuzhu Song
- Kunming University of Science and Technology, Kunming, China
| | - A-Mei Zhang
- Kunming University of Science and Technology, Kunming, China
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3
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Xu F, Zhao F, Zhao X, Zhang D, Liu X, Hu S, Mei S, Fan Z, Huang Y, Sun H, Wei L, Wu C, Li Q, Wang J, Cen S, Liang C, Guo F. Pro-515 of the dynamin-like GTPase MxB contributes to HIV-1 inhibition by regulating MxB oligomerization and binding to HIV-1 capsid. J Biol Chem 2020; 295:6447-6456. [PMID: 32217692 PMCID: PMC7212661 DOI: 10.1074/jbc.ra119.012439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/24/2020] [Indexed: 01/19/2023] Open
Abstract
Interferon-regulated myxovirus resistance protein B (MxB) is an interferon-induced GTPase belonging to the dynamin superfamily. It inhibits infection with a wide range of different viruses, including HIV-1, by impairing viral DNA entry into the nucleus. Unlike the related antiviral GTPase MxA, MxB possesses an N-terminal region that contains a nuclear localization signal and is crucial for inhibiting HIV-1. Because MxB previously has been shown to reside in both the nuclear envelope and the cytoplasm, here we used bioinformatics and biochemical approaches to identify a nuclear export signal (NES) responsible for MxB's cytoplasmic location. Using the online computational tool LocNES (Locating Nuclear Export Signals or NESs), we identified five putative NES candidates in MxB and investigated whether their deletion caused nuclear localization of MxB. Our results revealed that none of the five deletion variants relocates to the nucleus, suggesting that these five predicted NES sequences do not confer NES activity. Interestingly, deletion of one sequence, encompassing amino acids 505-527, abrogated the anti-HIV-1 activity of MxB. Further mutation experiments disclosed that amino acids 515-519, and Pro-515 in particular, regulate MxB oligomerization and its binding to HIV-1 capsid, thereby playing an important role in MxB-mediated restriction of HIV-1 infection. In summary, our results indicate that none of the five predicted NES sequences in MxB appears to be required for its nuclear export. Our findings also reveal several residues in MxB, including Pro-515, critical for its oligomerization and anti-HIV-1 function.
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Affiliation(s)
- Fengwen Xu
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Fei Zhao
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoxiao Zhao
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Di Zhang
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoman Liu
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Siqi Hu
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Shan Mei
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zhangling Fan
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yu Huang
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Hong Sun
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Liang Wei
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Chao Wu
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Quanjie Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Jianwei Wang
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Shan Cen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Chen Liang
- McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal H3T 1E2, Quebec, Canada
| | - Fei Guo
- NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Human Hepatitis B Virus Core Protein Inhibits IFNα-Induced IFITM1 Expression by Interacting with BAF200. Viruses 2019; 11:v11050427. [PMID: 31075894 PMCID: PMC6563218 DOI: 10.3390/v11050427] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 05/04/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023] Open
Abstract
Human hepatitis B virus core protein (HBc) is a structural protein of the hepatitis B virus (HBV) and contributes to HBV regulation of host-cell transcription. However, the mechanisms of transcriptional regulation remain poorly characterized. To dissect the function of HBc, a yeast two-hybrid was performed to identify HBc-binding proteins, and the C-terminal of BRG1/hBRM-associated factors 200 (BAF200C) was identified. Then, the existence of HBc interactions with BAF200C and full-length BAF200 was confirmed via co-immunoprecipitation assays in 293T, HepG2 and HepG2-NTCP cells. Furthermore, we show that the binding between HBc and BAF200 was of vital importance to HBc mediated downregulation of interferon-induced transmembrane protein 1 (IFITM1) expression, and the mechanisms for the downregulation were disclosed as follows. Basal level of IFITM1 expression depends on BAF200, rather than the JAK–STAT1 pathway. The interaction of HBc with BAF200 disturbs the stability of the polybromo-associated BAF (PBAF) complex and results in the suppression of IFTM1 transcription. Finally, the antiviral effects of IFITM1 on cell proliferation and HBV replication were found to be partially restored when HBc was co-transfected with BAF200. Collectively, our findings indicate that HBc plays a role in HBV resistance against the antiviral activities of IFNα, providing details about HBV evasion of host innate immunity.
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5
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Sexual dimorphism in hepatitis B and C and hepatocellular carcinoma. Semin Immunopathol 2018; 41:203-211. [PMID: 30498927 DOI: 10.1007/s00281-018-0727-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 11/04/2018] [Indexed: 12/14/2022]
Abstract
The incidence of viral hepatitis B or C (HBV/HCV) infection and hepatocellular carcinoma is higher in male compared to female populations, showing a faster disease progression and results in a worse overall survival. Indeed, women are in general better protected from viral infections and show a lower risk of death from malignant cancer in comparison to men. Females mount stronger innate and adaptive immune responses than males, and therefore, most of the autoimmune diseases occur predominantly in females. Next to occupational and/or behavioral factors, cellular and molecular differences between the two sexes contribute to this observation. In this review, we will discuss underlying mechanisms that are important for the observed sex-related differences in liver diseases. A better appreciation of these differences between the two sexes might be of value for better and gender-specific treatment options.
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Liu H, Li F, Zhang X, Yu J, Wang J, Jia J, Yu X, Shen Z, Yuan Z, Zhang X, Zhang Z, Zhang X, Lu L, Li H, Lu M, Zhang J. Differentially Expressed Intrahepatic Genes Contribute to Control of Hepatitis B Virus Replication in the Inactive Carrier Phase. J Infect Dis 2018; 217:1044-1054. [PMID: 29300924 DOI: 10.1093/infdis/jix683] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 12/29/2017] [Indexed: 01/04/2023] Open
Affiliation(s)
- Hongyan Liu
- Departmentof Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Germany
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Fahong Li
- Departmentof Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaoyong Zhang
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Germany
- Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Jie Yu
- Departmentof Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinyu Wang
- Departmentof Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jia Jia
- Shanghai Center of Bioinformatics and Biotechnology
| | - Xueping Yu
- Departmentof Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhongliang Shen
- Departmentof Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College
| | - Xiaonan Zhang
- Department of Viral Hepatitis, Shanghai Public Health Clinical Center, Fudan University
| | - Zhanqing Zhang
- Department of Viral Hepatitis, Shanghai Public Health Clinical Center, Fudan University
| | - Xinxin Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine
| | - Lungen Lu
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine
| | - Hai Li
- Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Germany
| | - Jiming Zhang
- Departmentof Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College
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7
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Yang Q, Li XP, Zhong YB, Xiang TX, Zhang LL. Interferon-α inhibits cell migration and invasion and induces the expression of antiviral proteins in Huh-7 cells transfected with hepatitis B virus X gene-expressing lentivirus. Exp Ther Med 2017; 14:5924-5930. [PMID: 29285141 PMCID: PMC5740601 DOI: 10.3892/etm.2017.5288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 07/14/2017] [Indexed: 11/06/2022] Open
Abstract
Hepatitis B virus (HBV) X protein (HBx) serves an important role in HBV infection and the development of HBV-related liver cancer. Interferon-α (IFN-α) is used to treat patients with HBV; however, the role of IFN-α in the development of HBV-related liver cancer remains unclear. The present study established a new HBV-related liver cancer model (Huh-7-HBx) by transfecting the hepatoma cell line Huh-7, with HBx-expressing lentivirus. Following IFN-α treatment, cell viability, migration and invasion, as well as the expression of antiviral proteins in Huh-7-HBx, were subsequently determined. The results demonstrated that HBx-expressing lentivirus had no significant effect on cell viability but promoted the migration and invasion of Huh-7 cells. The expression of the antiviral genes IFN α and β receptor subunit 1 (IFNAR1), IFNAR2, IFN-stimulated gene factor 3, double-stranded RNA-activated protein kinase and ribonuclease L, was also increased. Following treatment of Huh-7-HBx cells with IFN-α, the expression of antiviral genes was increased at the level of transcription and translation, whereas cell migration and invasion was decreased. The present study suggests that IFN-α may attenuate the development of HBV-related liver cancer by reducing cell migration and invasion and promoting the expression of antiviral proteins.
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Affiliation(s)
- Qian Yang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiao-Peng Li
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yuan-Bin Zhong
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Tian-Xin Xiang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Lun-Li Zhang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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8
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Zhou T, Block T, Liu F, Kondratowicz AS, Sun L, Rawat S, Branson J, Guo F, Steuer HM, Liang H, Bailey L, Moore C, Wang X, Cuconatti A, Gao M, Lee ACH, Harasym T, Chiu T, Gotchev D, Dorsey B, Rijnbrand R, Sofia MJ. HBsAg mRNA degradation induced by a dihydroquinolizinone compound depends on the HBV posttranscriptional regulatory element. Antiviral Res 2017; 149:191-201. [PMID: 29133129 DOI: 10.1016/j.antiviral.2017.11.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 11/01/2017] [Accepted: 11/07/2017] [Indexed: 12/23/2022]
Abstract
In pursuit of novel therapeutics targeting the hepatitis B virus (HBV) infection, we evaluated a dihydroquinolizinone compound (DHQ-1) that in the nanomolar range reduced the production of virion and surface protein (HBsAg) in tissue culture. This compound also showed broad HBV genotype coverage, but was inactive against a panel of DNA and RNA viruses of other species. Oral administration of DHQ-1 in the AAV-HBV mouse model resulted in a significant reduction of serum HBsAg as soon as 4 days following the commencement of treatment. Reduction of HBV markers in both in vitro and in vivo experiments was related to the reduced amount of viral RNA including pre-genomic RNA (pgRNA) and 2.4/2.1 kb HBsAg mRNA. Nuclear run-on and subcellular fractionation experiments indicated that DHQ-1 mediated HBV RNA reduction was the result of accelerated viral RNA degradation in the nucleus, rather than the consequence of inhibition of transcription initiation. Through mutagenesis of HBsAg gene sequences, we found induction of HBsAg mRNA decay by DHQ-1 required the presence of the HBV posttranscriptional regulatory element (HPRE), with a 109 nucleotides sequence within the central region of the HPRE alpha sub-element being the most critical. Taken together, the current study shows that a small molecule can reduce the overall levels of HBV RNA, especially the HBsAg mRNA, and viral surface proteins. This may shed light on the development of a new class of HBV therapeutics.
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Affiliation(s)
- Tianlun Zhou
- Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States.
| | - Timothy Block
- Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States
| | - Fei Liu
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Andrew S Kondratowicz
- Arbutus BioPharma, 100 - 8900 Glenlyon Parkway, Burnaby, British Columbia V5J 5J8, Canada
| | - Liren Sun
- Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States
| | - Siddhartha Rawat
- Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States
| | - Jeffrey Branson
- Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States
| | - Fang Guo
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | | | - Hongyan Liang
- Baruch S. Blumberg Institute, Department of Translational Medicine, Doylestown, PA 18902, United States
| | - Lauren Bailey
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Chris Moore
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Xiaohe Wang
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Andy Cuconatti
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Min Gao
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Amy C H Lee
- Arbutus BioPharma, 100 - 8900 Glenlyon Parkway, Burnaby, British Columbia V5J 5J8, Canada
| | - Troy Harasym
- Arbutus BioPharma, 100 - 8900 Glenlyon Parkway, Burnaby, British Columbia V5J 5J8, Canada
| | - Tim Chiu
- Arbutus BioPharma, 100 - 8900 Glenlyon Parkway, Burnaby, British Columbia V5J 5J8, Canada
| | - Dimitar Gotchev
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Bruce Dorsey
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Rene Rijnbrand
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States
| | - Michael J Sofia
- Arbutus BioPharma, 701 Veterans Circle, Warminster, PA 18974, United States.
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9
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Altered expression of interferon-stimulated genes is strongly associated with therapeutic outcomes in hepatitis B virus infection. Antiviral Res 2017; 147:75-85. [DOI: 10.1016/j.antiviral.2017.10.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/28/2017] [Accepted: 10/05/2017] [Indexed: 12/11/2022]
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10
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Expression of Interferon Effector Gene SART1 Correlates with Interferon Treatment Response against Hepatitis B Infection. Mediators Inflamm 2016; 2016:3894816. [PMID: 28077916 PMCID: PMC5203921 DOI: 10.1155/2016/3894816] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 10/17/2016] [Accepted: 10/20/2016] [Indexed: 12/14/2022] Open
Abstract
Interferon-α (IFN-α) has limited response rate in the treatment of chronic hepatitis B (CHB). The underlying mechanism of differential responsiveness to IFN remains elusive. It has been recently reported that SART1 mediates antiviral effects of IFN-α in the hepatitis C virus (HCV) cell culture model. In this study, we investigated the role of SART1 in antiviral activity of IFN-α against hepatitis B virus (HBV) using blood and liver biopsy samples from chronic hepatitis B patients treated with pegylated IFN-α and HepG2 cells transfected with cloned HBV DNA. We observed that the basal SART1 expression in liver and PBMCs before IFN treatment was significantly higher in responders than in nonresponders. Furthermore, baseline SART1 expression level positively correlated with the degree of HBV DNA and HBeAg decline after IFN treatment. Mechanistically, silencing SART1 abrogated the antiviral activity of IFN-α, reduced the expression of IFN-stimulated genes (ISGs) Mx, OAS, and PKR, and attenuated JAK-STAT signaling in HepG2 cells, suggesting that SART1 regulates IFN-mediated antiviral activity through JAK-STAT signaling and ISG expression. Our study elucidates the important role of SART1 in IFN-mediated anti-HBV response and provides new insights into understanding variation of IFN treatment response in CHB patients.
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11
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Wang SH, Chen PJ, Yeh SH. Gender disparity in chronic hepatitis B: Mechanisms of sex hormones. J Gastroenterol Hepatol 2015; 30:1237-45. [PMID: 25708186 DOI: 10.1111/jgh.12934] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/18/2015] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) is a common human pathogen transmitted worldwide, and its chronic infection is a well-known risk factor for hepatocellular carcinoma (HCC). The sex disparity of HBV-related liver diseases has been noticed for a long time, which could be attributed to sex hormone effects, other than gender behaviors or environmental impact. This difference is experimentally confirmed in HBV transgenic mice, as well as in immunocompetent mice receiving hydrodynamic delivery of HBV. Androgen and estrogen pathways were identified to play opposite regulations of HBV transcription by targeting viral enhancer I at molecular level. In addition to the direct effects on HBV life cycle, sex hormones may be also involved in the immune response to HBV infection and the progression of associated liver diseases, although the detailed mechanisms are still unclear. Besides, several unaddressed issues such as HBV entry, microRNA profiles, viral integration, and adaptability in which androgen and estrogen axes might be involved are warranted to be delineated. The comprehensive understanding of the sex disparity in HBV virology and pathogenesis will be helpful to provide newly biomarkers for clinical diagnosis and develop novel drugs to manage HBV-related HCC patients.
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Affiliation(s)
- Sheng-Han Wang
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,NTU Center for Genomic Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,NTU Center for Genomic Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
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12
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He D, Tao S, Guo S, Li M, Wu J, Huang H, Guo X, Yan G, Zhu P, Wang Y. Interaction of TLR-IFN and HLA polymorphisms on susceptibility of chronic HBV infection in Southwest Han Chinese. Liver Int 2015; 35:1941-1949. [PMID: 25469587 PMCID: PMC6680266 DOI: 10.1111/liv.12756] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 11/27/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The toll-like receptor-interferon (TLR-IFN) signalling pathway plays a crucial role in HBV infection. Human leucocyte antigen (HLA) polymorphisms are associated with chronic HBV infection by genome wide association study (GWAS). We aimed to explore interaction between TLR-IFN and HLA gene polymorphisms in susceptibility of chronic HBV infection. METHODS In the Chinese Southwest Han population, 1191 chronic HBV infection patients and 273 HBV clearance were selected. A total of 39 single nucleotide polymorphism loci in 23 genes of the TLR-IFN pathway and four HLA polymorphism loci associated with chronic HBV infection identified by GWAS were selected for genotyping. SNPStats, QVALUE, and multifactor dimensionality reduction were used for statistical analysis. RESULTS A significant association was seen in several of the TLR-IFN pathway genes, TLR9 rs352140 (OR = 0.70, P = 0.0088), IL1B rs16944 (OR = 0.67, P = 0.016), IL12B rs3212227 (OR = 1.38, P = 0.021), IFNGR1 rs3799488 (OR = 1.48, P = 0.0048), IFNGR2 rs1059293 (OR = 0.27, P = 0.011), MX1 rs467960 (OR = 0.68, P = 0.022), as well as four loci in HLA, rs3077 (OR = 0.55, P < 0.0001), rs2856718 (OR = 0.60, P = 4e-04), rs9277535 (OR = 0.54, P < 0.0001) and rs7453920 (OR = 0.43, P < 0.0001). A synergistic relationship was seen between rs9277535 and rs16944 (0.13%), rs1143623 and rs6613 (0.10%). The combination of rs9277535 in HLA and rs16944 in IL1B was the best model to predict chronic HBV infection (testing accuracy = 0.6040, P = 0.0010, cross-validation consistency = 10/10). CONCLUSIONS TLR-IFN pathway gene polymorphisms are associated with chronic HBV infection. Interactions with polymorphisms in these genes may be one mechanism by which HLA polymorphisms influence susceptibility to chronic HBV infection, as specific single nucleotide polymorphism combinations are highly predictive of chronic HBV infection.
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Affiliation(s)
- Dengming He
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- Liver Disease Diagnoses and Treatment Center of Chinese PLAThe 88th Hospital of Chinese PLATai'anShandong ProvinceChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Shiqi Tao
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Shimin Guo
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Maoshi Li
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Junqiu Wu
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Hongfei Huang
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Xinwu Guo
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
- Sansure Biotech Inc.ChangshaHunan ProvinceChina
| | - Guohua Yan
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Peng Zhu
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
| | - Yuming Wang
- Institute of Infectious DiseaseSouthwest HospitalThird Military Medical UniversityChongqingChina
- The Chongqing Key Laboratory for Research of Infectious DiseasesChongqingChina
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13
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Pei RJ, Chen XW, Lu MJ. Control of hepatitis B virus replication by interferons and Toll-like receptor signaling pathways. World J Gastroenterol 2014; 20:11618-11629. [PMID: 25206268 PMCID: PMC4155354 DOI: 10.3748/wjg.v20.i33.11618] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 12/23/2013] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at the different steps of viral life cycle. Indeed, IFN-α has been successfully used for treatment of patients with chronic hepatitis B. However, the role of the innate immune response in HBV replication and the mechanism of the anti-HBV effect of IFN-α are not completely explored. In this review, we summarized the currently available knowledge about the IFN-mediated anti-HBV effect in the HBV life cycle and the possible effectors downstream the IFN signaling pathway. The antiviral effect of Toll-like receptors (TLRs) in HBV replication is briefly discussed. The strategies exploited by HBV to evade the IFN- and TLR-mediated antiviral actions are summarized.
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14
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Guo P. Suppression of interferon-mediated antiviral immunity by hepatitis B virus: an overview of research progress. Scand J Immunol 2013; 78:230-7. [PMID: 23790137 DOI: 10.1111/sji.12086] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 06/04/2013] [Indexed: 01/30/2023]
Abstract
Interferon (IFN)-α is an indispensable drug for hepatitis B treatment in clinical settings. However, hepatitis B virus (HBV) can attenuate IFN-mediated antiviral responses to avoid being inhibited or cleared. Much progress has been made in exploring how the IFN-induced anti-HBV effect is inhibited. This review examines and summarizes new advances regarding the molecular mechanism underlying the HBV-induced suppression of type I IFN-mediated antiviral immunity.
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Affiliation(s)
- P Guo
- West Campus Hospital of Shandong University, Jinan, China
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15
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Lu HL, Liao F. Melanoma differentiation-associated gene 5 senses hepatitis B virus and activates innate immune signaling to suppress virus replication. THE JOURNAL OF IMMUNOLOGY 2013; 191:3264-76. [PMID: 23926323 DOI: 10.4049/jimmunol.1300512] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) belong to the RIG-I-like receptors family of pattern recognition receptors. Both RIG-I and MDA5 have been shown to recognize various viral RNAs, but whether they mediate hepatitis B virus (HBV) infection remains unclear. In this study, we demonstrated that the expression of MDA5, but not RIG-I, was increased in Huh7 cells transfected with the HBV replicative plasmid and in the livers of mice hydrodynamically injected with the HBV replicative plasmid. To further determine the effect of RIG-I-like receptors on HBV replication, we cotransfected the HBV replicative plasmid with RIG-I or MDA5 expression plasmid into Huh7 cells and found that MDA5, but not RIG-I at a similar protein level, significantly inhibited HBV replication. Knockdown of endogenous MDA5, but not RIG-I, in Huh7 cells transfected with the HBV replicative plasmid significantly increased HBV replication. Of particular interest, we found that MDA5, but not RIG-I, was able to associate with HBV-specific nucleic acids, suggesting that MDA5 may sense HBV. Finally, we performed in vivo experiments by hydrodynamic injection of the HBV replicative plasmid into wild-type, MDA5⁻/⁻, MDA5⁺/⁻, or RIG-I⁺/⁻ mice, and found that MDA5⁻/⁻ and MDA5⁺/⁻ mice, but not RIG-I⁺/⁻ mice, exhibited an increase of HBV replication as compared with wild-type mice. Collectively, our in vitro and in vivo studies both support a critical role for MDA5 in the innate immune response against HBV infection.
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Affiliation(s)
- Hsin-Lin Lu
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan
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16
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Pei R, Qin B, Zhang X, Zhu W, Kemper T, Ma Z, Trippler M, Schlaak J, Chen X, Lu M. Interferon-induced proteins with tetratricopeptide repeats 1 and 2 are cellular factors that limit hepatitis B virus replication. J Innate Immun 2013; 6:182-91. [PMID: 23867918 DOI: 10.1159/000353220] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 05/21/2013] [Indexed: 12/24/2022] Open
Abstract
Interferon (IFN)-α is able to stimulate many cellular genes and inhibit the replication of various viruses. However, it is unknown whether some IFN-stimulated genes (ISGs) specifically inhibit hepatitis B virus (HBV) replication. Therefore, we attempted to identify ISGs with antiviral activities against HBV. Knockdown of IFN-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1 and IFIT2) in HepG2.2.15 led to markedly increased HBV replication. Consistently, this effect was verified by transient transfection with a replication-competent HBV clone in HepG2 and Huh7. However, IFN-α stimulation could override the knockdown by siRNAs and enhance the expression of IFIT1 and IFIT2, leading to reduced HBV replication. Silencing of IFIT1 or IFIT2 decreased the expression of the corresponding genes while other ISGs like MxA were not affected. Northern blot analysis showed that IFIT1 and IFIT2 knockdown slightly increased the levels of HBV 3.5, 2.4 and 2.1 kb transcripts, while IFIT1 and IFIT2 overexpression did not change their levels. Consistently, the reporter assays with HBV promoters demonstrated that IFIT1 and IFIT2 differentially but only modestly regulated HBV promoter activity. Thus, IFIT1 and IFIT2 contribute significantly to the regulation of HBV replication, likely at both transcriptional and posttranscriptional steps.
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Affiliation(s)
- Rongjuan Pei
- Institute of Virology, University Hospital of Essen, Essen, Germany
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17
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Wang B, Zhao XP, Fan YC, Zhang JJ, Zhao J, Wang K. IL-17A but not IL-22 suppresses the replication of hepatitis B virus mediated by over-expression of MxA and OAS mRNA in the HepG2.2.15 cell line. Antiviral Res 2013; 97:285-292. [PMID: 23274784 DOI: 10.1016/j.antiviral.2012.12.018] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 12/14/2012] [Accepted: 12/17/2012] [Indexed: 02/08/2023]
Abstract
Interleukin-17A (IL-17A) and interleukin-22 (IL-22), mainly secreted by interleukin-17-producing T help cells (Th17), are pleiotropic cytokines that regulate the biological responses of several target cells, including hepatocytes. Th17 frequency was reported to negatively correlate with plasma hepatitis B virus (HBV) DNA load in patients with HBV infection. Several studies have indicated that cytokines, such as IL-6 and IL-4, are involved in the noncytopathic suppression of HBV replication. We therefore hypothesized that IL-17A and IL-22 might have a potent suppressive effect on HBV replication. In our present study, we analyzed the suppressive effect of IL-17A and IL-22 on HBV replication in the hepatocellular carcinoma cell line HepG2.2.15. IL-17A did not inhibit the proliferation of HepG2.2.15 cells. It decreased the levels of HBV s antigen (HBsAg) and HBV e antigen (HBeAg) in culture medium and the levels of intracellular HBV DNA. By contrast, blockage of IL-17 receptor (IL-17R) increased the levels of HBsAg and extracellular HBV DNA in culture medium and the levels of intracellular HBV DNA. The expression of antiviral proteins, including myxovirus resistance A (MxA) and oligoadenylate synthetase (OAS), was enhanced by IL-17A. IL-22 and anti-human IL-22 receptor (IL-22R) antibody did not change any indexes. We demonstrated that IL-17A effectively suppressed HBV replication in a noncytopathic manner and the over-expression of MxA and OAS mRNA was involved in the suppression of HBV replication by IL-17A.
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Affiliation(s)
- Bing Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan 250012, China
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18
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Li N, Zhang L, Chen L, Feng W, Xu Y, Chen F, Liu X, Chen Z, Liu W. MxA inhibits hepatitis B virus replication by interaction with hepatitis B core antigen. Hepatology 2012; 56:803-11. [PMID: 22271421 DOI: 10.1002/hep.25608] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 01/05/2012] [Indexed: 12/11/2022]
Abstract
UNLABELLED Human MxA, an interferon-inducible cytoplasmic dynamin-like GTPase, possesses antiviral activity against multiple RNA viruses. Recently, MxA has also been demonstrated to have activity against the hepatitis B virus (HBV), a well-known DNA virus responsible for acute and chronic liver disease in humans. We investigated the molecular mechanism for the anti-HBV activity of MxA. Our results demonstrated that in HepG2.2.15 cells, MxA GTPase independently suppressed the production of hepatitis B surface antigen and HBV DNA without changing the level of hepatitis B core antigen (HBcAg) and the distribution of HBV mRNA. MxA significantly reduced the level of the encapsidated pregenomic RNA. Through its central interactive domain, MxA interacted with HBcAg, causing accumulation of the proteins in perinuclear compartments. MxA-HBcAg interaction significantly affected the dynamics of HBcAg by immobilizing HBcAg in the perinuclear structures. CONCLUSION MxA displays antiviral activity against HBV involving a mechanism of MxA-HBcAg interaction that may interfere with core particle formation.
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Affiliation(s)
- Ning Li
- Department of Biochemistry and Molecular Biology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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19
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Yang J, Zhu X, Liu J, Ding X, Han M, Hu W, Wang X, Zhou Z, Wang S. Inhibition of Hepatitis B virus replication by phospholipid scramblase 1 in vitro and in vivo. Antiviral Res 2012; 94:9-17. [PMID: 22342889 DOI: 10.1016/j.antiviral.2012.01.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2011] [Revised: 01/20/2012] [Accepted: 01/30/2012] [Indexed: 01/03/2023]
Abstract
Human Phospholipid scramblase 1 (PLSCR1) is an α/β interferon-inducible protein that mediates antiviral activity against RNA viruses including vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). In the present study, we investigated the antiviral activity of PLSCR1 protein against HBV (Hepatitis B virus). Firstly, PLSCR1 mRNA and protein expression was found to be downregulated in HepG2 cells after HBV infection. Then by performing co-transient-transfection experiments in cells and hydrodynamics-based transfection experiments in mice using a HBV expression plasmid and a PLSCR1 expression plasmid, we found that PLSCR1 inhibited HBV replication in vitro and in vivo through a significant reduction in the synthesis of viral proteins, DNA replicative intermediates and HBV RNAs. We also demonstrated that the antiviral action of PLSCR1 against HBV occurs, partly at least, by activating the Jak/Stat pathway. In conclusion, our results suggest that the expression of PLSCR1 is involved in HBV replication and that PLSCR1 has antiviral activity against HBV.
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Affiliation(s)
- Jing Yang
- Beijing Institute of Radiation Medicine, PR China
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20
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Cheng JC, Yeh YJ, Huang YH, Liang KH, Chang ML, Lin CY, Yeh CT. Hepatic expression of MxA and OAS1 in an ex vivo liver slice assay independently predicts treatment outcomes in chronic hepatitis C. J Viral Hepat 2012; 19:e154-62. [PMID: 22239513 DOI: 10.1111/j.1365-2893.2011.01538.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Antiviral effect of interferon is mediated by the expression of interferon-stimulated genes (ISGs). However, because of the difficulty in obtaining paired liver biopsies before and after interferon treatment, the key ISGs expressed in human hepatocytes and responsible for interferon-based antiviral activities in chronic hepatitis C remain illusive. Prior to a standard course of peginterferon plus ribavirin therapy, 104 patients underwent a liver biopsy. A small piece of the liver biopsy sample from each patient was submitted for ex vivo tissue culture in the presence or absence of interferon. Hepatic expression of 8 ISGs was detected by RT-PCR. The ISG expression patterns and clinicopathological variables were correlated with subsequent treatment outcomes. Multivariate logistic regression analysis showed that hepatic MxA expression (P = 0.008) and leucocyte count (P = 0.040) independently predicted the end of therapeutic virological response, while hepatic OAS1 expression (P = 0.003), genotype 1 (P = 0.002), HCV-RNA level (P = 0.007), AST/ALT ratio (P = 0.004) and leucocyte count (P = 0.034) independently predicted the sustained virological response. Immunohistochemistry analysis showed that interferon-induced OAS1 expression localized to the hepatocytes. In conclusion, hepatic MxA and OAS1 expression predicted, respectively, the end of therapeutic and sustained virological responses in interferon-based treatment of chronic hepatitis C.
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Affiliation(s)
- J-C Cheng
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
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21
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Zhijian Y, Zhen H, Fan Z, Jin Y, Qiwen D, Zhongming Z. Hepatitis B virus core protein with hot-spot mutations inhibit MxA gene transcription but has no effect on inhibition of virus replication by interferon α. Virol J 2010; 7:278. [PMID: 20959021 PMCID: PMC2972278 DOI: 10.1186/1743-422x-7-278] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Accepted: 10/20/2010] [Indexed: 12/29/2022] Open
Abstract
It has been reported that hepatitis B virus (HBV) core protein (HBc) can inhibit the transcription of human interferon-induced MxA gene. In this study, we investigated whether HBc protein mutations at hot spots (L60V, S87G and I97L) could still inhibit MxA transcription and the potential significance of this inhibition in virus replication in vitro. Our data indicated that the IFN-induced MxA mRNA expression level and MxA promoter activity was significantly down-regulated by mutant protein of HBc(I97L), compared to WT and the other two mutated HBc proteins(L60V or S87G). However, in Huh7 cells stably expressing WT or the mutated HBc proteins (L60V, S87G or I97L), IFN-α could inhibit the extra- and intracellular HBV DNA level and HBsAg secretion to a similar level compared to that in cells transfected with control plasmids. In conclusion, HBc protein with I97L mutation may play an especial role in suppressing the transcription of MxA gene. Moreover, the inhibitory effect on MxA gene transcription by the WT or mutated HBc proteins (L60V, S87G and I97L) has no impact on inhibition of HBV replication by IFN-α in Huh7 cells. The clinical significance of the inhibitory effect of MxA gene transcription by HBc protein requires further study.
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Affiliation(s)
- Yu Zhijian
- Department of Infectious Diseases, the Affiliated Shenzhen Nanshan Hospital of Guangdong Medical College, Shenzhen, China
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22
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Inhibition of hepatitis B virus replication by MyD88 involves accelerated degradation of pregenomic RNA and nuclear retention of pre-S/S RNAs. J Virol 2010; 84:6387-99. [PMID: 20410269 DOI: 10.1128/jvi.00236-10] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Myeloid differentiation primary response protein 88 (MyD88), which can be induced by alpha interferon (IFN-alpha), has an antiviral activity against the hepatitis B virus (HBV). The mechanism of this antiviral activity remains poorly understood. Here, we report that MyD88 inhibited HBV replication in HepG2.2.15 cells and in a mouse model. The knockdown of MyD88 expression weakened the IFN-alpha-induced inhibition of HBV replication. Furthermore, MyD88 posttranscriptionally reduced the levels of viral RNA. Remarkably, MyD88 accelerated the decay of viral pregenomic RNA in the cytoplasm. Mapping analysis showed that the RNA sequence located in the 5'-proximal region of the pregenomic RNA was critical for the decay. In addition, MyD88 inhibited the nuclear export of pre-S/S RNAs via the posttranscriptional regulatory element (PRE). The retained pre-S/S RNAs were shown to degrade in the nucleus. Finally, we found that MyD88 inhibited the expression of polypyrimidine tract-binding protein (PTB), a key nuclear export factor for PRE-containing RNA. Taken together, our results define a novel antiviral mechanism against HBV mediated by MyD88.
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23
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Williams V, Brichler S, Radjef N, Lebon P, Goffard A, Hober D, Fagard R, Kremsdorf D, Dény P, Gordien E. Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene. J Gen Virol 2009; 90:2759-2767. [PMID: 19625466 DOI: 10.1099/vir.0.011239-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Co-infection and superinfection of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV replication both in patients and in animal and cellular models. The mechanisms behind this inhibition have not previously been explored fully. HBV replication is governed by four promoters and two enhancers, Enh1 and Enh2. Repression of these enhancers has been reported to be one of the main mechanisms of HBV inhibition. Moreover, in a previous study, it has been demonstrated that alpha interferon (IFN-alpha)-inducible MxA protein inhibits HBV replication. HDV encodes two proteins, p24 and p27. p27 was shown to activate several heterologous promoters, including HBV promoters. In an attempt to analyse the mechanisms of HBV inhibition by HDV, the question was raised whether HDV proteins could act directly by repressing HBV enhancers, and/or indirectly by activating the MxA gene. This issue was addressed in a co-transfection model in Huh-7 cells, using p24- or p27-expressing plasmids along with Enh1, Enh2, HBV and MxA promoter-luciferase constructs. Enh1 and Enh2 were strongly repressed, by 60 and 80 % and 40 and 60 %, by p24 and p27, respectively. In addition, p27 was responsible for threefold activation of the MxA promoter and potentiation of IFN-alpha on this promoter. MxA mRNA quantification and a virus yield reduction assay confirmed these results. In conclusion, this study shows that HDV proteins inhibit HBV replication by trans-repressing its enhancers and by trans-activating the IFN-alpha-inducible MxA gene.
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Affiliation(s)
- Virginie Williams
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Ségolène Brichler
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Nadjia Radjef
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Pierre Lebon
- Laboratoire de Virologie, Hôpital Saint Vincent de Paul, Université Paris 5, France
| | - Anne Goffard
- Service de Virologie, UPRES EA 3610 Faculté de Médecine, Université Lille 2, Centre Hospitalier Régional et Universitaire de Lille, France
| | - Didier Hober
- Service de Virologie, UPRES EA 3610 Faculté de Médecine, Université Lille 2, Centre Hospitalier Régional et Universitaire de Lille, France
| | - Remi Fagard
- Laboratoire de Biochimie, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Dina Kremsdorf
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
| | - Paul Dény
- INSERM U871, Lyon, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Emmanuel Gordien
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
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24
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Zhang X, Meng Z, Qiu S, Xu Y, Yang D, Schlaak JF, Roggendorf M, Lu M. Lipopolysaccharide-induced innate immune responses in primary hepatocytes downregulates woodchuck hepatitis virus replication via interferon-independent pathways. Cell Microbiol 2009; 11:1624-37. [PMID: 19573162 DOI: 10.1111/j.1462-5822.2009.01353.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Our previous studies have shown that Toll-like receptor (TLR) ligands, Poly I:C and lipopolysaccharide (LPS), are able to activate non-parenchymal liver cells and trigger the production of interferon (IFN) to inhibit hepatitis B virus replication in vivo and in vitro. However, little is known about TLR-mediated cellular responses in primary hepatocytes. By the model of woodchuck hepatitis virus (WHV) infected primary woodchuck hepatocytes (PWHs), Poly I:C and LPS stimulation resulted in upregulation of cellular antiviral genes and relevant TLRs mRNA expression respectively. LPS stimulation led to a pronounced reduction of WHV replicative intermediates without a significant IFN induction. Poly I:C transfection resulted in the production of IFN and a highly increased expression of antiviral genes in PWHs and slight inhibitory effect on WHV replication. LPS could activate nuclear factor kappa B, MAPK and PI-3k/Akt pathways in PWHs. Further, inhibitors of MAPK-ERK and PI-3k/Akt pathways, but not that of IFN signalling pathway, were able to block the antiviral effect of LPS. These results indicate that IFN- independent pathways which activated by LPS are able to downregulate hepadnaviral replication in hepatocytes.
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Affiliation(s)
- Xiaoyong Zhang
- Institute of Virology, Taihe Hospital, Yunyang Medical College, Shiyan, China
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25
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Liu HQ, Qin B. Advance in molecular mechanism of interferon to treat chronic hepatitis B. Shijie Huaren Xiaohua Zazhi 2009; 17:1803-1808. [DOI: 10.11569/wcjd.v17.i18.1803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The antiviral efficacy of interferon-α (IFN-α) therapy for chronic hepatitis B (CHB) is not only related to DNA load and genetype of HBV before treatment, gene mutation of HBV and polymorphism of type II HLA in the host, but also depends on the immunity of CHB patients. Researchers pay more and more attention to the mutant strain of virus and phenotypes of genes. However, the mechanism of interferon to resist HBV and the escape mechanism of HBV against the IFN therapy have not been clarified yet. This paper reviews the mechanism of IFN therapy and the influencing factors at molecular and genetic levels.
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Yu Z, Wang Z, Chen J, Li H, Lin Z, Zhang F, Zhou Y, Hou J. GTPase activity is not essential for the interferon-inducible MxA protein to inhibit the replication of hepatitis B virus. Arch Virol 2008; 153:1677-84. [PMID: 18668195 DOI: 10.1007/s00705-008-0168-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Accepted: 06/19/2008] [Indexed: 01/17/2023]
Abstract
Multiple studies have established that GTPase activity is critical for MxA to act against RNA viruses. Recently, it was shown that MxA can also restrict the replication of hepatitis B virus (HBV), a DNA virus, but the requirements for GTPase activity in inhibition of HBV by MxA remain unknown. Here, we report that GTPase-defective mutants (K83A, T103A, and L612K) can downregulate extracellular HBsAg and HBeAg and reduce the expression of extra- and intracellular HBV DNA in HepG2 cells to levels similar to that achieved by wild-type MxA. Furthermore, TMxA and T103, two nuclear forms of wild-type MxA and a GTPase-defective mutant (T103A) could only slightly decrease the expression of extra- and intracellular HBV DNA in HepG2 cells. In conclusion, GTPase activity is not essential for MxA protein to inhibit HBV replication, and MxA may have only a minimal effect on the replicative cycle of HBV in the nucleus.
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Affiliation(s)
- Zhijian Yu
- Department of Infectious Diseases, Nanfang Hospital, Nanfang Medical University, Guangzhou, China
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Kong XF, Zhang XX, Gong QM, Gao J, Zhang SY, Wang L, Xu J, Han Y, Jin GD, Jiang JH, Zhang DH, Lu ZM. MxA induction may predict sustained virologic responses of chronic hepatitis B patients with IFN-alpha treatment. J Interferon Cytokine Res 2007; 27:809-18. [PMID: 17892402 DOI: 10.1089/jir.2006.0163] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The objective of this study was to find potential biomarkers for predicting sustained virologic responses to interferon-alpha (IFN-alpha) treatment in chronic hepatitis B (CHB) patients. A total of 101 CHB patients were treated with pegylated IFN-alpha2a for 48 weeks and followed up for 24 weeks, including 34 IFN responders (IFN-Rs) and 67 IFN nonresponders (IFN-NRs). After peripheral blood mononuclear cells (PBMCs) and Epstein-Barr virus-transferred B (EBV-B) cell lines were treated with different concentrations of IFN-alpha in vitro, activated IFN-stimulated gene factor3 (ISGF3) and IFN-gamma-activation factor (GAF) were measured by EMSA, and MxA, OAS1, and PKR mRNA were measured by real-time PCR. Polymorphisms in the MxA promoter were genotyped to find the possible association. IFN-alpha-activated ISGF3 and GAF levels were similar between IFN-NRs and IFN-Rs. However, MxA mRNA induction in IFN-Rs was higher than that in IFN-NRs, and such discrepancy increased when highly concentrated IFN was used to stimulate. The OAS1 and PKR mRNA induction have a similar pattern between IFN-Rs and IFN-NRs. In addition, frequency of the MxA-88G/T genotype was significantly different between IFN-Rs and IFN-NRs, and this polymorphism was also functional because MxA mRNA induction in patients with GG genotype was lower than those with GT genotype. Regression analysis showed that MxA mRNA induction after 10,000 IU/mL IFN stimulation could serve as an independent factor for predicting IFN-alpha, with an area under curve (AUC) of 0.838, a positive predictive value of 68% for IFN-Rs, and a negative predictive value of 89% for IFN-NRs. MxA mRNA induced by IFN-alpha might predict sustained virologic responses to IFN-alpha treatment in CHB patients.
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Affiliation(s)
- Xiao-Fei Kong
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
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