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Jose-Abrego A, Roman S, Laguna-Meraz S, Panduro A. Host and HBV Interactions and Their Potential Impact on Clinical Outcomes. Pathogens 2023; 12:1146. [PMID: 37764954 PMCID: PMC10535809 DOI: 10.3390/pathogens12091146] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/27/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatitis B virus (HBV) is a challenge for global health services, affecting millions and leading thousands to end-stage liver disease each year. This comprehensive review explores the interactions between HBV and the host, examining their impact on clinical outcomes. HBV infection encompasses a spectrum of severity, ranging from acute hepatitis B to chronic hepatitis B, which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B infection (OBI), characterized by low HBV DNA levels in hepatitis B surface antigen-negative individuals, can reactivate and cause acute hepatitis B. HBV genotyping has revealed unique geographical patterns and relationships with clinical outcomes. Moreover, single nucleotide polymorphisms (SNPs) within the human host genome have been linked to several clinical outcomes, including cirrhosis, HCC, OBI, hepatitis B reactivation, and spontaneous clearance. The immune response plays a key role in controlling HBV infection by eliminating infected cells and neutralizing HBV in the bloodstream. Furthermore, HBV can modulate host metabolic pathways involved in glucose and lipid metabolism and bile acid absorption, influencing disease progression. HBV clinical outcomes correlate with three levels of viral adaptation. In conclusion, the clinical outcomes of HBV infection could result from complex immune and metabolic interactions between the host and HBV. These outcomes can vary among populations and are influenced by HBV genotypes, host genetics, environmental factors, and lifestyle. Understanding the degrees of HBV adaptation is essential for developing region-specific control and prevention measures.
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Affiliation(s)
- Alexis Jose-Abrego
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara 44280, Mexico; (A.J.-A.); (S.R.); (S.L.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara 44280, Mexico; (A.J.-A.); (S.R.); (S.L.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Saul Laguna-Meraz
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara 44280, Mexico; (A.J.-A.); (S.R.); (S.L.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, “Fray Antonio Alcalde”, Guadalajara 44280, Mexico; (A.J.-A.); (S.R.); (S.L.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
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A Systematic Review of T Cell Epitopes Defined from the Proteome of Hepatitis B Virus. Vaccines (Basel) 2022; 10:vaccines10020257. [PMID: 35214714 PMCID: PMC8878595 DOI: 10.3390/vaccines10020257] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) infection remains a worldwide health problem and no eradicative therapy is currently available. Host T cell immune responses have crucial influences on the outcome of HBV infection, however the development of therapeutic vaccines, T cell therapies and the clinical evaluation of HBV-specific T cell responses are hampered markedly by the lack of validated T cell epitopes. This review presented a map of T cell epitopes functionally validated from HBV antigens during the past 33 years; the human leukocyte antigen (HLA) supertypes to present these epitopes, and the methods to screen and identify T cell epitopes. To the best of our knowledge, a total of 205 CD8+ T cell epitopes and 79 CD4+ T cell epitopes have been defined from HBV antigens by cellular functional experiments thus far, but most are restricted to several common HLA supertypes, such as HLA-A0201, A2402, B0702, DR04, and DR12 molecules. Therefore, the currently defined T cell epitope repertoire cannot cover the major populations with HLA diversity in an indicated geographic region. More researches are needed to dissect a more comprehensive map of T cell epitopes, which covers overall HBV proteome and global patients.
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Ganesan M, Wang W, Mathews S, Makarov E, New-Aaron M, Dagur RS, Malo A, Protzer U, Kharbanda KK, Casey CA, Poluektova LY, Osna NA. Ethanol attenuates presentation of cytotoxic T-lymphocyte epitopes on hepatocytes of HBV-infected humanized mice. Alcohol Clin Exp Res 2022; 46:40-51. [PMID: 34773268 PMCID: PMC8799491 DOI: 10.1111/acer.14740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Approximately 3.5% of the global population is chronically infected with Hepatitis B Virus (HBV), which puts them at high risk of end-stage liver disease, with the risk of persistent infection potentiated by alcohol consumption. However, the mechanisms underlying the effects of alcohol on HBV persistence remain unclear. Here, we aimed to establish in vivo/ex vivo evidence that alcohol suppresses HBV peptides-major histocompatibility complex (MHC) class I antigen display on primary human hepatocytes (PHH), which diminishes the recognition and clearance of HBV-infected hepatocytes by cytotoxic T-lymphocytes (CTLs). METHODS We used fumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chain knock-out (FRG-KO) humanized mice transplanted with human leukocyte antigen-A2 (HLA-A2)-positive hepatocytes. The mice were HBV-infected and fed control and alcohol diets. Isolated hepatocytes were exposed ex vivo to HBV 18-27-HLA-A2-restricted CTLs to quantify cytotoxicity. For mechanistic studies, we measured proteasome activities, unfolded protein response (UPR), and endoplasmic reticulum (ER) stress in hepatocytes from HBV-infected humanized mouse livers. RESULTS AND CONCLUSIONS We found that alcohol feeding attenuated HBV core 18-27-HLA-A2 complex presentation on infected hepatocytes due to the suppression of proteasome function and ER stress induction, which diminished both the processing of HBV peptides and trafficking of HBV-MHC class I complexes to the hepatocyte surface. This alcohol-mediated decrease in MHC class I-restricted antigen presentation of the CTL epitope on target hepatocytes reduced the CTL-specific elimination of infected cells, potentially leading to HBV-infection persistence, which promotes end-stage liver disease outcomes.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Weimin Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Saumi Mathews
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Edward Makarov
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Moses New-Aaron
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, NE, 68105, USA
| | - Raghubendra Singh Dagur
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Antje Malo
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
| | - Ulrike Protzer
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Centre for Infection Research (DZIF), Munich, Hamburg, and Heidelberg partner sites, Germany
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Carol A Casey
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
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Chen C, Jiang X, Liu X, Guo L, Wang W, Gu S, Wen C, Yi X, Tang L, Li Y. Identification of the association between HBcAg-specific T cell and viral control in chronic HBV infection using a cultured ELISPOT assay. J Leukoc Biol 2020; 109:455-465. [PMID: 32620046 DOI: 10.1002/jlb.5ma0620-023rr] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/15/2020] [Accepted: 06/15/2020] [Indexed: 12/23/2022] Open
Abstract
Hepatitis B virus (HBV)-specific T cells play a critical role in determining the outcome of HBV infection. However, T cell response induced by predominant Ag in chronic infection is hardly detectable owing to the lack of a suitable assay. We herein established an optimized method to enumerate HBV-specific T cells and assessed the association between HBV surface Ag (HBsAg) and HBV DNA. Sixty chronic HBV infection patients were enrolled. HBV-specific T cells were expanded by using overlapping peptide pools covering the entire sequence of HBV genotypes B and C. IFN-γ-producing HBV-specific T cells were detected by a cultured enzyme-linked immunospot (ELISPOT) assay, ex vivo ELISPOT assay, or flow cytometry staining. The association between HBV-specific T cells and serum levels of HBsAg and HBV DNA were analyzed. Cultured ELISPOT assay had a higher sensitivity than ex vivo ELISPOT in the detection of HBV-specific T cells. Moreover, consistent results were acquired by flow cytometry analysis and cultured ELISPOT assay, but the latter required only a limited number of cells for detection. Interestingly, HBV core peptide pool induced a robust HBV-specific T cell response in patients with lower levels of HBV DNA and HBsAg. Specifically, the frequency of HBV core Ag-specific IFN-γ+ spot-forming cells was inversely correlated with serum levels of HBV DNA and HBsAg. An optimized cultured ELISPOT assay reveals the association between HBV core Ag-induced T cell response and HBV control; this method may favor the investigation of HBV-specific T cell in chronic HBV infection.
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Affiliation(s)
- Chengcong Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Proteomic, Guangzhou, China
| | - Xuan Liu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ling Guo
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weibin Wang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shuqin Gu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chunhua Wen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuan Yi
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Libo Tang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yongyin Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Design, Synthesis, and Bioactive Screen In Vitro of Cyclohexyl ( E)-4-(Hydroxyimino)-4-Phenylbutanoates and Their Ethers for Anti-Hepatitis B Virus Agents. Molecules 2019; 24:molecules24112063. [PMID: 31151219 PMCID: PMC6600592 DOI: 10.3390/molecules24112063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 05/24/2019] [Accepted: 05/27/2019] [Indexed: 12/14/2022] Open
Abstract
A series of oxime Cyclohexyl (E)-4-(hydroxyimino)-4-phenylbutanoates and their ethers were designed, synthesized, and evaluated for anti-hepatitis B virus (HBV) activities with HepG 2.2.15 cell line in vitro. Most of these compounds possessed anti-HBV activities, and among them, compound 4B-2 showed significant inhibiting effects on the secretion of HBsAg (IC50 = 63.85 ± 6.26 μM, SI = 13.41) and HBeAg (IC50 = 49.39 ± 4.17 μM, SI = 17.34) comparing to lamivudine (3TC) in HBsAg (IC50 = 234.2 ± 17.17 μM, SI = 2.2) and HBeAg (IC50 = 249.9 ± 21.51 μM, SI = 2.07). Docking study of these compounds binding to a protein residue (PDB ID: 3OX8) from HLA-A2 that with the immunodominant HBcAg18–27 epitope (HLA-A2.1- restricted CTL epitope) active site was carried out by using molecular operation environment (MOE) software. Docking results showed that behaviors of these compounds binding to the active site in HLA-A protein residue partly coincided with their behaviors in vitro anti-HBV active screening.
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Zhu J, Li Y, Li L, Wang J, Wang H, Hong W, Hao K, Xue Y, Chen B, Wang Z. A novel absorption spectrometric method, based on graphene nanomaterials, for detection of hepatocellular carcinoma-specific T lymphocyte cells. Int J Nanomedicine 2018; 13:5523-5536. [PMID: 30271145 PMCID: PMC6154735 DOI: 10.2147/ijn.s168574] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Introduction Detection of antigen-specific cytotoxic T lymphocytes (CTLs) is the foundation for understanding hepatocellular carcinoma immune pathology and hepatocellular carcinoma immunotherapy. However, the classical method for labeling CTLs, major histocompatibility complex (MHC)–peptide tetramer, has drawbacks and needs further improvement. Materials and methods Here, as a new detection probe, a graphene-based MHC–peptide multimer was developed for sensitively and selectively identifying hepatocellular carcinoma-specific T-cells. To assess its detection efficiency, reduced graphene oxide (RGO) was functionalized with hemin and streptavidin to prepare a functionalized HRGO–streptavidin complex. Biotinylated MHC–peptide monomer was subsequently constructed onto HRGO to generate a detection probe for CTL labeling. The number of T-cells was detected through the reaction between HRGO and tetramethylbenzidine. Results Using HRGO/MHC–peptide multimers, the number of T-cells was efficiently detected in both the induction system in vitro and in peripheral blood of patients. Conclusion HRGO/MHC-peptide multimers methodology has application prospects in the detection of antigen peptide-specific T cells.
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Affiliation(s)
- Jianmeng Zhu
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Yiping Li
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Lei Li
- Department of Pathophysiology, School of Basic Medical Science, Southern Medical University, Guangzhou, Zhejiang, China
| | - Jian Wang
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Hongqin Wang
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Wenzhong Hong
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, ,
| | - Ke Hao
- Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
| | - Yadan Xue
- Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
| | - Bingyu Chen
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, , .,Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
| | - Zhen Wang
- Department of Clinical Laboratory, Chun'an First People's Hospital (Zhejiang Provincial People's Hospital Chun'an Branch), Hangzhou, Zhejiang Province, China, , .,Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China, ,
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CD8 + T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress. J Virol 2018; 92:JVI.02120-17. [PMID: 29950410 DOI: 10.1128/jvi.02120-17] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 06/05/2018] [Indexed: 12/13/2022] Open
Abstract
Under the immune pressure of cytotoxic T cells (CTLs), hepatitis B virus (HBV) evolves to accumulate mutations more likely within epitopes to evade immune detection. However, little is known about the specific patterns of the immune pressure-associated HBV mutation of T-cell epitopes and their link to disease progression. Here, we observed a correlation of the accumulated variants on HBV core protein (HBc) with the disease severity of HBV infection. Further analysis indicated that these substitutions were mostly located within CD8+ T-cell epitopes of HBc protein, which were systematically screened and identified in an unbiased manner in our study. From individual peptide level to the human leukocyte antigen I (HLA-I)-restricted population level, we elucidated that the mutations in these well-defined HLA-I-restricted T-cell epitopes significantly decreased antiviral activity-specific CTLs and were positively associated with clinical parameters and disease progression in HBV-infected patients. The molecular pattern for viral epitope variations based on the sequencing of 105 HBV virus genomes indicated that the C-terminal portion (Pc), especially the Pc-1 and Pc-2 positions, have the highest mutation rates. Further structural analysis of HLA-A*02 complexed to diverse CD8+ T-cell epitopes revealed that the highly variable C-terminal bulged peak of M-shaped HBc-derived epitopes are solvent exposed, and most of the CDR3βs of the T-cell receptor hover over them. These data shed light on the molecular and immunological mechanisms of T-cell immunity-associated viral evolution in hepatitis B progression, which is beneficial for designing immunotherapies and vaccines.IMPORTANCE The specific patterns of sequence polymorphisms of T-cell epitopes and the immune mechanisms of the HBV epitope mutation-linked disease progression are largely unclear. In this study, we systematically evaluated the contribution of CD8+ T cells to the disease progress-associated evolution of HBV. By evaluation of patient T-cell responses based on the peptide repertoire, we comprehensively characterized the association of clinical parameters in chronic hepatitis B with the antiviral T-cell response-associated mutations of the viruses from the single-epitope level to the overall HLA-I-restricted peptide levels. Furthermore, we investigated the molecular basis of the HLA-A2-restricted peptide immune escape and found that the solvent-exposed C-terminal portion of the epitopes is highly variable under CDR3β recognition. Our work may provide a comprehensive evaluation of viral mutations impacted by the host CTL response in HBV disease progression in the context of the full repertoire of HBc-derived epitopes.
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Pumpens P, Grens E. The true story and advantages of the famous Hepatitis B virus core particles: Outlook 2016. Mol Biol 2016; 50:489-509. [DOI: 10.1134/s0026893316040099] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 01/14/2016] [Indexed: 01/02/2025]
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9
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Wang L, Zou ZQ, Wang K. Clinical Relevance of HLA Gene Variants in HBV Infection. J Immunol Res 2016; 2016:9069375. [PMID: 27243039 PMCID: PMC4875979 DOI: 10.1155/2016/9069375] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/14/2016] [Indexed: 01/01/2023] Open
Abstract
Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection.
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Affiliation(s)
- Li Wang
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Zhi-Qiang Zou
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Kai Wang
- Hepatology Department, Qilu Hospital of Shandong University, 44 Wenhua West Road, Lixia District, Jinan, Shandong 250012, China
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10
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Zhang ZH, Wu CC, Chen XW, Li X, Li J, Lu MJ. Genetic variation of hepatitis B virus and its significance for pathogenesis. World J Gastroenterol 2016; 22:126-144. [PMID: 26755865 PMCID: PMC4698480 DOI: 10.3748/wjg.v22.i1.126] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 09/25/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has a worldwide distribution and is endemic in many populations. Due to its unique life cycle which requires an error-prone reverse transcriptase for replication, it constantly evolves, resulting in tremendous genetic variation in the form of genotypes, sub-genotypes, and mutations. In recent years, there has been considerable research on the relationship between HBV genetic variation and HBV-related pathogenesis, which has profound implications in the natural history of HBV infection, viral detection, immune prevention, drug treatment and prognosis. In this review, we attempted to provide a brief account of the influence of HBV genotype on the pathogenesis of HBV infection and summarize our current knowledge on the effects of HBV mutations in different regions on HBV-associated pathogenesis, with an emphasis on mutations in the preS/S proteins in immune evasion, occult HBV infection and hepatocellular carcinoma (HCC), mutations in polymerase in relation to drug resistance, mutations in HBV core and e antigen in immune evasion, chronicalization of infection and hepatitis B-related acute-on-chronic liver failure, and finally mutations in HBV x proteins in HCC.
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11
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Blessing or curse? Proteomics in granzyme research. Proteomics Clin Appl 2014; 8:351-81. [DOI: 10.1002/prca.201300096] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 11/29/2013] [Accepted: 12/21/2013] [Indexed: 01/08/2023]
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12
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Sun L, Zhang Y, Zhao B, Deng M, Liu J, Li X, Hou J, Gui M, Zhang S, Li X, Gao GF, Meng S. A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes. Protein Cell 2014; 5:317-27. [PMID: 24659387 PMCID: PMC3978166 DOI: 10.1007/s13238-014-0041-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 02/11/2014] [Indexed: 01/02/2023] Open
Abstract
Cytotoxic T cells (CTLs) play a key role in the control of Hepatitis B virus (HBV) infection and viral clearance. However, most of identified CTL epitopes are derived from HBV of genotypes A and D, and few have been defined in virus of genotypes B and C which are more prevalent in Asia. As HBV core protein (HBc) is the most conservative and immunogenic component, in this study we used an overlapping 9-mer peptide pool covering HBc to screen and identify specific CTL epitopes. An unconventional HLA-A2-restricted epitope HBc141-149 was discovered and structurally characterized by crystallization analysis. The immunogenicity and anti-HBV activity were further determined in HBV and HLA-A2 transgenic mice. Finally, we show that mutations in HBc141-149 epitope are associated with viral parameters and disease progression in HBV infected patients. Our data therefore provide insights into the structure characteristics of this unconventional epitope binding to MHC-I molecules, as well as epitope specific CTL activity that orchestrate T cell response and immune evasion in HBV infected patients.
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Affiliation(s)
- Lu Sun
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Yu Zhang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Bao Zhao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Mengmeng Deng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Jun Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Xin Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Junwei Hou
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Mingming Gui
- Xinjiang Agricultural University, Ürümqi, 830052 China
| | - Shuijun Zhang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Xiaodong Li
- Beijing Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039 China
| | - George F. Gao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
| | - Songdong Meng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, 100101 China
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