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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [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: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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Xu ZY, Gao JS, He Y, Xiao XQ, Gong GZ, Zhang M. Hepatitis B virus confers innate immunity evasion through hepatitis B virus-miR-3 down-regulation of cGAS-Sting-IFN signaling. World J Hepatol 2025; 17:99292. [PMID: 40027574 PMCID: PMC11866139 DOI: 10.4254/wjh.v17.i2.99292] [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] [Received: 07/19/2024] [Revised: 12/05/2024] [Accepted: 01/18/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) evades the innate immunity and leads to persistent chronic infection, but the molecular mechanism is still not well known. AIM To investigate whether HBV-miR-3 is involved in HBV immune evasion. METHODS HBV-miR-3 agomir and antagomir were employed to verify the effectiveness of HBV-miR-3 on cGAS-Sting-IFN pathway through the experiments on relative luciferase activity, cGAS protein expression, Sting phosphorylation and interferon (IFN) production. RESULTS HBV-miR-3 down-regulates cGAS protein expression post-transcriptionally by inhibition of cGAS 3'-untranslated region (3'-UTR) activity, which results in lower Sting phosphorylation and IFN production. HBV-miR-3 antagomir rescued cGAS protein expression, Sting phosphorylation and IFN-β production. CONCLUSION HBV-miR-3 plays an important role in HBV immunity evasion by targeting cGAS 3'-UTR and interfering with cGAS-Sting-IFN pathway.
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Affiliation(s)
- Zhen-Yu Xu
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Jia-Shi Gao
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Ying He
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xin-Qiang Xiao
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Guo-Zhong Gong
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China.
| | - Min Zhang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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Wan H, Zhang YX, Shan GY, Cheng JY, Qiao DR, Liu YY, Shi WN, Li HJ. Antiviral therapy for hepatitis B virus infection is beneficial for the prognosis hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:93983. [PMID: 39817121 PMCID: PMC11664622 DOI: 10.4251/wjgo.v17.i1.93983] [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] [Received: 03/09/2024] [Revised: 09/20/2024] [Accepted: 09/29/2024] [Indexed: 12/12/2024] Open
Abstract
In this editorial, we comment on the article by Mu et al, published in the recent issue of the World Journal of Gastrointestinal Oncology. We pay special attention to the immune tolerance mechanism caused by hepatitis B virus (HBV) infection, the pathogenesis of hepatocellular carcinoma (HCC), and the role of antiviral therapy in treating HCC related to HBV infection. HBV infection leads to systemic innate immune tolerance by directly inhibiting pattern recognition receptor recognition and antiviral signaling pathways, as well as by inhibiting the immune functions of macrophages, natural killer cells and dendritic cells. In addition, HBV leads to an immunosuppressive cascade by expressing inhibitory molecules to induce exhaustion of HBV-specific cluster of differentiation 8 + T cells, ultimately leading to long-term viral infection. The loss of immune cell function caused by HBV infection ultimately leads to HCC. Long-term antiviral therapy can improve the prognosis of patients with HCC and prevent tumor recurrence and metastasis.
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Affiliation(s)
- Hui Wan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Yu-Xin Zhang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guan-Yue Shan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Jun-Ya Cheng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Duan-Rui Qiao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Yi-Ying Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Wen-Na Shi
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Hai-Jun Li
- Institute of Liver Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
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Lei Z, Wang L, Gao H, Guo S, Kang X, Yuan J, Lv Z, Jiang Y, Yi J, Chen Z, Wang G. Mechanisms underlying the compromised clinical efficacy of interferon in clearing HBV. Virol J 2024; 21:314. [PMID: 39633459 PMCID: PMC11619119 DOI: 10.1186/s12985-024-02589-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause acute or chronic hepatitis, representing a significant global health concern. By 2019, approximately 296 million individuals were chronically infected with HBV, with 1.5 million new cases annually and 820,000 deaths due to HBV-related cirrhosis and liver cancer. Current treatments for chronic hepatitis B include nucleotide analogs (NAs) and interferons (IFNs), particularly IFN-α. NAs, such as entecavir and tenofovir, inhibit viral reverse transcription, while IFN-α exerts antiviral effects by directly suppressing viral replication, modulating viral genome epigenetics, degrading cccDNA, and activating immune responses. Despite its potential, IFN-α shows limited clinical efficacy, partly due to HBV's interference with the IFN signaling pathway. HBV encodes proteins like HBc, Pol, HBsAg, and HBx that disrupt IFN-α function. For example, HBV Pol inhibits STAT1 phosphorylation, HBsAg suppresses STAT3 phosphorylation, and HBx interferes with IFN-α efficacy through multiple mechanisms. Additionally, HBV downregulates key genes in the IFN signaling pathway, further diminishing IFN-α's antiviral effects. Understanding these interactions is crucial for improving IFN-α-based therapies. Future research may focus on overcoming HBV resistance by targeting viral proteins or optimizing IFN-α delivery. In summary, HBV's ability to resist IFN-α limits its therapeutic effectiveness, highlighting the need for new strategies to enhance treatment outcomes.
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Affiliation(s)
- Zhuoyan Lei
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Luye Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Hanlin Gao
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Shubian Guo
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Xinjian Kang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jiajun Yuan
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Ziying Lv
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Yuxin Jiang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jinping Yi
- Department of Clinical Laboratory, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Gang Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China.
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Wang C, Huang C, Li Y, Bai J, Zhao K, Fang Z, Chen J. Hepatitis B surface antigen impairs TLR4 signaling by upregulating A20 expression in monocytes. Microbiol Spectr 2024; 12:e0090924. [PMID: 39248482 PMCID: PMC11448406 DOI: 10.1128/spectrum.00909-24] [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: 04/09/2024] [Accepted: 08/06/2024] [Indexed: 09/10/2024] Open
Abstract
Toll-like receptors (TLRs) play a crucial role in eliminating viral infection. Conversely, viruses have evolved various strategies to disrupt TLR signaling during chronic infection. In the case of hepatitis B virus (HBV), we previously reported that plasma hepatitis B surface antigen (HBsAg) is closely associated with impaired TLR responses in peripheral blood mononuclear cells from chronic hepatitis B (CHB) patients, but the reasons remain unclear. In this study, we investigated the mechanism by which HBsAg suppresses TLR4 signaling in monocyte cell lines. The monocyte cell line THP-1 was pretreated with HBsAg, followed by lipopolysaccharide (LPS) stimulation. Levels of proinflammatory cytokines and the activation of NF-κB, c-JNK, and ERK were examined. We found that HBsAg did not influence the LPS-induced activation of p65, but it disrupted NF-κB promoter activity through the ectopic expression of myeloid differentiation factor 88 (MyD88) and TAK1, suggesting that HBsAg can block downstream TLR4 signaling. Furthermore, we proved that LPS-induced polyubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) and the formation of the TRAF6-TAB2 complex were inhibited in HBsAg-pretreated cells. Interestingly, HBsAg led to a significant upregulation of A20, a ubiquitin-editing enzyme. Correspondingly, downregulation of A20 using siRNA restored LPS-mediated cytokines production, reflecting its crucial role in HBsAg-mediated inhibition of TLR4 signaling. These results demonstrated a novel mechanism by which HBsAg disrupts TLR4 signaling through the upregulation of A20, suggesting that targeting A20 may be a potential strategy to help restore monocyte functions. IMPORTANCE Clearance HBsAg indicates a functional cure of HBV infection, but in chronic hepatitis B (CHB), it is hard to achieve. HBsAg has been found to regulate anti-viral immune responses, such as the activation of TLR. Our previous jobs proved that HBsAg negatively correlates with TLR2/4 activation in monocytes from CHB patients and blocks TLR2 ligand-indcuced IL-12 production in monocytes. However, how TLR4 signaling is affected by HBsAg remains unknown. In this study, we not only observed impaired TLR4 activation after pretreated monocytes with HBsAg but also identified HBsAg-induced A20 play a role in this impairment, which suggests that targeting A20 may be a viable strategy to restore monocyte functions in CHB.
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Affiliation(s)
- Cong Wang
- Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Chenlu Huang
- Liver Cancer Institute of Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yaming Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection(CAMS, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jinjin Bai
- Liver Cancer Institute of Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Kuangjie Zhao
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection(CAMS, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhong Fang
- Liver Cancer Institute of Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection(CAMS, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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Feng Z, Fu J, Tang L, Bao C, Liu H, Liu K, Yang T, Yuan JH, Zhou CB, Zhang C, Xu R, Wang FS. HBeAg induces neutrophils activation impairing NK cells function in patients with chronic hepatitis B. Hepatol Int 2024; 18:1122-1134. [PMID: 38829576 DOI: 10.1007/s12072-024-10689-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 04/21/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND The role of neutrophils in hepatitis B virus (HBV) infection has been a subject of debate due to their involvement in antiviral responses and immune regulation. This study aimed to elucidate the neutrophil characteristics in patients with chronic hepatitis B (CHB). METHODS Through flow cytometry and ribonucleic acid-sequencing analysis, the phenotypes and counts of neutrophils were analyzed in patients with CHB. Moreover, the effects of HBeAg on neutrophils and the corresponding pattern recognition receptors were identified. Simultaneously, the cross-talk between neutrophils and natural killer (NK) cells was investigated. RESULTS Neutrophils were activated in patients with CHB, characterized by higher expression levels of programmed death-ligand 1 (PD-L1), cluster of differentiation 86, and interleukin-8, and lower levels of CXC motif chemokine receptor (CXCR) 1 and CXCR2. Hepatitis B e antigen (HBeAg) partially induces neutrophil activation through the Toll-like receptor 2 (TLR2). A consistent upregulation of the TLR2 and HBeAg expression was observed in patients with CHB. Notably, the genes encoding molecules pivotal for NK-cell function upon NK receptor engagement enriched in neutrophils after HBeAg activation. The HBeAg-activated neutrophils demonstrated the ability to decrease the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in NK cells, while the PD-1 and PD-L1 pathways partially mediated the immunosuppression. CONCLUSIONS The immunosuppression of neutrophils induced by HBeAg suggests a novel pathogenic mechanism contributing to immune tolerance in patients with CHB.
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Affiliation(s)
- Zhiqian Feng
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Junliang Fu
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Lili Tang
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Chunmei Bao
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Honghong Liu
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Kai Liu
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Tao Yang
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Jin-Hong Yuan
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Chun-Bao Zhou
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Chao Zhang
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China
| | - Ruonan Xu
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
| | - Fu-Sheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
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Li Y, Song Y, Xiao Y, Wang T, Li L, Liu M, Li J, Wang J. The Characteristic of HBV Quasispecies Is Related to Occult HBV Infection of Infants Born to Highly Viremic Mothers. Viruses 2024; 16:1104. [PMID: 39066265 PMCID: PMC11281566 DOI: 10.3390/v16071104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 06/28/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Although a combination of immunoprophylaxis and antiviral therapy can effectively prevent mother-to-child transmission (MTCT) of hepatitis B virus (HBV), a considerable number of infants born to highly viremic mothers still develop occult HBV infection (OBI). To uncover the virological factor and risk predictor for OBI in infants, we found that the diversity and complexity of maternal HBV quasispecies in the case group were lower than those in the control group. Mutations with significant differences between the two groups were most enriched in the NTCPbd and PreC regions. Genetic distance at the amino-acid level of the PreC region, especially the combination of three amino-acid mutations in the PreC region, could strongly predict the risk of OBI in infants. HBV quasispecies in OBI infants were highly complex, and the non-synonymous substitutions were mainly found in the RT and HBsAg regions. The sK47E (rtQ55R) and sP49L mutations in OBI infants might contribute to OBI through inhibiting the production of HBV DNA and HBsAg, respectively. This study found the potential virological factors and risk predictors for OBI in infants born to highly viremic mothers, which might be helpful for controlling OBI in infants.
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Affiliation(s)
- Yi Li
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China
| | - Yarong Song
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Yiwei Xiao
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Tong Wang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lili Li
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Minmin Liu
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jie Li
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Jie Wang
- Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
- NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China
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Huang DQ, Shen L, Phyo WW, Cloherty G, Butler EK, Kuhns MC, McNamara AL, Holzmayer V, Gersch J, Anderson M, Yang WL, Ngu JH, Chang J, Tan J, Ahmed T, Dan YY, Lee YM, Lee GH, Tan PS, Muthiah M, Khine HTW, Lee C, Tay A, Lim SG. Quantitative HBeAg is a strong predictor of HBeAg loss among patients receiving pegylated interferon. Antiviral Res 2024; 227:105876. [PMID: 38641023 DOI: 10.1016/j.antiviral.2024.105876] [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: 10/20/2023] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/21/2024]
Abstract
BACKGROUND HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy. AIM To evaluate the use of serum biomarkers to predict HBeAg loss. METHODS HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated. RESULTS HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm. CONCLUSIONS Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon.
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Affiliation(s)
- Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Liang Shen
- Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Wah Wah Phyo
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | | | | | | | | | | | | | | | - Wei Lyn Yang
- Department of Gastroenterology, Tan Tock Seng Hospital, Singapore
| | | | - Jason Chang
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
| | - Jessica Tan
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Taufique Ahmed
- Department of Gastroenterology and Hepatology, Raja Isteri Pengiran Anak Saleha Hospital, Brunei
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Guan Huei Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Poh Seng Tan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Mark Muthiah
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Htet Toe Wai Khine
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Chris Lee
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Amy Tay
- Division of Gastroenterology and Hepatology, National University Health System, Singapore
| | - Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Division of Gastroenterology and Hepatology, National University Health System, Singapore.
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Zhao P, Zhao Y, Du M, Chen X, Lu Y. Impact of lamivudine treatment in late pregnancy on the development of the foetal immune response to hepatitis B virus: a meta-analysis in R with the metafor package. Trans R Soc Trop Med Hyg 2024; 118:264-272. [PMID: 38048279 DOI: 10.1093/trstmh/trad084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 10/15/2023] [Accepted: 11/09/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a worldwide public health burden, especially in Asia and Africa. Concerns were raised that foetal exposure to HBV and antiretroviral therapy (ART) might suppress the innate immune response and reduce the production of hepatitis B surface antibody (HBsAb) in foetuses and infants. We therefore conducted the current study to evaluate the impact of ART on the development of the immune response to HBV in foetuses and infants. METHODS We selected lamivudine instead of telbivudine or tenofovir as the intervention measurement because it was the oldest and most widely used ART during pregnancy and its safety data have been sufficiently documented. A comprehensive search was conducted in eight electronic databases, including four Chinese and four English databases. Studies that met the following eligibility criteria were included: human randomized controlled trials (RCTs); participants in the treatment group were exclusively exposed to lamivudine; participants in the control group were exposed to placebo, no treatment or hepatitis B immunoglobulin; all participants were HBV-positive pregnant women with a high viral load and the main outcome of interest was neonatal HBsAb seropositivity. Data were tabulated and analysed using R software. RESULTS Nine RCTs were included and analysed. Compared with controls, lamivudine significantly decreased HBsAb seronegativity in the newborn within 24 h after birth (indicating the foetal immune response to HBV). Similar results were noted in infants within 6-7 months after birth and infants within 12 months (indicating the neonatal immune response to HBV vaccine). CONCLUSIONS Lamivudine treatment in late pregnancy boosted the foetal immune response to HBV in utero and enhanced the neonatal immune response to hepatitis B vaccine after birth.
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Affiliation(s)
- Peng Zhao
- Department of Obstetrics and Gynaecology, Women's Hospital, Zhejiang University School of Medicine, Zhejiang Province, 310006, Hangzhou, No. 1 Xueshi Road, China
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Zhejiang Province, 310006, Hangzhou, No. 1 Xueshi Road, China
| | - Ying Zhao
- Department of Obstetrics, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, 322000, Yiwu, No. N1 Shangcheng Avenue, China
| | - Minmin Du
- Department of Obstetrics, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, 322000, Yiwu, No. N1 Shangcheng Avenue, China
| | - Xiuying Chen
- Department of Obstetrics, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, 322000, Yiwu, No. N1 Shangcheng Avenue, China
| | - Yongchao Lu
- Department of Obstetrics and Gynaecology, Women's Hospital, Zhejiang University School of Medicine, Zhejiang Province, 310006, Hangzhou, No. 1 Xueshi Road, China
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10
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Choonnasard A, Shofa M, Okabayashi T, Saito A. Conserved Functions of Orthohepadnavirus X Proteins to Inhibit Type-I Interferon Signaling. Int J Mol Sci 2024; 25:3753. [PMID: 38612565 PMCID: PMC11011558 DOI: 10.3390/ijms25073753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 03/19/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Orthohepadnavirus causes chronic hepatitis in a broad range of mammals, including primates, cats, woodchucks, and bats. Hepatitis B virus (HBV) X protein inhibits type-I interferon (IFN) signaling, thereby promoting HBV escape from the human innate immune system and establishing persistent infection. However, whether X proteins of Orthohepadnavirus viruses in other species display a similar inhibitory activity remains unknown. Here, we investigated the anti-IFN activity of 17 Orthohepadnavirus X proteins derived from various hosts. We observed conserved activity of Orthohepadnavirus X proteins in inhibiting TIR-domain-containing adaptor protein inducing IFN-β (TRIF)-mediated IFN-β signaling pathway through TRIF degradation. X proteins from domestic cat hepadnavirus (DCH), a novel member of Orthohepadnavirus, inhibited mitochondrial antiviral signaling protein (MAVS)-mediated IFNβ signaling pathway comparable with HBV X. These results indicate that inhibition of IFN signaling is conserved in Orthohepadnavirus X proteins.
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Affiliation(s)
- Amonrat Choonnasard
- Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan; (A.C.); (M.S.); (T.O.)
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Maya Shofa
- Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan; (A.C.); (M.S.); (T.O.)
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Tamaki Okabayashi
- Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan; (A.C.); (M.S.); (T.O.)
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
- Center for Animal Disease Control, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Akatsuki Saito
- Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan; (A.C.); (M.S.); (T.O.)
- Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
- Center for Animal Disease Control, University of Miyazaki, Miyazaki 889-2192, Japan
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11
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Nakaya Y, Nishizawa T, Nishitsuji H, Morita H, Yamagata T, Onomura D, Murata K. TRIM26 positively affects hepatitis B virus replication by inhibiting proteasome-dependent degradation of viral core protein. Sci Rep 2023; 13:13584. [PMID: 37604854 PMCID: PMC10442393 DOI: 10.1038/s41598-023-40688-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 08/16/2023] [Indexed: 08/23/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major medical concern worldwide. Current treatments for HBV infection effectively inhibit virus replication; however, these treatments cannot cure HBV and novel treatment-strategies should be necessary. In this study, we identified tripartite motif-containing protein 26 (TRIM26) could be a supportive factor for HBV replication. Small interfering RNA-mediated TRIM26 knockdown (KD) modestly attenuated HBV replication in human hepatocytes. Endogenous TRIM26 physically interacted with HBV core protein (HBc), but not polymerase and HBx, through the TRIM26 SPRY domain. Unexpectedly, TRIM26 inhibited HBc ubiquitination even though TRIM26 is an E3 ligase. HBc was degraded by TRIM26 KD in Huh-7 cells, whereas the reduction was restored by a proteasome inhibitor. RING domain-deleted TRIM26 mutant (TRIM26ΔR), a dominant negative form of TRIM26, sequestered TRIM26 from HBc, resulting in promoting HBc degradation. Taking together, this study demonstrated that HBV utilizes TRIM26 to avoid the proteasome-dependent HBc degradation. The interaction between TRIM26 and HBc might be a novel therapeutic target against HBV infection.
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Affiliation(s)
- Yuki Nakaya
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, 329-0498, Japan.
| | - Tsutomu Nishizawa
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, 329-0498, Japan
| | - Hironori Nishitsuji
- Department of Virology and Parasitology, School of Medicine, Fujita Health University, Toyoake, 470-1192, Japan
| | - Hiromi Morita
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, 329-0498, Japan
| | - Tomoko Yamagata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, 329-0498, Japan
| | - Daichi Onomura
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, 329-0498, Japan
| | - Kazumoto Murata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, 329-0498, Japan.
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Schefczyk S, Luo X, Liang Y, Trippler M, Lu M, Wedemeyer H, Schmidt HH, Broering R. Poly(I:C) Induces Distinct Liver Cell Type-Specific Responses in Hepatitis B Virus-Transgenic Mice In Vitro, but Fails to Induce These Signals In Vivo. Viruses 2023; 15:v15051203. [PMID: 37243287 DOI: 10.3390/v15051203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/12/2023] [Accepted: 05/13/2023] [Indexed: 05/28/2023] Open
Abstract
Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral signalling was investigated in HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1HBV]Bri44), lack (Tg1.4HBV-s-mut3) or secrete (Tg1.4HBV-s-rec (F1, Tg1.4HBV-s-mut × Alb/HBs) the HBsAg. Herein, the responsiveness of TLR3 and RIG-I in primary parenchymal and non-parenchymal liver cells was determined in vitro and in vivo. Cell type-specific and mouse strain-dependent interferon, cytokine and chemokine expression were observed by LEGENDplex™ and validated by quantitative PCR. In vitro, the hepatocytes, liver sinusoidal endothelial cells and Kupffer cells of Tg1.4HBV-s-rec mice showed poly(I:C) susceptibilities similar to the wild-type controls, while in the remaining leucocyte fraction the interferon, cytokine and chemokine induction was reduced. On the contrary, poly(I:C)-injected 1.4TgHBV-s-rec mice showed suppressed interferon, cytokine and chemokine levels in hepatocytes but increased levels in the leucocyte fraction. Thus, we concluded that liver cells of Tg1.4HBV-s-rec mice, which produce HBV particles and release the HBsAg, responded to exogenous TLR3/RIG-I stimuli in vitro but exhibited a tolerogenic environment in vivo.
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Affiliation(s)
- Stefan Schefczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Xufeng Luo
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Yaojie Liang
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Martin Trippler
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
| | - Hartmut H Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
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Shi Y, Wang Z, Ge S, Xia N, Yuan Q. Hepatitis B Core Antibody Level: A Surrogate Marker for Host Antiviral Immunity in Chronic Hepatitis B Virus Infections. Viruses 2023; 15:1111. [PMID: 37243197 PMCID: PMC10221631 DOI: 10.3390/v15051111] [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: 04/10/2023] [Revised: 04/28/2023] [Accepted: 04/30/2023] [Indexed: 05/28/2023] Open
Abstract
The hepatitis B virus core protein (HBcAg) is a highly immunogenic particulate antigen. Nearly all patients with persistent or resolved hepatitis B virus (HBV) infection show seropositivity for hepatitis B core antibody (anti-HBc), which appears in the early stage of infection and is mostly present for life. Traditionally, the anti-HBc is regarded as an evidential serological marker of HBV infections. In the last ten years, several studies revealed the predictive value of quantitative anti-HBc (qAnti-HBc) level in the treatment response and clinical outcome of chronic HBV infections, implying new insights into this classic marker. Overall, qAnti-HBc should be regarded as an indicator of the host's immune response specific to HBV, which correlates with HBV-related hepatitis activity and liver pathology. This review summarized the latest understanding of the clinical values of qAnti-HBc for differentiating the CHB phase, predicting treatment response, and providing disease prognosis. Moreover, we also discussed the possible mechanism of qAnti-HBc regulation during different courses of HBV infection.
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Affiliation(s)
- Yang Shi
- State Key Laboratory of Infectious Disease Vaccine Development, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; (Y.S.); (Z.W.); (S.G.); (N.X.)
- NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, National Institute of Diagnostics Vaccine Development in Infectious Diseases, School of Public Health, Xiamen 361102, China
| | - Zihan Wang
- State Key Laboratory of Infectious Disease Vaccine Development, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; (Y.S.); (Z.W.); (S.G.); (N.X.)
- NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, National Institute of Diagnostics Vaccine Development in Infectious Diseases, School of Public Health, Xiamen 361102, China
| | - Shengxiang Ge
- State Key Laboratory of Infectious Disease Vaccine Development, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; (Y.S.); (Z.W.); (S.G.); (N.X.)
- NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, National Institute of Diagnostics Vaccine Development in Infectious Diseases, School of Public Health, Xiamen 361102, China
| | - Ningshao Xia
- State Key Laboratory of Infectious Disease Vaccine Development, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; (Y.S.); (Z.W.); (S.G.); (N.X.)
- NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, National Institute of Diagnostics Vaccine Development in Infectious Diseases, School of Public Health, Xiamen 361102, China
| | - Quan Yuan
- State Key Laboratory of Infectious Disease Vaccine Development, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; (Y.S.); (Z.W.); (S.G.); (N.X.)
- NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, National Institute of Diagnostics Vaccine Development in Infectious Diseases, School of Public Health, Xiamen 361102, China
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Padarath K, Deroubaix A, Kramvis A. The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma. Viruses 2023; 15:v15040857. [PMID: 37112837 PMCID: PMC10144019 DOI: 10.3390/v15040857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the pathogenesis of hepatocellular carcinoma, and various HBV proteins have been implicated in promoting this persistence. The precursor of hepatitis e antigen (HBeAg), is translated from the precore/core region and is post-translationally modified to yield HBeAg, which is secreted in the serum. HBeAg is a non-particulate protein of HBV and can act as both a tolerogen and an immunogen. HBeAg can protect hepatocytes from apoptosis by interfering with host signalling pathways and acting as a decoy to the immune response. By evading the immune response and interfering with apoptosis, HBeAg has the potential to contribute to the hepatocarcinogenic potential of HBV. In particular, this review summarises the various signalling pathways through which HBeAg and its precursors can promote hepatocarcinogenesis via the various hallmarks of cancer.
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15
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Characterization of Intracellular Precore-Derived Proteins and Their Functions in Hepatitis B Virus-Infected Human Hepatocytes. mBio 2023; 14:e0350122. [PMID: 36715515 PMCID: PMC9973328 DOI: 10.1128/mbio.03501-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Hepatitis B virus (HBV) precore protein is not essential for viral replication but is thought to facilitate chronic infection. In addition to the secreted precore products, including the hepatitis B e antigen (HBeAg) and PreC protein, intracellular precore-derived proteins in HBV-infected human hepatocytes remain poorly characterized, and their roles, if any, remain largely unknown. Here, we detected multiple precore derivatives, including the nonprocessed precursor p25 and the processing intermediate p22, in HBV-infected human hepatocytes as well as human hepatoma cells overexpressing the HBV precore protein. Both p25 and p22 showed phosphorylated and unphosphorylated forms, which were located in different intracellular compartments. Interestingly, precore expression was associated with decreases in intracellular HBV core protein (HBc) and secreted DNA-containing virions but was also associated with an increase in secreted empty virions. The decrease in HBc by precore could be attributed to cytosolic p22, which caused HBc degradation, at least in part by the proteasome, and consequently decreased HBV pregenomic RNA packaging and DNA synthesis. In addition, cytosolic p22 formed chimeric capsids with HBc in the cell, which were further secreted in virions. In contrast, the PreC antigen, like HBeAg, was secreted via the endoplasmic reticulum (ER)-Golgi secretory pathway and was thus unable to form capsids in the cell or be secreted in virions. Furthermore, p25, as well as p22, were secreted in virions from HBV-infected human hepatocytes and were detected in the sera of HBV-infected chimpanzees. In summary, we have detected multiple intracellular precore-derived proteins in HBV-infected human hepatocytes and revealed novel precore functions in the viral life cycle. IMPORTANCE Chronic hepatitis B remains a worldwide public health issue. The hepatitis B virus (HBV) precore protein is not essential for HBV replication but may facilitate viral persistence. In this study, we have detected multiple precore protein species in HBV-infected human hepatocytes and studied their functions in the HBV life cycle. We found that the HBV precore proteins decreased intracellular HBV core protein and reduced secretion of complete virions but enhanced secretion of empty virions. Interestingly, the cytosolic precore protein species formed chimeric capsids with the core protein and were secreted in virions. Our results shed new light on the functions of intracellular precore protein species in the HBV life cycle and have implications for the roles of precore proteins in HBV persistence and pathogenesis.
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Farnesoid X Receptor Activation Decreases Toll-like Receptor 2 Expression by Upregulating HBeAg Production. HEPATITIS MONTHLY 2023. [DOI: 10.5812/hepatmon-129128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Background: Previous investigations have demonstrated that hepatitis B virus (HBV) infection leads to elevated serum bile acid levels, which is considered to cause liver damage. Thus, we suppose that bile acids may be of considerable significance in inducing immune tolerance. Methods: In this investigation, we explored the functions of the farnesoid X receptor (FXR), a nuclear receptor activated by bile acids, in modulating hepatitis B e antigen (HBeAg) production and toll-like receptor (TLR) expression in vitro and in vivo. Results: The results showed that FXR activation promoted secreted and intracellular HBeAg expression in HepG2 and HEK293T cells. However, FXR antagonist Z-guggulsterone (Z-g) decreased the bile acid-mediated HBeAg production. Meanwhile, TLR2 expression significantly reduced in HepG2 cells transfected with pAAV/HBV1.2 plasmid comprising whole HBV genome and treated with bile acids, but not with mutant pAAV/HBV1.2 plasmid with defected HBeAg product. In the hydrodynamic injection HBV mouse model, the level of serum HBeAg was decreased, but intrahepatic TLR2 expression was elevated in FXR-/- mice. Conclusions: In conclusion, FXR activation inhibits TLR2-mediated innate immunity by upregulating HBeAg production. Our data indicate that a mild elevation of serum bile acids may cause immune tolerance and lead to virus persistence in HBV-infected patients.
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Lan MY, Lin HC, Hu TH, Chen SF, Chen CH, Chang YY, Chiu KW, Lin TK, Chen SS. Telbivudine-Induced Myopathy: Clinical Features, Histopathological Characteristics, and Risk Factors. J Clin Neurol 2023; 19:52-59. [PMID: 36606646 PMCID: PMC9833882 DOI: 10.3988/jcn.2023.19.1.52] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND AND PURPOSE Oral nucleos(t)ide analogs (NAs) are the mainstay treatment for chronic hepatitis B (CHB). Myotoxicity is an important extrahepatic effect related to NA treatment. Telbivudine is the NA for CHB that is frequently associated with muscle-related side effects. The risk factors for telbivudine-induced myopathy (TIM) are not yet clear. METHODS This study characterized the clinical, magnetic resonance images (MRI), and pathological features of 12 TIM cases. A group of telbivudine-tolerant (TT) patients with CHB who received regular telbivudine treatment during the same period without the occurrence of myopathy was collected. Demographic and clinical factors were compared between the patients with TIM and the TT controls. Factors independently associated with TIM were identified using logistic regression analysis. RESULTS The patients with TIM (males/females: 7/5, mean age: 57 years) developed myopathy after using telbivudine for a median period of 19.5 months. Muscle histopathology revealed abnormal proliferation, subsarcolemmal or sarcoplasmic accumulations, and ultrastructural defects of mitochondria. When compared with TT cases, patients with TIM had a lower estimated glomerular filtration rate and were more frequently positive for hepatitis B e antigen (HBeAg). CONCLUSIONS Mitochondrial abnormalities are characteristic histopathological features, and impaired renal function and HBeAg positivity are risk factors for TIM. Telbivudine-induced mitochondrial dysfunction and immune activation related to mitochondrial damage and HBeAg serostatus changes may underlie TIM. Constant clinical surveillance of myopathy during telbivudine treatment is needed due to the significant latency of its development. Dose adjustment for impaired renal function does not eliminate the risk of TIM occurrence.
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Affiliation(s)
- Min-Yu Lan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Parkinson’s Disease, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hui-Chen Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shu-Fang Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yung-Yee Chang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Parkinson’s Disease, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - King-Wah Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsu-Kung Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Parkinson’s Disease, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shun-Sheng Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Xu C, Fan J, Liu D, Tuerdi A, Chen J, Wei Y, Pan Y, Dang H, Wei X, Yousif AS, Yogaratnam J, Zhou Q, Lichenstein H, Xu T. Alpha-kinase 1 (ALPK1) agonist DF-006 demonstrates potent efficacy in mouse and primary human hepatocyte (PHH) models of hepatitis B. Hepatology 2023; 77:275-289. [PMID: 35699669 DOI: 10.1002/hep.32614] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 05/30/2022] [Accepted: 06/04/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS In the treatment of chronic hepatitis B (CHB) infection, stimulation of innate immunity may lead to hepatitis B virus (HBV) cure. Alpha-kinase 1 (ALPK1) is a pattern recognition receptor (PRR) that activates the NF-κB pathway and stimulates innate immunity. Here we characterized the preclinical anti-HBV efficacy of DF-006, an orally active agonist of ALPK1 currently in clinical development for CHB. APPROACH AND RESULTS In adeno-associated virus (AAV)-HBV mouse models and primary human hepatocytes (PHHs) infected with HBV, we evaluated the antiviral efficacy of DF-006. In the mouse models, DF-006 rapidly reduced serum HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen levels using doses as low as 0.08 μg/kg, 1 μg/kg, and 5 μg/kg, respectively. DF-006 in combination with the HBV nucleoside reverse transcriptase inhibitor, entecavir, further reduced HBV DNA. Antiviral efficacy in mice was associated with an increase in immune cell infiltration and decrease of hepatitis B core antigen, encapsidated pregenomic RNA, and covalently closed circular DNA in liver. At subnanomolar concentrations, DF-006 also showed anti-HBV efficacy in PHH with significant reductions of HBV DNA. Following dosing with DF-006, there was upregulation of NF-κB-targeted genes that are involved in innate immunity. CONCLUSION DF-006 was efficacious in mouse and PHH models of HBV without any indications of overt toxicity. In mice, DF-006 localized primarily to the liver where it potently activated innate immunity. The transcriptional response in mouse liver provides insights into mechanisms that mediate anti-HBV efficacy by DF-006.
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Affiliation(s)
- Cong Xu
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
- Zhejiang Yao Yuan Biotechnology Ltd , Jiashan , Zhejiang , China
| | - Jieqing Fan
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
- Zhejiang Yao Yuan Biotechnology Ltd , Jiashan , Zhejiang , China
| | - Danyang Liu
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
- Zhejiang Yao Yuan Biotechnology Ltd , Jiashan , Zhejiang , China
| | - Aimaier Tuerdi
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
| | - Juanjuan Chen
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
| | - Yuning Wei
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
| | - Yanfang Pan
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
| | - Huaixin Dang
- Zhejiang Yao Yuan Biotechnology Ltd , Jiashan , Zhejiang , China
| | - Xiong Wei
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
| | | | | | - Qiong Zhou
- Biology Department , Wuxi Apptec (Shanghai) Co. Ltd , Shanghai , China
| | | | - Tian Xu
- Shanghai Yao Yuan Biotechnology Ltd (Drug Farm) , Shanghai , China
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Kar A, Samanta A, Mukherjee S, Barik S, Biswas A. The HBV web: An insight into molecular interactomes between the hepatitis B virus and its host en route to hepatocellular carcinoma. J Med Virol 2023; 95:e28436. [PMID: 36573429 DOI: 10.1002/jmv.28436] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/26/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022]
Abstract
Hepatitis B virus (HBV) is a major aetiology associated with the development and progression of hepatocellular carcinoma (HCC), the most common primary liver malignancy. Over the past few decades, direct and indirect mechanisms have been identified in the pathogenesis of HBV-associated HCC which include altered signaling pathways, genome integration, mutation-induced genomic instability, chromosomal deletions and rearrangements. Intertwining of the HBV counterparts with the host cellular factors, though well established, needs to be systemized to understand the dynamics of host-HBV crosstalk and its consequences on HCC progression. Existence of a vast array of protein-protein and protein-nucleic acid interaction databases has led to the uncoiling of the compendia of genes/gene products associated with these interactions. This review covers the existing knowledge about the HBV-host interplay and brings it down under one canopy emphasizing on the HBV-host interactomics; and thereby highlights new strategies for therapeutic advancements against HBV-induced HCC.
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Affiliation(s)
- Arpita Kar
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
| | - Abhisekh Samanta
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
| | - Soumyadeep Mukherjee
- Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
| | - Subhasis Barik
- Department of In Vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
| | - Avik Biswas
- Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
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20
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Chen X, Liu X, Jiang Y, Xia N, Liu C, Luo W. Abnormally primed CD8 T cells: The Achilles' heel of CHB. Front Immunol 2023; 14:1106700. [PMID: 36936922 PMCID: PMC10014547 DOI: 10.3389/fimmu.2023.1106700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a significant public health challenge, and more than 250 million people around world are infected with HBV. The clearance of HBV with virus-specific CD8 T cells is critical for a functional cure. However, naïve HBV-specific CD8 T cells are heavily hindered during the priming process, and this phenomenon is closely related to abnormal cell and signal interactions in the complex immune microenvironment. Here, we briefly summarize the recent progress in understanding the abnormal priming of HBV-specific CD8 T cells and some corresponding immunotherapies to facilitate their functional recovery, which provides a novel perspective for the design and development of immunotherapy for chronic HBV infection (CHB). Finally, we also highlight the balance between viral clearance and pathological liver injury induced by CD8 T-cell activation that should be carefully considered during drug development.
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Affiliation(s)
- Xiaoqing Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Yichao Jiang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- The Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, Xiamen, Fujian, China
| | - Chao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
| | - Wenxin Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
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21
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Hwang SY, Yoo SH, Chang HY, Kim S, Lee JI, Lee KS, Cho YY, Joon KH, Lee HW. Baseline and on-treatment HBcrAg levels as predictors of HBeAg seroconversion in chronic hepatitis B patients treated with antivirals. J Viral Hepat 2023; 30:39-45. [PMID: 36321949 DOI: 10.1111/jvh.13765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 10/14/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
HBeAg seroconversion is an important treatment endpoint. We aimed to identify predictors of seroconversion using serum HBsAg and hepatitis B core-related antigen (HBcrAg) in HBeAg-positive patients treated with nucleos(t)ide analogs (NAs). Data and samples from 70 HBeAg-positive patients treated with entecavir or tenofovir between January 2007 and December 2017 were retrospectively analysed. The mean follow-up period was 11 years. The predictive power for HBeAg seroconversion of HBcrAg levels at baseline and 2 years after antiviral therapy was determined using receiver operating curve analysis. Twenty-one patients (30%) achieved HBeAg seroconversion at a mean of 28 (range, 12-84) months after antiviral treatment. The median baseline HBcrAg and HBsAg levels were 6.9(5.7-7.0) vs. 5.8(5.5-6.5) log10 U/mL (p = .006), 4.9(4.5-5.1) vs. 4.5(4.1-5.0) log10 IU/mL (p = .044) in the no seroconversion group and seroconversion group, respectively. In the multivariate analysis, the serum HBcrAg levels at baseline and 2 years after antiviral therapy were predictive factors for HBeAg seroconversion ([HR]; 0.326; [CI], 0.111-0.958; p = .042 and HR, 0.4555; CI, 0.211-0.984; p = .045). HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy had sensitivities of 53.1% and 69.8%, specificities of 95.2% and 70.6%, positive predictive values of 82.6% and 50.0%, and negative predictive values of 82.6% and 84.5%, respectively, with AUROCs of 0.712 (95%CI, 0.596-0.830) and 0.745 (95%CI, 0.599-0.891) for predicting HBeAg seroconversion. In chronic hepatitis B patients treated with NAs, HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy were useful predictive factors of HBeAg seroconversion.
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Affiliation(s)
- Soo Young Hwang
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Sung Hwan Yoo
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Hye Young Chang
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Sora Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Young Youn Cho
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Kim Hyung Joon
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea
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22
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Hatton AA, Guerra FE. Scratching the Surface Takes a Toll: Immune Recognition of Viral Proteins by Surface Toll-like Receptors. Viruses 2022; 15:52. [PMID: 36680092 PMCID: PMC9863796 DOI: 10.3390/v15010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
Early innate viral recognition by the host is critical for the rapid response and subsequent clearance of an infection. Innate immune cells patrol sites of infection to detect and respond to invading microorganisms including viruses. Surface Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) that can be activated by viruses even before the host cell becomes infected. However, the early activation of surface TLRs by viruses can lead to viral clearance by the host or promote pathogenesis. Thus, a plethora of research has attempted to identify specific viral ligands that bind to surface TLRs and mediate progression of viral infection. Herein, we will discuss the past two decades of research that have identified specific viral proteins recognized by cell surface-associated TLRs, how these viral proteins and host surface TLR interactions affect the host inflammatory response and outcome of infection, and address why controversy remains regarding host surface TLR recognition of viral proteins.
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Affiliation(s)
- Alexis A. Hatton
- Department of Microbiology & Cell Biology, Montana State University, Bozeman, MT 59718, USA
| | - Fermin E. Guerra
- Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA 98195, USA
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23
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Yang G, Wan P, Zhang Y, Tan Q, Qudus MS, Yue Z, Luo W, Zhang W, Ouyang J, Li Y, Wu J. Innate Immunity, Inflammation, and Intervention in HBV Infection. Viruses 2022; 14:2275. [PMID: 36298831 PMCID: PMC9609328 DOI: 10.3390/v14102275] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/12/2022] [Accepted: 10/15/2022] [Indexed: 07/30/2023] Open
Abstract
Hepatitis B virus (HBV) infection is still one of the most dangerous viral illnesses. HBV infects around 257 million individuals worldwide. Hepatitis B in many individuals ultimately develops hepatocellular carcinoma (HCC), which is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide. The innate immunity acts as the first line of defense against HBV infection through activating antiviral genes. Along with the immune responses, pro-inflammatory cytokines are triggered to enhance the antiviral responses, but this may result in acute or chronic liver inflammation, especially when the clearance of virus is unsuccessful. To a degree, the host innate immune and inflammatory responses dominate the HBV infection and liver pathogenesis. Thus, it is crucial to figure out the signaling pathways involved in the activation of antiviral factors and inflammatory cytokines. Here, we review the interplay between HBV and the signal pathways that mediates innate immune responses and inflammation. In addition, we summarize current therapeutic strategies for HBV infection via modulating innate immunity or inflammation. Characterizing the mechanisms that underlie these HBV-host interplays might provide new approaches for the cure of chronic HBV infection.
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Affiliation(s)
- Ge Yang
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Pin Wan
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Yaru Zhang
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
| | - Qiaoru Tan
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Muhammad Suhaib Qudus
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
| | - Zhaoyang Yue
- Foshan Institute of Medical Microbiology, Foshan 528315, China
| | - Wei Luo
- Clinical Research Institute, The First People’s Hospital, Foshan 528000, China
| | - Wen Zhang
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Jianhua Ouyang
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Yongkui Li
- Foshan Institute of Medical Microbiology, Foshan 528315, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
- Guangdong Longfan Biological Science and Technology, Foshan 528315, China
| | - Jianguo Wu
- Foshan Institute of Medical Microbiology, Foshan 528315, China
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, China
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
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24
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Du Y, Wu J, Liu J, Zheng X, Yang D, Lu M. Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection. Front Immunol 2022; 13:965018. [PMID: 35967443 PMCID: PMC9372436 DOI: 10.3389/fimmu.2022.965018] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains to be a substantial global burden, especially for end-stage liver diseases. It is well accepted that HBV-specific T and B cells are essential for controlling HBV infection. Toll-like receptors (TLRs) represent one of the major first-line antiviral defenses through intracellular signaling pathways that induce antiviral inflammatory cytokines and interferons, thereby shaping adaptive immunity. However, HBV has evolved strategies to counter TLR responses by suppressing the expression of TLRs and blocking the downstream signaling pathways, thus limiting HBV-specific adaptive immunity and facilitating viral persistence. Recent studies have stated that stimulation of the TLR signaling pathway by different TLR agonists strengthens host innate immune responses and results in suppression of HBV replication. In this review, we will discuss how TLR-mediated responses shape HBV-specific adaptive immunity as demonstrated in different experimental models. This information may provide important insight for HBV functional cure based on TLR agonists as immunomodulators.
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Affiliation(s)
- Yanqin Du
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Mengji Lu,
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Chu JYK, Chuang YC, Tsai KN, Pantuso J, Ishida Y, Saito T, Ou JHJ. Autophagic membranes participate in hepatitis B virus nucleocapsid assembly, precore and core protein trafficking, and viral release. Proc Natl Acad Sci U S A 2022; 119:e2201927119. [PMID: 35858426 PMCID: PMC9335259 DOI: 10.1073/pnas.2201927119] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 06/05/2022] [Indexed: 01/21/2023] Open
Abstract
Hepatitis B virus (HBV) DNA replication takes place inside the viral core particle and is dependent on autophagy. Here we show that HBV core particles are associated with autophagosomes and phagophores in cells that productively replicate HBV. These autophagic membrane-associated core particles contain almost entirely the hypophosphorylated core protein and are DNA replication competent. As the hyperphosphorylated core protein can be localized to phagophores and the dephosphorylation of the core protein is associated with the packaging of viral pregenomic RNA (pgRNA), these results are in support of the model that phagophores can serve as the sites for the packaging of pgRNA. In contrast, in cells that replicate HBV, the precore protein derivatives, which are related to the core protein, are associated with autophagosomes but not with phagophores via a pathway that is independent of its signal peptide. Interestingly, when the core protein is expressed by itself, it is associated with phagophores but not with autophagosomes. These observations indicate that autophagic membranes are differentially involved in the trafficking of precore and core proteins. HBV induces the fusion of autophagosomes and multivesicular bodies and the silencing of Rab11, a regulator of this fusion, is associated with the reduction of release of mature HBV particles. Our studies thus indicate that autophagic membranes participate in the assembly of HBV nucleocapsids, the trafficking of HBV precore and core proteins, and likely also the egress of HBV particles.
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Affiliation(s)
- Ja Yeon Kim Chu
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
| | - Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
| | - Jessica Pantuso
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
| | - Yuji Ishida
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
- Research and Development Department, PhoenixBio, Co., Ltd, Kagamiyama, Higashi-Hiroshima City, 739-0046 Japan
| | - Takeshi Saito
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
- Department of Medicine, Division of Gastrointestinal and Liver Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
| | - Jing-hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033
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26
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Li J, Yu M, Zong R, Fan C, Ren F, Wu W, Li C. Deacetylation of Notch1 by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization. Am J Physiol Gastrointest Liver Physiol 2022; 322:G459-G471. [PMID: 35234049 DOI: 10.1152/ajpgi.00338.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic macrophages are involved in both pathogen clearance and immunopathogenesis. Emerging evidence demonstrates that macrophage polarization plays a critical role in hepatitis B virus (HBV)-induced immune impairment and liver pathology. However, it remains largely unknown as to how HBV infection facilitates M2 macrophage polarization. Here, a mouse HBV infection model was established by hydrodynamic injection with a vector containing 1.3-fold overlength HBV genome via the tail vein. Coculture experiments with HBV-producing HepG2.2.15 cells and macrophages were established in vitro. We found that HBV-inhibited M1 while enhancing M2 markers, which was accompanied by decreased proinflammatory tumor necrosis factor-α (TNF-α) and augmented anti-inflammatory IL-10 expression. Furthermore, both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) secretion contributed to HBV-triggered macrophage polarization from M1 toward M2 phenotype. Mechanistically, HBsAg and HBeAg could upregulate the sirtuins 1 (SIRT1) deacetylase expression, which in turn promote deacetylation of the Notch1 intracellular domain (NICD), leading to increased Akt phosphorylation and decreased NF-κB nuclear translocation in macrophages. Our findings suggest that NICD deacetylation by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, raising the possibility of targeting SIRT1/Notch1 pathway in macrophages to treat HBV immune evasion and chronic HBV infection.NEW & NOTEWORTHY This study identified a previously unrecognized molecular mechanism of HBV-mediated suppression of innate immune responses. We demonstrate that deacetylation of NICD by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization, which may aid in the development of new macrophage-based immunotherapy for chronic HBV infection and related diseases.
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Affiliation(s)
- Jiahui Li
- Department of Anatomy and Histology Embryology, Jinzhou Medical University, Jinzhou, People's Republic of China.,Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China.,Department of Anatomy, Youjiang Medical University for Nationalities, Baise, People's Republic of China
| | - Mengxue Yu
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Ruobin Zong
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Chengpeng Fan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
| | - Fu Ren
- Department of Anatomy, Shenyang Medical College, Shenyang, People's Republic of China
| | - Wei Wu
- Institute of Humanities and Social Sciences, Shenyang University, Shenyang, People's Republic of China
| | - Changyong Li
- Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, People's Republic of China
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27
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Taverniti V, Ligat G, Debing Y, Kum DB, Baumert TF, Verrier ER. Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives. J Clin Med 2022; 11:1349. [PMID: 35268440 PMCID: PMC8911156 DOI: 10.3390/jcm11051349] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/25/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Despite a preventive vaccine being available, more than 250 million people suffer from chronic hepatitis B virus (HBV) infection, a major cause of liver disease and HCC. HBV infects human hepatocytes where it establishes its genome, the cccDNA with chromosomal features. Therapies controlling HBV replication exist; however, they are not sufficient to eradicate HBV cccDNA, the main cause for HBV persistence in patients. Core protein is the building block of HBV nucleocapsid. This viral protein modulates almost every step of the HBV life cycle; hence, it represents an attractive target for the development of new antiviral therapies. Capsid assembly modulators (CAM) bind to core dimers and perturb the proper nucleocapsid assembly. The potent antiviral activity of CAM has been demonstrated in cell-based and in vivo models. Moreover, several CAMs have entered clinical development. The aim of this review is to summarize the mechanism of action (MoA) and the advancements in the clinical development of CAMs and in the characterization of their mod of action.
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Affiliation(s)
- Valerio Taverniti
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France; (V.T.); (G.L.); (T.F.B.)
| | - Gaëtan Ligat
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France; (V.T.); (G.L.); (T.F.B.)
| | - Yannick Debing
- Aligos Belgium BV, 3001 Leuven, Belgium; (Y.D.); (D.B.K.)
| | | | - Thomas F. Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France; (V.T.); (G.L.); (T.F.B.)
- Institut Hospitalo-Universitaire, Pôle Hépato-Digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France
| | - Eloi R. Verrier
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France; (V.T.); (G.L.); (T.F.B.)
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28
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You H, Qin S, Zhang F, Hu W, Li X, Liu D, Kong F, Pan X, Zheng K, Tang R. Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection. Front Immunol 2022; 13:829923. [PMID: 35251017 PMCID: PMC8891514 DOI: 10.3389/fimmu.2022.829923] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/24/2022] [Indexed: 12/16/2022] Open
Abstract
As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.
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Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Suping Qin
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Wei Hu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Dongsheng Liu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
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Xie X, Luo J, Zhu D, Zhou W, Yang X, Feng X, Lu M, Zheng X, Dittmer U, Yang D, Liu J. HBeAg Is Indispensable for Inducing Liver Sinusoidal Endothelial Cell Activation by Hepatitis B Virus. Front Cell Infect Microbiol 2022; 12:797915. [PMID: 35174107 PMCID: PMC8842949 DOI: 10.3389/fcimb.2022.797915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background and AimsLiver sinusoidal endothelial cells (LSECs) serve as sentinel cells to detect microbial infection and actively contribute to regulating immune responses for surveillance against intrahepatic pathogens. We recently reported that hepatitis B e antigen (HBeAg) stimulation could induce LSEC maturation and abrogate LSEC-mediated T cell suppression in a TNF-α and IL27 dependent manner. However, it remains unclear how HBeAg deficiency during HBV infection influences LSEC immunoregulation function and intrahepatic HBV-specific CD8 T cell responses.MethodsThe function of LSECs in regulating effector T cell response, intrahepatic HBV-specific CD8 T cell responses and HBV viremia were characterized in both HBeAg-deficient and -competent HBV hydrodynamic injection (HDI) mouse models.ResultsLSECs isolated from HBeAg-deficient HBV HDI mice showed a reduced capacity to promote T cell immunity in vitro compared with those isolated from wild-type HBV HDI mice. HBeAg expression replenishment in HBeAg-deficient HBV HDI mice restored the HBV-induced LSEC maturation, and resulted in potent intrahepatic anti-HBV CD8 T cell responses and efficient control of HBV replication. Moreover, in vivo TNF-α, but not IL27 blockade in HBV HDI mice impaired HBV-specific CD8 T cell immunity and delayed HBV clearance.ConclusionOur study underlines that HBeAg is indispensable for HBV-induced LSEC maturation to trigger intrahepatic HBV-specific T cell activation, and provides a new mechanism to elucidate the intrahepatic immune microenvironment regulation upon HBV exposure.
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Affiliation(s)
- Xiaohong Xie
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinzhuo Luo
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Zhu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenqing Zhou
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ulf Dittmer
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Jia Liu,
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Abstract
Hepatitis B virus (HBV) is a hepatotropic virus and an important human pathogen. There are an estimated 296 million people in the world that are chronically infected by this virus, and many of them will develop severe liver diseases including hepatitis, cirrhosis and hepatocellular carcinoma (HCC). HBV is a small DNA virus that replicates via the reverse transcription pathway. In this review, we summarize the molecular pathways that govern the replication of HBV and its interactions with host cells. We also discuss viral and non-viral factors that are associated with HBV-induced carcinogenesis and pathogenesis, as well as the role of host immune responses in HBV persistence and liver pathogenesis.
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Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
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Naghib M, Kariminik A, Kazemi Arababadi M. TLR2, as a Pathogen Recognition Receptor, Plays Critical Roles in Hepatitis B Outcome. Viral Immunol 2022; 35:15-23. [PMID: 35020525 DOI: 10.1089/vim.2021.0141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The immune system of active and inactive chronic hepatitis B, as prolonged forms of hepatitis B, is unable to eradicate hepatitis B virus (HBV) from the infected hepatocytes completely. Toll-like receptors (TLRs) play key roles in the viral recognition and promotion of appropriate immune responses. The molecules also participate in the alteration of the target cell functions and transformation. TLR2 is the unique molecule that makes either homodimer or heterodimer with TLR1 and 6 and shows variable roles against viral infections. Therefore, it has been hypothesized that TLR2 may participate in both immune response against HBV and induction of the virus-related hepatic complications. The studies confirm the hypothesis and revealed that TLR2 is not only one of the main molecules altering the course of HBV infection, but also plays key roles in induction of hepatocellular carcinoma (HCC) and liver cirrhosis. However, recent studies demonstrated that the molecule can fight against HCC and liver cirrhosis. Collectively, it appears that nutrition habits, TLR2 gene polymorphisms, gut microbiome, HBV antigens, and activation of other receptors may play key roles in the determination of TLR2 functions.
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Affiliation(s)
- Maryam Naghib
- Department of Microbiology, Kerman Branch, Islamic Azad University, Kerman, Iran
| | - Ashraf Kariminik
- Department of Microbiology, Kerman Branch, Islamic Azad University, Kerman, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Macrophages activated by hepatitis B virus have distinct metabolic profiles and suppress the virus via IL-1β to downregulate PPARα and FOXO3. Cell Rep 2022; 38:110284. [PMID: 35081341 PMCID: PMC8830375 DOI: 10.1016/j.celrep.2021.110284] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/30/2021] [Accepted: 12/28/2021] [Indexed: 01/15/2023] Open
Abstract
Macrophages display phenotypic plasticity and can be induced by hepatitis B virus (HBV) to undergo either M1-like pro-inflammatory or M2-like anti-inflammatory polarization. Here, we report that M1-like macrophages stimulated by HBV exhibit a strong HBV-suppressive effect, which is diminished in M2-like macrophages. Transcriptomic analysis reveals that HBV induces the expression of interleukin-1β (IL-1β) in M1-like macrophages, which display a high oxidative phosphorylation (OXPHOS) activity distinct from that of conventional M1-like macrophages. Further analysis indicates that OXPHOS attenuates the expression of IL-1β, which suppresses the expression of peroxisome proliferator-activated receptor α (PPARα) and forkhead box O3 (FOXO3) in hepatocytes to suppress HBV gene expression and replication. Moreover, multiple HBV proteins can induce the expression of IL-1β in macrophages. Our results thus indicate that macrophages can respond to HBV by producing IL-1β to suppress HBV replication. However, HBV can also metabolically reprogram macrophages to enhance OXPHOS to minimize this host antiviral response.
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33
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Kostyusheva A, Brezgin S, Glebe D, Kostyushev D, Chulanov V. Host-cell interactions in HBV infection and pathogenesis: the emerging role of m6A modification. Emerg Microbes Infect 2021; 10:2264-2275. [PMID: 34767497 PMCID: PMC8648018 DOI: 10.1080/22221751.2021.2006580] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/28/2022]
Abstract
Hepatitis B virus (HBV) is a DNA virus with a complex life cycle that includes a reverse transcription step. HBV is poorly sensed by the immune system and frequently establishes persistent infection that can cause chronic infection, the leading cause of liver cancer and cirrhosis worldwide. Recent mounting evidence has indicated the growing importance of RNA methylation (m6A modification) in viral replication, immune escape, and carcinogenesis. The value of m6A RNA modification for the prediction and clinical management of chronic HBV infection remains to be assessed. However, a number of studies indicate the important role of m6A-marked transcripts and factors of m6A machinery in managing HBV-related pathologies. In this review, we discuss the fundamental and potential clinical impact of m6A modifications on HBV infection and pathogenesis, as well as highlight the important molecular techniques and tools that can be used for studying RNA m6A methylome.
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Affiliation(s)
- Anastasiya Kostyusheva
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow, Russia
| | - Sergey Brezgin
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow, Russia
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi, Russia
| | - Dieter Glebe
- National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University of Giessen, Giessen, Germany
| | - Dmitry Kostyushev
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow, Russia
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi, Russia
| | - Vladimir Chulanov
- National Medical Research Center of Tuberculosis and Infectious Diseases, Ministry of Health, Moscow, Russia
- Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, Sochi, Russia
- Department of Infectious Diseases, Sechenov University, Moscow, Russia
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Zábranská H, Zábranský A, Lubyová B, Hodek J, Křenková A, Hubálek M, Weber J, Pichová I. Biogenesis of hepatitis B virus e antigen is driven by translocon-associated protein complex and regulated by conserved cysteine residues within its signal peptide sequence. FEBS J 2021; 289:2895-2914. [PMID: 34839586 PMCID: PMC9300162 DOI: 10.1111/febs.16304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/27/2021] [Accepted: 11/26/2021] [Indexed: 11/28/2022]
Abstract
Hepatitis B virus uses e antigen (HBe), which is dispensable for virus infectivity, to modulate host immune responses and achieve viral persistence in human hepatocytes. The HBe precursor (p25) is directed to the endoplasmic reticulum (ER), where cleavage of the signal peptide (sp) gives rise to the first processing product, p22. P22 can be retro-translocated back to the cytosol or enter the secretory pathway and undergo a second cleavage event, resulting in secreted p17 (HBe). Here, we report that translocation of p25 to the ER is promoted by translocon-associated protein complex. We have found that p25 is not completely translocated into the ER; a fraction of p25 is phosphorylated and remains in the cytoplasm and nucleus. Within the p25 sp sequence, we have identified three cysteine residues that control the efficiency of sp cleavage and contribute to proper subcellular distribution of the precore pool.
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Affiliation(s)
- Helena Zábranská
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Aleš Zábranský
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Barbora Lubyová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jan Hodek
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Alena Křenková
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Hubálek
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jan Weber
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Iva Pichová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
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35
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Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg-IFN-ɑ. Antiviral Res 2021; 197:105220. [PMID: 34848218 DOI: 10.1016/j.antiviral.2021.105220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/16/2021] [Accepted: 11/25/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg-IFN-ɑ). This study aimed to characterize the clinical and immunological features of VBT. METHODS In NAs-treated patients switching to Peg-IFN-ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8+T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication. RESULTS 33 of 166 patients switching to Peg-IFN-ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2+monocyte and increased PD1+HBV-specific CD8+T cell during the early phase of Peg-IFN-ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2+CD68+macrophages but more PDL1+CD68+macrophages and PD1+CD8+T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8+T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1+monocytes and PD1+CD8+T cells were upregulated, whereas TLR2+monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers. CONCLUSIONS In NAs-treated patients, lower TLR2+monocyte and increased PD1+HBV-specific CD8+T cell proportions potentially contribute to VBT after switching to Peg-IFN-ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.
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36
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Xu C, Chen J, Chen X. Host Innate Immunity Against Hepatitis Viruses and Viral Immune Evasion. Front Microbiol 2021; 12:740464. [PMID: 34803956 PMCID: PMC8598044 DOI: 10.3389/fmicb.2021.740464] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/29/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis viruses are primary causative agents of hepatitis and represent a major source of public health problems in the world. The host innate immune system forms the first line of defense against hepatitis viruses. Hepatitis viruses are sensed by specific pathogen recognition receptors (PRRs) that subsequently trigger the innate immune response and interferon (IFN) production. However, hepatitis viruses evade host immune surveillance via multiple strategies, which help compromise the innate immune response and create a favorable environment for viral replication. Therefore, this article reviews published findings regarding host innate immune sensing and response against hepatitis viruses. Furthermore, we also focus on how hepatitis viruses abrogate the antiviral effects of the host innate immune system.
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Affiliation(s)
- Chonghui Xu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jizheng Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.,Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
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37
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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, Faure-Dupuy S. How to get away with liver innate immunity? A viruses' tale. Liver Int 2021; 41:2547-2559. [PMID: 34520597 DOI: 10.1111/liv.15054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022]
Abstract
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).
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Affiliation(s)
- Marion Delphin
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Manon Desmares
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Svenja Schuehle
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - David Durantel
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France.,DEVweCAN Laboratory of Excellence, Lyon, France
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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38
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Sartorius R, Trovato M, Manco R, D'Apice L, De Berardinis P. Exploiting viral sensing mediated by Toll-like receptors to design innovative vaccines. NPJ Vaccines 2021; 6:127. [PMID: 34711839 PMCID: PMC8553822 DOI: 10.1038/s41541-021-00391-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are transmembrane proteins belonging to the family of pattern-recognition receptors. They function as sensors of invading pathogens through recognition of pathogen-associated molecular patterns. After their engagement by microbial ligands, TLRs trigger downstream signaling pathways that culminate into transcriptional upregulation of genes involved in immune defense. Here we provide an updated overview on members of the TLR family and we focus on their role in antiviral response. Understanding of innate sensing and signaling of viruses triggered by these receptors would provide useful knowledge to prompt the development of vaccines able to elicit effective and long-lasting immune responses. We describe the mechanisms developed by viral pathogens to escape from immune surveillance mediated by TLRs and finally discuss how TLR/virus interplay might be exploited to guide the design of innovative vaccine platforms.
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Affiliation(s)
- Rossella Sartorius
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
| | - Maria Trovato
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Roberta Manco
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Luciana D'Apice
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
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Tsai KN, Ou JHJ. Hepatitis B virus e antigen and viral persistence. Curr Opin Virol 2021; 51:158-163. [PMID: 34717215 PMCID: PMC8643334 DOI: 10.1016/j.coviro.2021.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 08/27/2021] [Accepted: 10/07/2021] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) e antigen (HBeAg) was discovered in the sera of HBV patients nearly 50 years ago. It is not essential for HBV to infect or replicate in hepatocytes. Earlier clinical studies suggested that this antigen might play an important role for HBV to establish persistence in babies after its mother-to-child transmission. Subsequent clinical studies also suggested that HBeAg might have immunomodulatory activities. In recent years, a large body of information on how HBeAg might modulate host immunity was published. In this review, we summarize recent research progresses on the immunomodulatory activities of HBeAg and discuss how these activities of HBeAg may promote HBV persistence.
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Affiliation(s)
- Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA.
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Xie X, Lv H, Liu C, Su X, Yu Z, Song S, Bian H, Tian M, Qin C, Qi J, Zhu Q. HBeAg mediates inflammatory functions of macrophages by TLR2 contributing to hepatic fibrosis. BMC Med 2021; 19:247. [PMID: 34649530 PMCID: PMC8518250 DOI: 10.1186/s12916-021-02085-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 08/03/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND We and others have confirmed activation of macrophages plays a critical role in liver injury and fibrogenesis during HBV infection. And we have also proved HBeAg can obviously induce the production of macrophage inflammatory cytokines compared with HBsAg and HBcAg. However, the receptor and functional domain of HBeAg in macrophage activation and its effects and mechanisms on hepatic fibrosis remain elusive. METHODS The potentially direct binding receptors of HBeAg were screened and verified by Co-IP assay. Meanwhile, the function domain and accessible peptides of HBeAg for macrophage activation were analyzed by prediction of surface accessible peptide, construction, and synthesis of truncated fragments. Furthermore, effects and mechanisms of the activation of hepatic stellate cells induced by HBeAg-treated macrophages were investigated by Transwell, CCK-8, Gel contraction assay, Phospho Explorer antibody microarray, and Luminex assay. Finally, the effect of HBeAg in hepatic inflammation and fibrosis was evaluated in both human and murine tissues by immunohistochemistry, immunofluorescence, ELISA, and detection of liver enzymes. RESULTS Herein, we verified TLR-2 was the direct binding receptor of HBeAg. Meanwhile, C-terminal peptide (122-143 aa.) of core domain in HBeAg was critical for macrophage activation. But arginine-rich domain of HBcAg hided this function, although HBcAg and HBeAg shared the same core domain. Furthermore, HBeAg promoted the proliferation, motility, and contraction of hepatic stellate cells (HSCs) in a macrophage-dependent manner, but not alone. PI3K-AKT-mTOR and p38 MAPK signaling pathway were responsible for motility phenotype of HSCs, while the Smad-dependent TGF-β signaling pathway for proliferation and contraction of them. Additionally, multiple chemokines and cytokines, such as CCL2, CCL5, CXCL10, and TNF-α, might be key mediators of HSC activation. Consistently, HBeAg induced transient inflammation response and promoted early fibrogenesis via TLR-2 in mice. Finally, clinical investigations suggested that the level of HBeAg is associated with inflammation and fibrosis degrees in patients infected with HBV. CONCLUSIONS HBeAg activated macrophages via the TLR-2/NF-κB signal pathway and further exacerbated hepatic fibrosis by facilitating motility, proliferation, and contraction of HSCs with the help of macrophages.
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Affiliation(s)
- Xiaoyu Xie
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China
| | - Huanran Lv
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China
| | - Chenxi Liu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Xiaonan Su
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Zhen Yu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Shouyang Song
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Hongjun Bian
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Miaomiao Tian
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China
| | - Chengyong Qin
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China
| | - Jianni Qi
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China.
| | - Qiang Zhu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People's Republic of China. .,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, 250021, People's Republic of China. .,The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People's Republic of China.
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van Bömmel F, Berg T. Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B. Hepatol Commun 2021; 5:1632-1648. [PMID: 34558833 PMCID: PMC8485892 DOI: 10.1002/hep4.1708] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Systematic discontinuation of long-term treatment with nucleos(t)ide analogues (NAs) is one strategy to increase functional cure rates in patients with chronic hepatitis B e antigen (HBeAg)-negative hepatitis B. Currently, available study results are heterogeneous; however, long-term hepatitis B surface antigen (HBsAg) loss rates of up to 20% have been reported in prospective trials. This review proposes criteria that can be used when considering NA discontinuation in patients with chronic hepatitis B virus (HBV). Discontinuing NA treatment frequently results in a virologic and biochemical relapse that runs through different phases: the lag phase, reactivation phase, and consolidation phase. The HBV-DNA flares observed during the reactivation phase are often transient and most likely represent a trigger for inducing a long-term immune control by specific CD8+ T cells, and therefore do not need immediate interventions but close follow-up evaluation. Low HBsAg levels at the time of treatment cessation predict a positive long-term response to NA discontinuation associated with a higher likelihood of HBsAg clearance. Other host and viral biomarkers are currently under evaluation that may prove to be helpful to further characterize the population that may benefit most from the finite NA treatment concept. Potential harmful biochemical flares during the reactivation phase need to be identified early and can be effectively terminated by reintroducing NA treatment. Hepatic decompensation represents a risk to patients with cirrhosis undergoing NA discontinuation. Therefore, the finite NA approach should only be considered after excluding advanced fibrosis and cirrhosis and if a close follow-up of the patient and supervision by an experienced physician can be guaranteed. Conclusion: For selected patients, NA discontinuation has become a powerful tool to achieve control over HBeAg-negative HBV infections. Its significant effect represents a challenge to novel treatment approaches, but it may also serve as their enhancer.
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Affiliation(s)
- Florian van Bömmel
- Division of HepatologyDepartment of Medicine IILeipzig University Medical CenterLeipzigGermany
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42
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Ye J, Chen J. Interferon and Hepatitis B: Current and Future Perspectives. Front Immunol 2021; 12:733364. [PMID: 34557195 PMCID: PMC8452902 DOI: 10.3389/fimmu.2021.733364] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health burden worldwide for which there is still no effective curative treatment. Interferon (IFN) consists of a group of cytokines with antiviral activity and immunoregulatory and antitumor effects, that play crucial roles in both innate and adaptive immune responses. IFN-α and its pegylated form have been used for over thirty years to treat chronic hepatitis B (CHB) with advantages of finite treatment duration and sustained virologic response, however, the efficacy is limited and side effects are common. Here, we summarize the status and unique advantages of IFN therapy against CHB, review the mechanisms of IFN-α action and factors affecting IFN response, and discuss the possible improvement of IFN-based therapy and the rationale of combinations with other antiviral agents in seeking an HBV cure.
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Affiliation(s)
- Jianyu Ye
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,Research Unit of Cure of Chronic Hepatitis B Virus Infection, Chinese Academy of Medical Sciences, Shanghai, China
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43
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Zhao F, Xie X, Tan X, Yu H, Tian M, Lv H, Qin C, Qi J, Zhu Q. The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis. Front Immunol 2021; 12:691766. [PMID: 34456908 PMCID: PMC8387624 DOI: 10.3389/fimmu.2021.691766] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022] Open
Abstract
About 250 million people worldwide are chronically infected with Hepatitis B virus (HBV), contributing to a large burden on public health. Despite the existence of vaccines and antiviral drugs to prevent infection and suppress viral replication respectively, chronic hepatitis B (CHB) cure remains a remote treatment goal. The viral persistence caused by HBV is account for the chronic infection which increases the risk for developing liver cirrhosis and hepatocellular carcinoma (HCC). HBV virion utilizes various strategies to escape surveillance of host immune system therefore enhancing its replication, while the precise mechanisms involved remain elusive. Accumulating evidence suggests that the proteins encoded by HBV (hepatitis B surface antigen, hepatitis B core antigen, hepatitis B envelope antigen, HBx and polymerase) play an important role in viral persistence and liver pathogenesis. This review summarizes the major findings in functions of HBV encoding proteins, illustrating how these proteins affect hepatocytes and the immune system, which may open new venues for CHB therapies.
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Affiliation(s)
- Fenglin Zhao
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Xiaoyu Xie
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xu Tan
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hongli Yu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Miaomiao Tian
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Huanran Lv
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chengyong Qin
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jianni Qi
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiang Zhu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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44
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Wang SJ, Chen ZM, Wei M, Liu JQ, Li ZL, Shi TS, Nian S, Fu R, Wu YT, Zhang YL, Wang YB, Zhang TY, Zhang J, Xiong JH, Tong SP, Ge SX, Yuan Q, Xia NS. Specific determination of hepatitis B e antigen by antibodies targeting precore unique epitope facilitates clinical diagnosis and drug evaluation against hepatitis B virus infection. Emerg Microbes Infect 2021; 10:37-50. [PMID: 33296295 PMCID: PMC7832009 DOI: 10.1080/22221751.2020.1862631] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis B e antigen (HBeAg) is a widely used marker both for chronic hepatitis B (CHB) clinical management and HBV-related basic research. However, due to its high amino acid sequence homology to hepatitis B core antigen (HBcAg), most of available anti-HBe antibodies are cross-reactive with HBcAg resulting in high interference against accurate measurement of the status and level of HBeAg. In the study, we generated several monoclonal antibodies (mAbs) targeting various epitopes on HBeAg and HBcAg. Among these mAbs, a novel mAb 16D9, which recognizes the SKLCLG (aa -10 to -5) motif on the N-terminal residues of HBeAg that is absent on HBcAg, exhibited excellent detection sensitivity and specificity in pairing with another 14A7 mAb targeting the HBeAg C-terminus (STLPETTVVRRRGR, aa141 to 154). Based on these two mAbs, we developed a novel chemiluminescent HBeAg immunoassay (NTR-HBeAg) which could detect HBeAg derived from various HBV genotypes. In contrast to widely used commercial assays, the NTR-HBeAg completely eliminated the cross-reactivity with secreted HBcAg from precore mutant (G1896A) virus in either cell culture or patient sera. The improved specificity of the NTR-HBeAg assay enables its applicability in cccDNA-targeting drug screening in cell culture systems and also provides an accurate tool for clinical HBeAg detection.
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Affiliation(s)
- Shao-Juan Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Zi-Min Chen
- Xiamen Innodx Biotech Co., Ltd., Xiamen, People's Republic of China
| | - Min Wei
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Jia-Qi Liu
- Xiamen Innodx Biotech Co., Ltd., Xiamen, People's Republic of China
| | - Zong-Lin Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Tian-Shu Shi
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Sheng Nian
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Rao Fu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Yang-Tao Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Ya-Li Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Ying-Bin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Tian-Ying Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Jun-Hui Xiong
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China.,Xiamen Innodx Biotech Co., Ltd., Xiamen, People's Republic of China
| | - Shu-Ping Tong
- Liver Research Center, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Sheng-Xiang Ge
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Quan Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
| | - Ning-Shao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, People's Republic of China.,National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science, Xiamen University, Xiamen, People's Republic of China
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45
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Vaillant A. HBsAg, Subviral Particles, and Their Clearance in Establishing a Functional Cure of Chronic Hepatitis B Virus Infection. ACS Infect Dis 2021; 7:1351-1368. [PMID: 33302622 DOI: 10.1021/acsinfecdis.0c00638] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In diverse viral infections, the production of excess viral particles containing only viral glycoproteins (subviral particles or SVP) is commonly observed and is a commonly evolved mechanism for immune evasion. In hepatitis B virus (HBV) infection, spherical particles contain the hepatitis B surface antigen, outnumber infectious virus 10 000-100 000 to 1, and have diverse inhibitory effects on the innate and adaptive immune response, playing a major role in the chronic nature of HBV infection. The current goal of therapies in development for HBV infection is a clinical outcome called functional cure, which signals a persistent and effective immune control of the infection. Although removal of spherical SVP (and the HBsAg they carry) is an important milestone in achieving functional cure, this outcome is rarely achieved with current therapies due to distinct mechanisms for assembly, secretion, and persistence of SVP, which are poorly targeted by direct acting antivirals or immunotherapies. In this Review, the current understanding of the distinct mechanisms involved in the production and persistence of spherical SVP in chronic HBV infection and their immunoinhibitory activity will be reviewed as well as current therapies in development with the goal of clearing spherical SVP and achieving functional cure.
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Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec H8Y 3E6, Canada
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46
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Novotny LA, Evans JG, Su L, Guo H, Meissner EG. Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies. Viruses 2021; 13:1090. [PMID: 34207487 PMCID: PMC8230240 DOI: 10.3390/v13061090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.
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Affiliation(s)
- Laura A. Novotny
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - John Grayson Evans
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
| | - Lishan Su
- Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology, Microbiology, and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;
| | - Eric G. Meissner
- Division of Infectious Diseases, Medical University of South Carolina, Charleston, SC 29525, USA; (L.A.N.); (J.G.E.)
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
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47
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Innate immunity in hepatitis B and D virus infection: consequences for viral persistence, inflammation, and T cell recognition. Semin Immunopathol 2021; 43:535-548. [PMID: 34019142 PMCID: PMC8443521 DOI: 10.1007/s00281-021-00864-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/30/2021] [Indexed: 12/16/2022]
Abstract
Chronic infections with human hepatitis viruses continue to be a major health burden worldwide. Despite the availability of an effective prophylactic vaccine against the hepatitis B virus (HBV) and of antiviral agents efficiently suppressing HBV replication, more than 250 million people are currently chronically infected with this hepatotropic DNA virus, and resolution of chronic hepatitis B (CHB) is rarely achieved. Moreover, coinfection with the hepatitis D virus (HDV), a human RNA satellite virus requiring the envelope proteins of HBV for productive viral spreading, substantially aggravates the disease course of CHB. The molecular mechanisms by which these viruses interact with each other and with the intrinsic innate responses of the hepatocytes are not fully understood. While HBV appears to avoid innate immune recognition, HDV elicits a strong enhancement of innate responses. Notwithstanding, such induction does not hamper HDV replication but contributes to liver inflammation and pathogenesis. Intriguingly, HDV appears to influence the ability of T cells to recognize infected hepatocytes by boosting antigen presentation. This review focuses on current knowledge regarding how these viruses can shape and counteract the intrinsic innate responses of the hepatocytes, thus affecting the immune system and pathogenesis. Understanding the distinct strategies of persistence that HBV and HDV have evolved is central for advancing the development of curative therapies.
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48
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Abaalkhail FA, Al-Hamoudi WK, Khathlan A, Alghamdi S, Alghamdi M, Alqahtani SA, Sanai FM. SASLT practice guidelines for the management of Hepatitis B virus - An update. Saudi J Gastroenterol 2021; 27:115-126. [PMID: 33976009 PMCID: PMC8265399 DOI: 10.4103/sjg.sjg_539_20] [Citation(s) in RCA: 11] [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: 09/27/2020] [Accepted: 02/23/2021] [Indexed: 12/30/2022] Open
Abstract
Infection with hepatitis B virus (HBV) remains an important public health problem with a high burden worldwide. The Saudi Association for the Study of Liver diseases and Transplantation formed a working group to develop HBV practice guidelines in Saudi Arabia. The methodology used to develop these guidelines was based on reviewing the available evidence, local data, and major international practice guidelines on the management of HBV. The aim of these guidelines is to assist healthcare providers in the management of HBV in Saudi Arabia. These updated guidelines summarize the latest local studies performed on HBV epidemiology, major changes in the prevalence of this virus, and advances in disease management.
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Affiliation(s)
- Faisal A. Abaalkhail
- Gastroenterology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- College of Medicine, Al Faisal University, Riyadh, Saudi Arabia
| | - Waleed K. Al-Hamoudi
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Department of Medicine, Liver Transplant Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Abdullah Khathlan
- Department of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Saad Alghamdi
- Department of Medicine, Liver Transplant Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Alghamdi
- Department of Medicine, King Fahd Military Medical Complex, Dhahran, Saudi Arabia
| | - Saleh A. Alqahtani
- Department of Medicine, Liver Transplant Center, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, USA
| | - Faisal M. Sanai
- Liver Disease Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
- Gastroenterology Unit, Department of Medicine, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
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49
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In vitro expression of precore proteins of hepatitis B virus subgenotype A1 is affected by HBcAg, and can affect HBsAg secretion. Sci Rep 2021; 11:8167. [PMID: 33854155 PMCID: PMC8046783 DOI: 10.1038/s41598-021-87529-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 03/30/2021] [Indexed: 12/16/2022] Open
Abstract
HBeAg, a non-particulate protein of hepatitis B virus (HBV), is translated from the precore/core region as a precursor, which is post-translationally modified. Subgenotype A1 of HBV, which is a risk factor for hepatocellular carcinoma (HCC), has unique molecular characteristics in the basic core promoter/precore regions. Carriers of A1 exhibit early HBeAg loss. We sought to further characterize the precore proteins of A1 in vitro. HuH-7 cells were transfected with subgenomic constructs expressing individual precore proteins. Western blot analysis using DAKO anti-core antibody showed the expected sizes and a 1 kDa larger band for P22, P20 and P17. Using confocal microscopy, a cytoplasmic accumulation of HBeAg and precursors was observed with P25-expressing plasmid, whereas P22 localized both in the cytoplasm and nucleus. P20 and P17, which lack the carboxy end of P22 showed strong nuclear accumulation, implicating a nuclear localization signal in the N-terminal 10 amino acids. G1862T, unique to subgenotype A1, is frequently found in HBV from HCC patients. P25 with G1862T showed delayed and reduced HBeAg expression/secretion. Knock-out of core in the replication competent clones led to precore protein accumulation in the cytoplasm/perinuclear region, and decreased HBeAg secretion. Knock-out of precore proteins increased HBsAg secretion but intracellular HBsAg expression was unaffected. Over-expression of precore proteins in trans led to decreased HBsAg expression and secretion. Intracellular trafficking of HBV A1 precore proteins was followed. This was unaffected by the CMV promoter and different cell types. In the viral context, precore protein expression was affected by absence of core, and affected HBsAg expression, suggesting an interrelationship between precore proteins, HBcAg and HBsAg. This modulatory role of HBeAg and its precursors may be important in viral persistence and ultimate development of HCC.
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50
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Deng F, Xu G, Cheng Z, Huang Y, Ma C, Luo C, Yu C, Wang J, Xu X, Liu S, Zhu Y. Hepatitis B Surface Antigen Suppresses the Activation of Nuclear Factor Kappa B Pathway via Interaction With the TAK1-TAB2 Complex. Front Immunol 2021; 12:618196. [PMID: 33717111 PMCID: PMC7947203 DOI: 10.3389/fimmu.2021.618196] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/19/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis B is a major health problem worldwide, with more than 250 million chronic carriers. Hepatitis B virus interferes with the host innate immune system so as to evade elimination via almost all of its constituent proteins; nevertheless, the function of HBsAg with respect to immune escape remains unclear. This study aimed to determine the role HBsAg plays in assisting HBV to escape from immune responses. We found that HBsAg suppressed the activation of the nuclear factor kappa B (NF-кB) pathway, leading to downregulation of innate immune responses. HBsAg interacted with TAK1 and TAB2 specifically, inhibiting the phosphorylation and polyubiquitination of TAK1 and the K63-linked polyubiquitination of TAB2. Autophagy is a major catabolic process participating in many cellular processes, including the life cycle of HBV. We found that HBsAg promoted the autophagic degradation of TAK1 and TAB2 via the formation of complexes with TAK1 and TAB2, resulting in suppression of the NF-κB pathway. The expression of TAK1, TAB2, and the translocation of NF-κB inversely correlated with HBsAg levels in clinical liver tissues. Taken together, our findings suggest a novel mechanism by which HBsAg interacts with TAK1-TAB2 complex and suppresses the activation of NF-κB signaling pathway via reduction of the post-translational modifications and autophagic degradation.
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Affiliation(s)
- Feiyan Deng
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Gang Xu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Zhikui Cheng
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Yu Huang
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Caijiao Ma
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Chuanjin Luo
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Chen Yu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Jun Wang
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiupeng Xu
- Department of Clinical Laboratory, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic, Huangshi, China
| | - Shi Liu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
| | - Ying Zhu
- State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China
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