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1
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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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Zheng J, Wang Z, Huang L, Qiu Z, Xie Y, Jiang S, Feng B. Achieving chronic hepatitis B functional cure: Factors and potential mechanisms. Virus Res 2025; 351:199507. [PMID: 39662778 PMCID: PMC11699463 DOI: 10.1016/j.virusres.2024.199507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/20/2024] [Accepted: 12/03/2024] [Indexed: 12/13/2024]
Abstract
Chronic hepatitis B (CHB) is a significant global health issue affecting approximately 254 million individuals worldwide. Achieving the loss of hepatitis B surface antigen (HBsAg), either with or without seroconversion to hepatitis B surface antibody (HBsAb), is regarded as a functional cure and the optimal goal for addressing CHB, and can be achieved through various approaches, including induction with nucleos(t)ide analogues (NAs), induction with pegylated interferon alpha (PegIFNα), and spontaneous clearance of HBsAg. Spontaneous clearance of HBsAg is rare, while NAs can directly inhibit HBV DNA, they are unable to act on covalently closed circular DNA (cccDNA), hence inhibiting HBsAg production or clearing HBsAg is extremely challenging. On the other hand, functional cure based on PegIFNα shows good long-term durability, but over 10 % of patients still experience relapse, mostly within 48 weeks after functional cure. Factors related to CHB functional cure with antiviral therapy are complex, including host factors, viral factors, environmental factors, etc. The integration of HBV DNA into liver cells, persistence of HBV cccDNA, insufficient B cell responses and compromised T cell function pose significant barriers to HBV clearance. Therefore, this study systematically reviewed the relevant factors and potential mechanisms influencing functional cure CHB, which can provide a basis for personalized treatment, help predict treatment outcomes and assess prognosis, and provide theoretical support for the advancement of novel treatment strategies and medications.
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Affiliation(s)
- Jiarui Zheng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Zilong Wang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Linxiang Huang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Zixuan Qiu
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Yandi Xie
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Suzhen Jiang
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China.
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3
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Chen SL, Shen YJ, Chen GZ. RNA Sequencing Analysis of Patients with Chronic Hepatitis B Treated Using PEGylated Interferon. Int J Gen Med 2024; 17:4465-4474. [PMID: 39372134 PMCID: PMC11453141 DOI: 10.2147/ijgm.s474284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 09/25/2024] [Indexed: 10/08/2024] Open
Abstract
Purpose Worldwide, chronic hepatitis B virus (CHB) infection is a public health concern, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Currently, patients with CHB can be treated using polyethylene glycol (PEG)ylated interferon (PEG-IFN) antiviral therapy, which has both immune modulatory and antiviral properties. This study aimed to reveal the mechanism underlying the effect of PEG-IFN therapy, to rationally optimize this therapeutic option. Patients and Methods Ten patients with CHB who were positive for the hepatitis B virus e antigen (HBeAg) and were receiving PEG-IFN treatment were enrolled. Clinical and virological parameters were monitored during 48 weeks of treatment. In addition, peripheral blood mononuclear cells (PBMCs) were collected from the 10 patients at 0, 24, and 36 weeks. RNA sequencing technology was used to analyze the RNA expression profile in the PBMC samples. Results Following PEG-IFN treatment, we identified 217 differentially expressed genes (DEGs), most of which were upregulated. Gene ontology enrichment analysis of the DEGs revealed that they were enriched in 29 clusters, mainly associated with "antiviral defense", "innate immunity", "immunity", "defense response to virus", "response to virus", "type I interferon signaling pathway", "negative regulation of viral genome replication", "innate immune response", and "RNA-binding". Conclusion After PEG-IFN treatment, a certain mRNA expression profile was observed in patients with CHB, providing further mechanistic insights into the antiviral effect of this therapy.
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Affiliation(s)
- Shao-Long Chen
- Department of Infectious Disease Control and Prevention, Yueqing Center for Disease Control and Prevention, Wenzhou, 325600, People’s Republic of China
| | - Yao-Jie Shen
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China
| | - Guo-Zhi Chen
- Department of Infectious Disease Control and Prevention, Yueqing Center for Disease Control and Prevention, Wenzhou, 325600, People’s Republic of China
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4
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Pondé RADA, Amorim GDSP. Elimination of the hepatitis B virus: A goal, a challenge. Med Res Rev 2024; 44:2015-2034. [PMID: 38528684 DOI: 10.1002/med.22030] [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: 10/06/2023] [Revised: 01/24/2024] [Accepted: 02/05/2024] [Indexed: 03/27/2024]
Abstract
The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde-SES, Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil
- Department of Microbiology, Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil
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Li Y, Wang F, Zhou J, Li L, Song C, Chen E. Optimal Treatment Based on Interferon No Longer Makes Clinical Cure of Chronic Hepatitis B Far Away: An Evidence-Based Review on Emerging Clinical Data. Clin Pharmacol Ther 2024; 116:295-303. [PMID: 38686952 DOI: 10.1002/cpt.3287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 04/12/2024] [Indexed: 05/02/2024]
Abstract
Chronic hepatitis B (CHB) remains a major global public health problem. The functional cure is the ideal therapeutic target recommended by the latest guidelines, and pursuing a functional cure has become the key treatment end point of current therapy and for upcoming clinical trials. In this review, based on the latest published clinical research evidence, we analyzed the concept and connotation of clinical cures and elaborated on the benefits of clinical cures in detail. Secondly, we have summarized various potential treatment methods for achieving clinical cures, especially elaborating on the latest research progress of interferon-based optimized treatment strategies in achieving clinical cures. We also analyzed which populations can achieve clinical cures and conducted a detailed analysis of relevant virological and serological markers in screening clinical cure advantage populations and predicting clinical cure achievement. In addition, we also introduced the difficulties that may be encountered in the current pursuit of achieving a clinical cure.
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Affiliation(s)
- Yujing Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Fada Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lanqing Li
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chengrun Song
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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6
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Costa JP, de Carvalho A, Paiva A, Borges O. Insights into Immune Exhaustion in Chronic Hepatitis B: A Review of Checkpoint Receptor Expression. Pharmaceuticals (Basel) 2024; 17:964. [PMID: 39065812 PMCID: PMC11279883 DOI: 10.3390/ph17070964] [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: 06/24/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatitis B, caused by the hepatitis B virus (HBV), often progresses to chronic infection, leading to severe complications, such as cirrhosis, liver failure, and hepatocellular carcinoma. Chronic HBV infection is characterized by a complex interplay between the virus and the host immune system, resulting in immune cell exhaustion, a phenomenon commonly observed in chronic viral infections and cancer. This state of exhaustion involves elevated levels of inhibitory molecules, cells, and cell surface receptors, as opposed to stimulatory counterparts. This review aims to elucidate the expression patterns of various co-inhibitory and co-stimulatory receptors on immune cells isolated from chronic hepatitis B (CHB) patients. By analyzing existing data, the review conducts comparisons between CHB patients and healthy adults, explores the differences between HBV-specific and total T cells in CHB patients, and examines variations between intrahepatic and peripheral immune cells in CHB patients. Understanding the mechanisms underlying immune exhaustion in CHB is crucial for developing novel immunotherapeutic approaches. This detailed analysis sheds light on the immune exhaustion observed in CHB and lays the groundwork for future combined immunotherapy strategies aimed at leveraging checkpoint receptors to restore immune function and improve clinical outcomes.
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Affiliation(s)
- João Panão Costa
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;
- CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Armando de Carvalho
- Centro Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal; (A.d.C.); (A.P.)
- Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal
| | - Artur Paiva
- Centro Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal; (A.d.C.); (A.P.)
| | - Olga Borges
- Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal;
- CNC-UC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
- CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
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Guerrache A, Micheau O. TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling. Cells 2024; 13:521. [PMID: 38534365 PMCID: PMC10968836 DOI: 10.3390/cells13060521] [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: 02/07/2024] [Revised: 03/01/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. However, emerging evidence indicates that TRAIL can also trigger a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, an increasing number of studies suggest that in some circumstances TRAIL can induce, via Death receptor 5 (DR5), tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. In this study, we the current state of knowledge of TRAIL non-canonical signalling.
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Affiliation(s)
- Abderrahmane Guerrache
- Université de Bourgogne, 21000 Dijon, France
- INSERM Research Center U1231, «Equipe DesCarTes», 21000 Dijon, France
| | - Olivier Micheau
- Université de Bourgogne, 21000 Dijon, France
- INSERM Research Center U1231, «Equipe DesCarTes», 21000 Dijon, France
- Laboratoire d’Excellence LipSTIC, 21000 Dijon, France
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8
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Li X, Wang HY, Gao F, Guo FF, Wang XN, Pan YX, Bai GQ. Tenofovir alters the immune microenvironment of pregnant women with hepatitis B virus infection: Evidence from single-cell RNA sequencing. Int Immunopharmacol 2023; 119:110245. [PMID: 37163920 DOI: 10.1016/j.intimp.2023.110245] [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: 03/23/2023] [Revised: 04/16/2023] [Accepted: 04/23/2023] [Indexed: 05/12/2023]
Abstract
BACKGROUND Mother-to-child is the main route of the transmission of hepatitis B virus (HBV) infection. Tenofovir fumarate (TDF) antiviral treatment has become the most extensive choice worldwide. However, the effects of TDF treatment on the immune function of pregnant women remains unclear. Here we investigate the effect of TDF treatment on the immune microenvironment of pregnant women with HBV infection using single-cell RNA sequencing (scRNA-seq). METHODS Three HBV-infected pregnant women were treated with TDF and six samples were collected before and after the treatment. In total, 68,200 peripheral blood mononuclear cells (PBMCs) were extracted for 10 × scRNA-seq. The cells were clustered using t-distributed stochastic neighbor embedding (t-SNE) and unbiased computational informatics analysis. RESULTS The analysis identified four-cell subtypes, including T cells, monocytes, natural killer (NK) cells, and B cells, and unraveled the developmental trajectory and maturation of CD4+ T and CD8+ T cell subtypes. The cellular state and molecular features of the effector/memory T cells revealed a significant increase in the inflammatory state of CD4+ T cells and the cytotoxic characteristics of CD8+ T cells. Additionally, after TDF treatment, the monocytes showed a tendency for M1 polarization, and the cytotoxicity of NK cells was enhanced. Furthermore, the analysis of intercellular communication revealed the interaction of various subtypes of cells and the heterogeneous expression of key signal pathways. CONCLUSIONS The findings of this study reveal significant differences in cellular subtypes and molecular characteristics of PBMCs of pregnant women with HBV infection before and after TDF treatment and demonstrate the recovery of immune response after treatment. These findings could help develop immune intervention measures to control HBV during pregnancy and the puerperium period.
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Affiliation(s)
- Xia Li
- Gene Joint Laboratory, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hong-Yan Wang
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Fan Gao
- Clinical Research Center, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Fan-Fan Guo
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiao-Na Wang
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yi-Xia Pan
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Gui-Qin Bai
- Gene Joint Laboratory, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
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9
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Ao X, Gan Q, Huang X, Bao D, Wu X, Lin Q, Lin A, Ding Y, Wang L, Chen Y, Huang Z. TLR8 agonist partially improves IFN-γ deficiency of NK cells in chronic hepatitis B through the synergy of monocytes. Aliment Pharmacol Ther 2023; 57:387-398. [PMID: 36585909 DOI: 10.1111/apt.17382] [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: 06/14/2022] [Revised: 07/18/2022] [Accepted: 12/23/2022] [Indexed: 01/01/2023]
Abstract
BACKGROUND Natural killer (NK) cells exhibit a selective deficiency of IFN-γ production in chronic hepatitis B (CHB). Toll-like receptor 8 (TLR8) agonists could induce IFN-γ production in immune cells, although their effects on the deficiency in NK cells remain unclear. AIMS To investigate TLR8 expression in NK cells and the effect of TLR8 agonists in patients with CHB METHODS: We enrolled 32 patients with CHB and 19 healthy controls to assess TLR8 expression and IFN-γ production in NK cells. The sorted NK cells and monocytes were co-cultured to compare the extent of IFN-γ and IL-10 production after TLR8 agonist ssRNA40 stimulation. The synergic effect of NK cells and monocytes was assessed by blocking IL-12 and IL-18. We recruited another 22 patients with CHB undergoing nucleotide analogue (NA) therapy to explore the impact of antiviral treatment on the ssRNA40-mediated response of NK cells. RESULTS In patients with CHB, TLR8 expression in NK cells was up-regulated, accompanied by insufficient IFN-γ production. The enhanced IFN-γ secretion by ssRNA40 in NK cells depended on monocyte-derived IL-12 and IL-18. NK cells displayed an imbalanced response to ssRNA40 in patients with CHB with a weak increase in IFN-γ despite a higher IL-10 production. The response was improved in patients with CHB undergoing NA therapy. CONCLUSIONS In patients with CHB, targeting TLR8 partially rescues the IFN-γ insufficiency in NK cells. However, NK cells show an inhibitory response to TLR8 agonist stimulation. TLR8 agonist combined with NA may enhance the antiviral effect of NK cells.
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Affiliation(s)
- Xiulan Ao
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Qiaorong Gan
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xuan Huang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dongpeng Bao
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xuwei Wu
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Qiuxiang Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Aifang Lin
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yating Ding
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Lingxia Wang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yanping Chen
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
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10
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Zheng JR, Wang ZL, Feng B. Hepatitis B functional cure and immune response. Front Immunol 2022; 13:1075916. [PMID: 36466821 PMCID: PMC9714500 DOI: 10.3389/fimmu.2022.1075916] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 11/02/2022] [Indexed: 07/30/2023] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus, which damage to hepatocytes is not direct, but through the immune system. HBV specific CD4+ T cells can induce HBV specific B cells and CD8+ T cells. HBV specific B cells produce antibodies to control HBV infection, while HBV specific CD8+ T cells destroy infected hepatocytes. One of the reasons for the chronicity of HBV infection is that it cannot effectively activate adoptive immunity and the function of virus specific immune cells is exhausted. Among them, virus antigens (including HBV surface antigen, e antigen, core antigen, etc.) can inhibit the function of immune cells and induce immune tolerance. Long term nucleos(t)ide analogues (NAs) treatment and inactive HBsAg carriers with low HBsAg level may "wake up" immune cells with abnormal function due to the decrease of viral antigen level in blood and liver, and the specific immune function of HBV will recover to a certain extent, thus becoming the "dominant population" for functional cure. In turn, the functional cure will further promote the recovery of HBV specific immune function, which is also the theoretical basis for complete cure of hepatitis B. In the future, the complete cure of chronic HBV infection must be the combination of three drugs: inhibiting virus replication, reducing surface antigen levels and specific immune regulation, among which specific immunotherapy is indispensable. Here we review the relationship, mechanism and clinical significance between the cure of hepatitis B and immune system.
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Affiliation(s)
| | | | - Bo Feng
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Peking University Hepatology Institute, Beijing, China
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11
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Wang F, Xie S, Ran C, Hao H, Jiang T, Deng W, Bi X, Lin Y, Yang L, Sun F, Zeng Z, Xie Y, Li M, Yi W. Effect of Antiviral Therapy During Pregnancy on Natural Killer Cells in Pregnant Women With Chronic HBV Infection. Front Immunol 2022; 13:893628. [PMID: 35677040 PMCID: PMC9168030 DOI: 10.3389/fimmu.2022.893628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 04/22/2022] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE To study the effect of antiviral therapy during pregnancy on the frequency of natural killer (NK) cells in peripheral blood of women with HBV DNA positive chronic hepatitis B (CHB). METHOD In total 124 female subjects were divided into four groups: 11 healthy non-pregnant women (Normal group), 26 non-pregnant women in immune tolerance period of chronic hepatitis B virus (HBV) infection (CHB group), 41 pregnant CHB women without antiviral treatment during pregnancy (Untreated group), and 46 pregnant CHB women receiving antiviral treatment during pregnancy (Treated group). The frequency of NK cells in peripheral blood were detected by flow cytometry. RESULT The frequency of NK cells in healthy women [15.30 (12.80, 18.40)] was higher than that in women with HBV infection, but there was no significant statistical difference (p=0.436). The frequency of NK cells in CHB group [10.60 (6.00, 18.30)] was higher than those in pregnant CHB women [Untreated: 6.90 (4.89, 10.04), P=0.001; Treated: 9.42 (6.55, 14.10), P=0.047]. The frequency of NK cells in treated group was significantly higher than that in untreated group (P = 0.019). The frequencies of NK cells, CD56bright NK cells and NKp46dim NK cells at 12 and 24 weeks postpartum in the untreated group were increased significantly than those before delivery. In treated group, the frequencies of NK cells, CD56bright NK cells, NKp46+ NK cells and NKp46dim NK cells were significantly increased at 6 and 12 weeks than those before delivery. The frequencies of NK cells and CD56bright NK cells postpartum were increased significantly in treated group than those in untreated group. The frequencies of CD56dim NK cells decreased significantly after delivery in treated than those in untreated patients. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) significantly increased after delivery than those before delivery. The results showed that the postpartum ALT level was weak positive correlated with NKp46high frequency (r=0.199) and was weak negative correlated with NKp46dim frequency (r= -0.199). CONCLUSION Antiviral treatment during pregnancy could significantly increase the frequency of NK cells postpartum. Postpartum hepatitis may be related to the immune injury caused by change of NK cell frequency and HBV infection.
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Affiliation(s)
- Fuchuan Wang
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Si Xie
- Division of Hepatology, Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Chongping Ran
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Fangfang Sun
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhan Zeng
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Nagra N, Kozarek RA, Burman BE. Therapeutic Advances in Viral Hepatitis A-E. Adv Ther 2022; 39:1524-1552. [PMID: 35220557 DOI: 10.1007/s12325-022-02070-z] [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: 12/16/2021] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
Abstract
Viral hepatitis remains a significant global health problem. All forms of viral hepatitis A through E (A-E) can lead to acute symptomatic infection, while hepatitis B and C can lead to chronic infection associated with significant morbidity and mortality related to progression to cirrhosis, end-stage-liver disease, and liver cancer. Viral hepatitis occurs worldwide, though certain regions are disproportionately affected. We now, remarkably, have highly effective curative regimens for hepatitis C, and safe and tolerable medications to suppress hepatitis B activity, and to prevent liver damage and slow disease progression. We have effective vaccines for hepatitis A and B which provide long-lasting immunity, while improved sanitation and awareness can curb outbreaks of hepatitis A and E. However, more effective and available preventive and curative strategies are needed to achieve global eradication of viral hepatitis. This review provides an overview of the epidemiology, transmission, diagnosis, and clinical features of each viral hepatitis with a primary focus on current and future therapeutic and curative options.
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Affiliation(s)
- Navroop Nagra
- Department of Gastroenterology, University of Louisville, Louisville, KY, 40202, USA
| | - Richard A Kozarek
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA
| | - Blaire E Burman
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA.
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13
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Zhou L, He Q, Liu X, Yang X, Ou X, Situ B, Li Y, Pan X, Xu Q. Follow-Up of 108 Patients with Chronic Hepatitis B Virus Infection Treated with Polyethylene Glycol-Conjugated Derivatives of Interferon-Alpha and Monitoring of Off-Treatment Virological Relapse. Med Sci Monit 2022; 28:e934785. [PMID: 35351845 PMCID: PMC8978592 DOI: 10.12659/msm.934785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/09/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND This single center study, which enrolled 108 patients with chronic hepatitis B virus infection treated with pegylated interferon-alpha (PEG-IFN-alpha), aimed to follow up and monitor off-treatment responses, including virological relapse, and analyze predictors of long-term efficacy of the PEG-IFN-alpha regimen. MATERIAL AND METHODS In total, 108 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B who had completed the PEG-IFN-alpha regimen and achieved virological suppression were enrolled. The patients were followed up for 5 years to monitor off-treatment responses. Twenty-eight relevant factors, including the history of antiviral therapy and HBeAg seroconversion, were analyzed using the Cox proportional hazards regression model. RESULTS The cumulative rates of virological suppression were 75.70%, 68.68%, 65.25%, 63.91%, and 63.91% at 1, 2, 3, 4, and 5 years of the follow-up period, respectively. Compared with the rates of virological suppression, the cumulative rates of clinical suppression were 88.41%, 79.83%, 78.59%, 75.65%, and 75.65%, respectively, for the 5 years. Alanine aminotransferase (ALT) normalization at 24 weeks after off-therapy (relative risk [RR]=3.430, P=0.013) was a potential predictor for sustained virological suppression, and the history of anti-viral therapy (RR=0.164, P=0.004), quantitative value of hepatitis B virus surface antigen (HBsAg) at 48 weeks of anti-viral therapy (RR=2.697, P=0.039), and ALT normalization at 24 weeks after off-therapy (RR=5.467, P=0.004) were potential predictors for sustained clinical suppression. CONCLUSIONS Our results suggested that increased HBsAg levels at 48 weeks and normalization of ALT at 24 weeks after off-therapy might be predictive factors for long-term treatment efficacy.[color=red] [/color].
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Affiliation(s)
- Liyang Zhou
- Department of Infectious Diseases, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Qin He
- Department of Infectious Diseases, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Xitao Liu
- Clinical Research Management Office, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Xiaoan Yang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, PR China
| | - Xueting Ou
- Department of Infectious Diseases, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Bing Situ
- Clinical Research Management Office, Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Yueping Li
- Intensive Care Unit of Infectious Diseases, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Xingfei Pan
- Department of Infectious Diseases, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, PR China
| | - Qihuan Xu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, PR China
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14
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Li Y, Yin S, Issa R, Tong X, Wang G, Xia J, Huang R, Chen G, Weng D, Chen C, Wu C, Chen Y. B Cell-mediated Humoral Immunity in Chronic Hepatitis B Infection. J Clin Transl Hepatol 2021; 9:592-597. [PMID: 34447690 PMCID: PMC8369012 DOI: 10.14218/jcth.2021.00051] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/24/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.
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Affiliation(s)
- Yang Li
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rahma Issa
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guiyang Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Juan Xia
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Guangmei Chen
- Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Dan Weng
- School of Environmental and Biological Engineering, Nanjing University of Science & Technology, Nanjing, Jiangsu, China
| | - Chen Chen
- Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
| | - Yuxin Chen
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Correspondence to: Yuxin Chen, Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0001-5955-687X. Tel: +86-25-8968-3827, Fax: +86-25-8330-7115, E-mail: ; Wu Chao, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. ORCID: https://orcid.org/0000-0002-1657-010X. Tel: +86-25-8310-5890, Fax: +86-25-8330-7115, E-mail:
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15
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Nishio A, Bolte FJ, Takeda K, Park N, Yu ZX, Park H, Valdez K, Ghany MG, Rehermann B. Clearance of pegylated interferon by Kupffer cells limits NK cell activation and therapy response of patients with HBV infection. Sci Transl Med 2021; 13:13/587/eaba6322. [PMID: 33790025 DOI: 10.1126/scitranslmed.aba6322] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 02/24/2021] [Indexed: 12/12/2022]
Abstract
Pegylated interferon-α (PEG-IFN-α), where IFN-α is attached to polyethylene glycol (PEG), is an approved treatment for chronic hepatitis B virus (HBV) infection, a disease that causes liver-related morbidity and mortality in 257 million people worldwide. It is unknown why only a minority of patients respond to PEG-IFN-α. Using sequential blood samples and liver biopsies of patients with chronic HBV infection before, during, and after PEG-IFN-α treatment, we find that patients with early natural killer (NK) cell activation after PEG-IFN-α injection experienced greater liver inflammation, lysis of HBV-infected hepatocytes, and hepatitis B surface antigen (HBsAg) decline than those without. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG-IFN-α pharmacokinetics. Patients with delayed increases in PEG-IFN-α concentrations had greater amounts of PEG-specific immunoglobulin M (IgM) immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG-IFN-α concentration. This was associated with reduced NK cell activation. These results indicate that the immunomodulatory functions of PEG-IFN-α, particularly activation of NK cells, play a pivotal role in the response to treatment and further demonstrate that these functions are affected by PEG-IFN-α pharmacokinetics. Accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of HBV therapeutics. Thus, these findings may contribute to improving the efficacy of pegylated drugs that are now being developed for other chronic diseases and cancer.
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Affiliation(s)
- Akira Nishio
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Fabian J Bolte
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Kazuyo Takeda
- Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Nana Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Zu-Xi Yu
- Pathology Core, National Heart, Lung and Blood Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Heiyoung Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Kristin Valdez
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Marc G Ghany
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA.
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16
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Schoenberg MB, Li X, Li X, Han Y, Hao J, Miksch RC, Koch D, Börner N, Beger NT, Bucher JN, Schiergens TS, Guba MO, Werner J, Bazhin AV. The predictive value of tumor infiltrating leukocytes in Hepatocellular Carcinoma: A systematic review and meta-analysis. Eur J Surg Oncol 2021; 47:2561-2570. [PMID: 33966947 DOI: 10.1016/j.ejso.2021.04.042] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/26/2021] [Accepted: 04/28/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND For Hepatocellular carcinoma (HCC) surgery either through resection or transplantation often provides the only chance for cure. Since hepatocarcinogenesis and postsurgical prognosis is not only dependent on cirrhosis but also on immune activation and exhaustion, many studies have investigated tumor infiltrating leukocyte (TIL) subsets. This systematic review and meta-analysis aims at describing the cell groups and their predictive power regarding overall (OS), disease free (DFS) and recurrence free survival (RFS). MATERIAL AND METHODS A systematic search of the PubMed database was conducted (PROSPERO 172324). Data on CD3+, CD8+, Treg, B cells, macrophages, neutrophil and NK-cells were collected from Pubmed and related references up to December 2018. Overall (OS), disease-free (DFS) and recurrence free survival (RFS) in dependence of high vs. low infiltration rates were compared using a random effects meta-analysis. RESULTS Altogether data from 3541 patients enrolled in 20 publications were included. Except for Tregs and Neutrophils, heterogeneity analysis was found to be moderate to high across the studies. High CD3+, CD8+, NK-cell infiltration predicted better survival (OS, DFS and RFS; p < 0.05). Higher Treg and Neutrophil infiltration predicted lower OS and DFS. For Macrophages and B cells no difference in survival could be found. DISCUSSION As with other solid tumors immune infiltration has a great influence on survival after resection. However, a considerable publication bias cannot be ruled out in mostly retrospective analyses. Nevertheless, in light of novel immune modulatory treatments this opens a new avenue towards effective and well-tolerated adjuvant treatment.
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Affiliation(s)
- Markus Bo Schoenberg
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Xiaokang Li
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Xinyu Li
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Yongsheng Han
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jingcheng Hao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, PR China
| | - Rainer Christoph Miksch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Dominik Koch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Nikolaus Börner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Nicola Theresa Beger
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Julian Nikolaus Bucher
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Tobias Simon Schiergens
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Markus Otto Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
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17
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Cao Z, Meng S, Zheng Y, Wang J, Wang R, Chen X. Contribution of NK cells to HBsAg seroconversion in inactive HBsAg carriers following pegylated IFN therapy. Innate Immun 2020; 26:601-608. [PMID: 32772775 PMCID: PMC7556194 DOI: 10.1177/1753425920942580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Our recent study showed a high rate of HBsAg seroconversion in inactive HBsAg carriers (IHCs) treated with pegylated IFN (PEG-IFN). To understand the immune-mediated component of the HBsAg seroconversion better, this study investigated the role of NK cells. A total of 44 IHCs were given 48 wk of PEG-IFN. Fifteen cases achieved HBsAg seroconversion (R group), whereas 29 failed (NR group). The proportion and activity (CD107α and IFN-γ production) of NK cells were measured before and during treatment. We found that the proportion of NK cells in the R group was higher than in the NR group at baseline and during PEG-IFN treatment, even when patients were matched for age, sex and treatment period. IFN- γ secretion and CD107α expression from NK cells in cases who achieved HBsAg seroconversion were significantly higher than patients matched for age, sex, HBsAg and treatment period in the NR group at baseline and during PEG-IFN treatment. We also found that in HBsAg seroconversion cases, NK cells activity increased after PEG-IFN treatment, especially before HBsAg seroconversion. These effects were not found in non-responders. In conclusion, we demonstrated that the increase of NK cells accompanied by enhanced activity during PEG-IFN treatment favoured HBsAg seroconversion for IHC, and that NK cells may play a role in HBV seroconversion.
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Affiliation(s)
- Zhenhuan Cao
- International Medical Department, Beijing You'an Hospital, Capital Medical University, PR China
| | - Sha Meng
- Science and Technology Department, Beijing You'an Hospital, Capital Medical University, PR China
| | - Yanhong Zheng
- International Medical Department, Beijing You'an Hospital, Capital Medical University, PR China
| | - Junli Wang
- International Medical Department, Beijing You'an Hospital, Capital Medical University, PR China
| | - Rui Wang
- Beijing Key Laboratory for HIV/AIDS Research, PR China
| | - Xinyue Chen
- International Medical Department, Beijing You'an Hospital, Capital Medical University, PR China
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18
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Bouayad A. Innate immune evasion by SARS-CoV-2: Comparison with SARS-CoV. Rev Med Virol 2020; 30:1-9. [PMID: 32734714 DOI: 10.1002/rmv.2135] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 05/27/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023]
Abstract
SARS-CoV-2 virus, a member of the Coronaviridae family, causes Covid-19 pandemic disease with severe respiratory illness. Multiple strategies enable SARS-CoV-2 to eventually overcome antiviral innate immune mechanisms which are important components of viral pathogenesis. This review considers several mechanisms of SARS-CoV-2 innate immune evasion including suppression of IFN-α/β production at the earliest stage of infection, mechanisms that exhaust natural killer cell-mediated cytotoxicity, overstimulation of NLRP3 inflammasome and induction of a cytokine storm. A comparison with SARS-CoV is made. Greater knowledge of these and other immune evasion tactics may provide us with improved possibilities for research into this novel deadly virus.
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Affiliation(s)
- Abdellatif Bouayad
- Laboratory of Immunohematology and Cellular Therapy, Faculty of Medicine and Pharmacy, Mohammed First University, Oujda, Morocco.,Laboratory of Immunology, Mohammed VI Hospital, Oujda, Morocco
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19
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Pang X, Zhang L, Liu N, Liu B, Chen Z, Li H, Chen M, Peng M, Ren H, Hu P. Combination of pegylated interferon-alpha and nucleos(t)ide analogue treatment enhances the activity of natural killer cells in nucleos(t)ide analogue experienced chronic hepatitis B patients. Clin Exp Immunol 2020; 202:80-92. [PMID: 32638357 DOI: 10.1111/cei.13486] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/07/2020] [Accepted: 06/11/2020] [Indexed: 02/06/2023] Open
Abstract
A combination of pegylated interferon-alpha (peg-IFN-α) and nucleos(t)ides analogue (NA) therapy can effectively reduce hepatitis B surface antigen (HBsAg), especially in NA-experienced chronic hepatitis B (CHB) patients. However, the immune mechanism of this therapy is unclear. Forty NA-experienced CHB patients were enrolled into this study. The frequencies of peripheral blood natural killer (NK) cells, dendritic cells (DCs), CD4+ T cells, CD8+ T cells, T helper (Th) cells, regulatory T cells (Treg ), B cells and follicular T helper (Tfh) cells were evaluated by flow cytometry. Seven of the 40 patients converted to peg-IFN-α combined with NA treatment, while the other 33 continued to NA therapy. The decrease in HBsAg was more pronounced in the combination treatment group, and only patients receiving combination treatment achieved HBsAg loss. The frequency and absolute number of CD56bright NK cells in the combination treatment group increased significantly compared with the NA treatment group, whereas the CD56dim NK cells were decreased. In the NA treatment group, the proportions of CD4+ TN , CD8+ TN , CD19+ B and cytotoxic T lymphocyte antigen-4 (CTLA-4)+ CD4+ T cells were increased, while the proportions of CD4+ TEM , CD8+ TEM , CD25+ CD4+ Treg , CD25high CD4+ Treg , CD127low CD25+ Treg , programmed cell death 1 (PD-1)+ CD4+ T, PD-1+ CD8+ T, CTLA-4+ CD8+ T, CCR4+ CD25+ Treg and CCR4+ CD25high Treg cells were decreased after therapy. For NA-experienced CHB patients who achieved low HBsAg levels, combination treatment is more likely to result in HBsAg decline and HBsAg clearance by increasing the activity of CD56bright NK cells.
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Affiliation(s)
- X Pang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - L Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - N Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - B Liu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Z Chen
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - H Li
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - M Chen
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - M Peng
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - H Ren
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - P Hu
- Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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20
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Ou Q, Guo J, Zeng Y, Chen H. Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection. J Viral Hepat 2020; 27:224-232. [PMID: 31954089 DOI: 10.1111/jvh.13260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 10/19/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023]
Abstract
Covalently closed circular DNA (cccDNA), which is stably present in the nucleus of hepatocytes, is an important indicator for evaluating antiviral efficacy. Since cccDNA quantification requires an invasive procedure, serum biological markers that can effectively reflect the transcriptional activity of intrahepatic virus and the efficacy of treatment are required. Here, from the aspects of virus and host, we outline the focus of clinical research of HBV in recent years, including HBV RNA, empty virus, hepatitis B core-related antigen and changes in the immune response. We briefly discuss their significance in predicting disease activity and monitoring treatment response in chronic hepatitis B. On this basis, some issues worthy of attention in laboratory diagnosis are proposed.
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Affiliation(s)
- Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Jianhui Guo
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Yongbin Zeng
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Huijuan Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
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21
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Meng Z, Chen Y, Lu M. Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection. Front Immunol 2020; 10:3127. [PMID: 32117201 PMCID: PMC7018702 DOI: 10.3389/fimmu.2019.03127] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
“Functional cure” is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. “Functional cure” can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.
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Affiliation(s)
- Zhongji Meng
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yuanyuan Chen
- Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, Essen, Germany
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22
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Abstract
Chronic hepatitis B (CHB) is a widespread global infection and a leading cause of hepatocellular carcinoma and liver failure. Current approaches to treat CHB involve the suppression of viral replication with either interferon or nucleos(t)ide analog therapy, but neither of these approaches can reliably induce viral eradication, immunologic control or long-lived viral suppression in the absence of continued therapy. In this update, we explore the major obstacles of CHB cure and review new therapeutic strategies and drug candidates.
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Affiliation(s)
- Lydia Tang
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Shyam Kottilil
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Eleanor Wilson
- Division of Clinical Care & Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Program in Oncology, University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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23
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Ma Z, Zhang E, Gao S, Xiong Y, Lu M. Toward a Functional Cure for Hepatitis B: The Rationale and Challenges for Therapeutic Targeting of the B Cell Immune Response. Front Immunol 2019; 10:2308. [PMID: 31608073 PMCID: PMC6769125 DOI: 10.3389/fimmu.2019.02308] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022] Open
Abstract
The central role of the cellular immune response in the control and clearance of the hepatitis B virus (HBV) infection has been well-established. The contribution of humoral immunity, including B cell and antibody responses against HBV, has been investigated for a long time but has attracted increasing attention again in recent years. The anti-HBs antibody was first recognized as a marker of protective immunity after the acute resolution of the HBV infection (or vaccination) and is now defined as a biomarker for the functional cure of chronic hepatitis B (CHB). In this way, therapies targeting HBV-specific B cells and the induction of an anti-HBs antibody response are essential elements of a rational strategy to terminate chronic HBV infection. However, a high load of HBsAg in the blood, which has been proposed to induce antigen-specific immune tolerance, represents a major obstacle to curing CHB. Long-term antiviral treatment by nucleoside analogs, by targeting viral translation by siRNA, by inhibiting HBsAg release via nucleic acid polymers, or by neutralizing HBsAg via specific antibodies could potentially reduce the HBsAg load in CHB patients. A combined strategy including a reduction of the HBsAg load via the above treatments and the therapeutic targeting of B cells by vaccination may induce the appearance of anti-HBs antibodies and lead to a functional cure of CHB.
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Affiliation(s)
- Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ejuan Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Shicheng Gao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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24
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Li TY, Yang Y, Zhou G, Tu ZK. Immune suppression in chronic hepatitis B infection associated liver disease: A review. World J Gastroenterol 2019; 25:3527-3537. [PMID: 31367154 PMCID: PMC6658392 DOI: 10.3748/wjg.v25.i27.3527] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/29/2019] [Accepted: 06/01/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is one the leading risk factors for chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular cancer (HCC), which are a major global health problem. A large number of clinical studies have shown that chronic HBV persistent infection causes the dysfunction of innate and adaptive immune response involving monocytes/macrophages, dendritic cells, natural killer (NK) cells, T cells. Among these immune cells, cell subsets with suppressive features have been recognized such as myeloid derived suppressive cells(MDSC), NK-reg, T-reg, which represent a critical regulatory system during liver fibrogenesis or tumourigenesis. However, the mechanisms that link HBV-induced immune dysfunction and HBV-related liver diseases are not understood. In this review we summarize the recent studies on innate and adaptive immune cell dysfunction in chronic HBV infection, liver fibrosis, cirrhosis, and HCC, and further discuss the potential mechanism of HBV-induced immunosuppressive cascade in HBV infection and consequences. It is hoped that this article will help ongoing research about the pathogenesis of HBV-related hepatic fibrosis and HBV-related HCC.
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Affiliation(s)
- Tian-Yang Li
- Infectious Disease, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Yang Yang
- Institute of Liver diseases, the First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guo Zhou
- Infectious Disease, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
| | - Zheng-Kun Tu
- Infectious Disease, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, Guangdong Province, China
- Institute of Liver diseases, the First Hospital of Jilin University, Changchun 130061, Jilin Province, China
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25
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Zheng B, Yang Y, Han Q, Yin C, Pan Z, Zhang J. STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients. J Leukoc Biol 2019; 106:987-996. [PMID: 31132315 DOI: 10.1002/jlb.2a1118-421r] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 03/29/2019] [Accepted: 05/16/2019] [Indexed: 12/14/2022] Open
Abstract
NK cells play an important role in early control of HBV infection. The function of NK cells is inhibited in chronic hepatitis B virus (CHB) infection, although the underlying mechanism remains unknown. We found that the expression of STAT3 decreased in peripheral NK cells of CHB patients, and was associated with low levels of degranulation and IFN-γ secretion. In addition, STAT3 levels were positively correlated with cytolysis-associated molecules and antiviral cytokines, such as CD107a, granzyme B, perforin, and IFN-γ. HBsAg directly inhibited the expression and activation of STAT3 in NK cells, and knocking down STAT3 expression in NK cells inhibited proliferation, decreased cyclin d1 levels, and suppressed responsiveness to IL-21 stimulation. Furthermore, STAT3 directly bound to the promoter of NKp46, an important activating receptor of NK cells, to regulate its transcription and expression. Taken together, our findings indicate that STAT3 is an important positive regulator of NK cells, and provide a new mechanism of NK cell dysfunction in CHB.
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Affiliation(s)
- Bingqing Zheng
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Yinli Yang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Qiuju Han
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Chunlai Yin
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Zhaoyi Pan
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Jian Zhang
- Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China
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26
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Vaillant A. REP 2139: Antiviral Mechanisms and Applications in Achieving Functional Control of HBV and HDV Infection. ACS Infect Dis 2019; 5:675-687. [PMID: 30199230 DOI: 10.1021/acsinfecdis.8b00156] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nucleic acid polymers (NAPs) are broad spectrum antiviral agents whose antiviral activity in hepatitis B virus (HBV) infection is derived from their ability to block the release of the hepatitis B virus surface antigen (HBsAg). This pharmacological activity blocks replenishment of HBsAg in the circulation, allowing host mediated clearance. This effect has important clinical significance as the clearance of circulating HBsAg dramatically potentiates the ability of immunotherapies to restore functional control of HBV infection which persists after antiviral therapy is removed. These effects are reproducible in preclinical evaluations and in several clinical trials that have evaluated the activity of the lead NAP, REP 2139, in monotherapy and in combination with immunotherapy in hepatitis B e antigen (HBeAg) negative and HBeAg positive HBV infection and also in HBeAg negative HBV/hepatitis D virus (HDV) coinfection. These antiviral effects of REP 2139 are achieved in the absence of any direct immunostimulatory effect in the liver and also without any discernible direct interaction with viral components. The search for the host protein interaction with NAPs that drives their antiviral effects is ongoing, and the interaction targeted by REP 2139 within infected cells has not yet been elucidated. This article provides an updated review of available data on the effects of REP 2139 in HBV and HDV infection and the ability of REP 2139-based combination therapy to achieve functional control of HBV and HDV infection in patients.
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Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, Quebec H4P 2R2, Canada
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27
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Gill US, Kennedy PTF. The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics. J Viral Hepat 2019; 26:4-15. [PMID: 30415490 DOI: 10.1111/jvh.13040] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 10/25/2018] [Indexed: 12/14/2022]
Abstract
Despite the availability of a preventative vaccine, chronic hepatitis B (CHB) remains a global healthcare challenge with the risk of disease progression due to cirrhosis and hepatocellular carcinoma. Although current treatment strategies, interferon and nucleos(t)ide analogues have contributed to reducing morbidity and mortality related to CHB, these therapies are limited in providing functional cure. The treatment paradigm in CHB is rapidly evolving with a number of new agents in the developmental pipeline. However, until novel agents with functional cure capability are available in the clinical setting, there is a pressing need to optimize currently licensed therapies. Here, we discuss current agents used alone and/or in combination strategies along with the impact of these therapies on viral and immune responses. Novel treatment strategies are outlined, and the potential role of current therapies in the employment of pipeline agents is discussed.
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Affiliation(s)
- Upkar S Gill
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Patrick T F Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK
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28
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Shi A, Zhang X, Xiao F, Zhu L, Yan W, Han M, Luo X, Chen T, Ning Q. CD56 bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long-term entecavir-treated patients switching to peginterferon alfa-2a. J Viral Hepat 2018; 25:1352-1362. [PMID: 29888839 DOI: 10.1111/jvh.12946] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 04/30/2018] [Indexed: 12/12/2022]
Abstract
HBV surface antigen (HBsAg) reduction is well observed in chronic hepatitis B (CHB) patients treated with pegylated interferon alpha-2a (PegIFNα). However, the mechanism of HBsAg suppression has not been fully elucidated. Twenty-seven of 55 entecavir-treated CHB e antigen positive patients were switched to PegIFNα treatment (Group A) whereas 28 patients continued entecavir treatment (Group B). The percentage or absolute number of CD56bright /CD56dim NK cells, expression of receptors and cytokines were evaluated by flow cytometry for 48 weeks and correlated with treatment efficacy. In vitro, purified NK cells were co-cultured with HepAD38 cells for measurement of HBsAg, apoptosis and covalently closed circular DNA (cccDNA). In association with a reduction of HBsAg, the percentage and absolute number of CD56bright NK cells was significantly elevated in patients in group A, especially in Virologic Responders (VRs, HBsAg decreased). Furthermore, the percentage of NKp30+ , NKp46+ , TRAIL+ , TNF-α+ and IFNγ+ CD56bright NK cells were significantly expanded in Group A, which were positively correlated with the decline of HBsAg at week 48. In vitro, peripheral NK cells from Group A induced a decline of HBsAg in comparison with NK cells from Group B which was significantly inhibited by anti-TRAIL, anti-TNF-α and anti-IFNγ antibodies. Furthermore, apoptosis of HepAD38 cells and levels of cccDNA, were significantly reduced by TRAIL+ and TNF-α+ /IFNγ+ NK cells from Group A, respectively. A functional restoration of CD56bright NK cells in entecavir-treated patients who were switched to PegIFNα contributes to HBsAg and cccDNA clearance through TRAIL-induced cytolysis and TNF-α/IFNγ-mediated noncytolytic pathways.
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Affiliation(s)
- A Shi
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - X Zhang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - F Xiao
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - L Zhu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - W Yan
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - M Han
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - X Luo
- Department of Pediatric Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - T Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Q Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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29
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Li H, Zhai N, Wang Z, Song H, Yang Y, Cui A, Li T, Wang G, Niu J, Crispe IN, Su L, Tu Z. Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection. Gut 2018; 67:2035-2044. [PMID: 28899983 PMCID: PMC6176520 DOI: 10.1136/gutjnl-2017-314098] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 07/05/2017] [Accepted: 07/24/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS HBV infection represents a major health problem worldwide, but the immunological mechanisms by which HBV causes chronic persistent infection remain only partly understood. Recently, cell subsets with suppressive features have been recognised among monocytes and natural killer (NK) cells. Here we examine the effects of HBV on monocytes and NK cells. METHODS Monocytes and NK cells derived from chronic HBV-infected patients and healthy controls were purified and characterised for phenotype, gene expression and cytokines secretion by flow cytometry, quantitative real-time (qRT)-PCR, ELISA and western blotting. Culture and coculture of monocytes and NK cells were used to determine NK cell activation, using intracellular cytokines staining. RESULTS In chronic HBV infection, monocytes express higher levels of PD-L1, HLA-E, interleukin (IL)-10 and TGF-β, and NK cells express higher levels of PD-1, CD94 and IL-10, compared with healthy individuals. HBV employs hepatitis B surface antigen (HBsAg) to induce suppressive monocytes with HLA-E, PD-L1, IL-10 and TGF-β expression via the MyD88/NFκB signalling pathway. HBV-treated monocytes induce NK cells to produce IL-10, via PD-L1 and HLA-E signals. Such NK cells inhibit autologous T cell activation. CONCLUSIONS Our findings reveal an immunosuppressive cascade, in which HBV generates suppressive monocytes, which initiate regulatory NK cells differentiation resulting in T cell inhibition.
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Affiliation(s)
- Haijun Li
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Naicui Zhai
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Zhongfeng Wang
- Institute of Liver Diseases, The First Hospital, Jilin University, Changchun, China
| | - Hongxiao Song
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Yang Yang
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - An Cui
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Tianyang Li
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
| | - Guangyi Wang
- Department of Liver and Gall Surgery, The First Hospital, Jilin University, Changchun, China
| | - Junqi Niu
- Institute of Liver Diseases, The First Hospital, Jilin University, Changchun, China
| | - Ian Nicholas Crispe
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Lishan Su
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Zhengkun Tu
- Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, China
- Institute of Liver Diseases, The First Hospital, Jilin University, Changchun, China
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30
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Zhuang Y, Li X, Li X, Xu H, Ye H, Sun D, Liu X, Ren G. Association of KIR Genotypes and Haplotypes in HBeAg-positive Chronic Hepatitis B Patients Treated with Entecavir. Immunol Invest 2018; 48:333-344. [PMID: 30325691 DOI: 10.1080/08820139.2018.1529791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND A large proportion of patients with chronic hepatitis B (CHB) in China do not respond to entecavir (ETV) treatment. It remains unclear whether the Killer immunoglobulin-like receptor (KIR) genotypes and haplotypes were associated with the advantage of seroconversion in phepatitis B e-Antigen (HBeAg) positive CHB patients treated with ETV. METHODS Polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to analyze KIR genes in a Chinese Han population of 198 ETV-treated HBeAg-positive CHB patients and 200 healthy controls. Of the 198 patients, 59 were complete response group (CRG) and 139 were null or partial response group (NPRG) to the treatment with ETV. RESULTS The frequencies of KIR genotype M, and haplotype 8 were significantly higher(P = 0.017, OR = 2.497，95%CI = 5.39-1.16 and P = 0.034, OR = 1.905，95%CI = 3.48-1.04, respectively), while the frequencies of genotype AH and haplotype 5 were significantly lower (P = 0.039, OR = 0.504, 95%CI = 0.97-0.26 and P = 0.031, OR = 0.601, 95%CI = 0.96-0.38, respectively) in HBeAg-positive CHB patient group than those in healthy group. Of note, the frequencies of KIR genotype AF and haplotype 1 were significantly higher (P = 0.022, OR = 2.860, 95%CI = 7.24-1.13 and P = 0.001, OR = 3.261, 95%CI = 6.47-1.64, respectively), while the frequencies of genotype AH and haplotype 5 were significantly lower (P = 0.038, OR = 0.338, 95%CI = 0.98-0.12 and P = 0.004, OR = 0.354, 95%CI = 0.73-0.17, respectively) in NPRG than those in CRG. CONCLUSIONS The patients with KIR genotype AF and haplotype 1 might be negative, while genotype AH and haplotype 5 might be of advantage to the therapy with ETV, which are useful for improving novel personalized precise therapy strategy in HBeAg-positive CHB patients.
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Affiliation(s)
- YunLong Zhuang
- a Institute of hematology , Blood Center of Shandong Province , Jinan , Shandong Province , P. R. China
| | - XiXi Li
- b Department of Blood Transfusion , Taian City Central Hospital , Taian , Shandong Province , P. R. China
| | - Xiaohua Li
- c Department of Blood Component Preparations , Yantai Blood Bank , Yantai , Shandong Province , P. R. China
| | - HuiCong Xu
- a Institute of hematology , Blood Center of Shandong Province , Jinan , Shandong Province , P. R. China
| | - Hui Ye
- a Institute of hematology , Blood Center of Shandong Province , Jinan , Shandong Province , P. R. China
| | - Di Sun
- c Department of Blood Component Preparations , Yantai Blood Bank , Yantai , Shandong Province , P. R. China
| | - XiangZhong Liu
- d Department of Liver Disease , Yantai Infectious Disease Hospital , Yantai , Shandong Province , P. R. China
| | - GuiJie Ren
- e Department of Biochemistry and Molecular Biology , Medical college of Shandong University , Jinan , Shandong Province , P. R. China
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31
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Suslov A, Wieland S, Menne S. Modulators of innate immunity as novel therapeutics for treatment of chronic hepatitis B. Curr Opin Virol 2018; 30:9-17. [PMID: 29444493 PMCID: PMC5988934 DOI: 10.1016/j.coviro.2018.01.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/18/2018] [Accepted: 01/25/2018] [Indexed: 02/07/2023]
Abstract
The first line defense mechanisms against viral infection are mediated by the innate immune system. Viral components are detected by infected cells and/or innate immune cells that express different sensory receptors. They in turn mediate induction of direct antiviral mechanisms and further modulation of innate and adaptive immune responses. For evading the innate system, most viruses have evolved efficient mechanisms to block sensing and/or antiviral functions of the innate response. Interestingly, hepatitis B virus (HBV) seems to act like a stealth virus that escapes cell intrinsic antiviral mechanisms through avoiding recognition by the innate system rather than blocking its effector functions. In line with this concept, agonistic activation of innate immunity has emerged as a promising novel anti-HBV therapy approach with several compounds having advanced to the clinical stage.
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Affiliation(s)
- Aleksei Suslov
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland
| | - Stefan Wieland
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel CH-4031, Switzerland.
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, United States.
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Zimmer CL, Rinker F, Höner Zu Siederdissen C, Manns MP, Wedemeyer H, Cornberg M, Björkström NK. Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss. J Infect Dis 2018; 217:1656-1666. [PMID: 29471497 DOI: 10.1093/infdis/jiy097] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 02/16/2018] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND Treatment with nucleos(t)ide analogues (NA) suppresses hepatitis B virus (HBV) DNA but rarely leads to functional cure of chronic hepatitis B (CHB). Following NA cessation, some hepatitis B e antigen (HBeAg)-negative CHB patients experience hepatitis B s antigen (HBsAg) loss. Cellular immune responses, including natural killer (NK) cell responses, explaining virological events following NA treatment cessation remain elusive. METHODS In a single-center prospective trial, 15 HBeAg-negative CHB patients on long-term NA treatment underwent structured NA cessation and were studied longitudinally. The NK cell compartment was assessed using high-dimensional flow cytometry and correlated with the clinical course. RESULTS Unsupervised stochastic neighbor embedding analysis revealed NA-treated CHB patients to have a significantly affected NK cell compartment compared to controls. Cessation of NA treatment resulted in minor phenotypic alterations, but it significantly augmented NK cell natural cytotoxicity responses in the CHB patients. This increased NK cell functionality correlated with alanine aminotransferase flares in the patients and was particularly enhanced in patients experiencing HBsAg seroclearance at long-term follow-up. CONCLUSIONS Increased NK cell function is associated with active hepatitis and HBsAg seroclearance following structured NA cessation. This adds to our knowledge of the immunological events that develop following cessation of NA treatment in CHB.
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Affiliation(s)
- Christine L Zimmer
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Franziska Rinker
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School
| | | | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School
- German Center for Infection Research, Partner Site Hannover-Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School
- German Center for Infection Research, Partner Site Hannover-Braunschweig, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School
- German Center for Infection Research, Partner Site Hannover-Braunschweig, Germany
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Huang J, Zhang K, Chen W, Liao J, Luo X, Chen R. Switching to PegIFNα-2b leads to HBsAg loss in patients with low HBsAg levels and HBV DNA suppressed by NAs. Sci Rep 2017; 7:13383. [PMID: 29042662 PMCID: PMC5645387 DOI: 10.1038/s41598-017-13747-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 09/26/2017] [Indexed: 02/02/2023] Open
Abstract
Patients with low hepatitis B surface antigen (HBsAg) levels and hepatitis B virus (HBV) DNA suppression by nucleos(t)ide analogues (NAs) achieve high rate of HBsAg loss through switching to PegIFNα in pre-registration study. The aim of this study was to achieve higher rate of HBsAg loss through extended PegIFN treatment. 98 patients with HBsAg < 2,000 IU/ml and HBV DNA < 20 IU/ml were randomized to receive PegIFNα-2b or continuing NA therapy for 60 weeks. At the end of treatment (EOT) and end of follow-up (EOF), only patients who switched to PegIFNα-2b achieved HBsAg loss (32.6%) and HBsAg seroconversion (27.9% and 25.6%). Patients who switched to PegIFNα-2b also achieved higher HBeAg seroconversion rates (65.1%) and HBeAg loss (81.4% and 90.7%) than those who continued NAs treatment. On-treatment HBsAg declines predicted the responses at EOT, and HBsAg declines at post-baseline times predicted the responses at EOF. The rates of responses were not increased through extended PegIFNα treatment. For patients with low HBsAg and HBV suppression with NAs, switching to PegIFNα-2b significantly increased the rates of HBsAg loss and HBsAg seroconversion. HBsAg decline can predict the response of switching to PegIFNα-2b following from NAs.
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Affiliation(s)
- Jing Huang
- Department of Infectious Diseases, Guangdong General Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China
| | - Ka Zhang
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wenli Chen
- Department of Infectious Diseases, Guangdong General Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China
| | - Jinyao Liao
- Department of Infectious Diseases, Guangdong General Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China
| | - Xiaodan Luo
- Department of Infectious Diseases, Guangdong General Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China
| | - Ren Chen
- Department of Infectious Diseases, Guangdong General Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China.
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Stelma F, van der Ree MH, Sinnige MJ, Brown A, Swadling L, de Vree JML, Willemse SB, van der Valk M, Grint P, Neben S, Klenerman P, Barnes E, Kootstra NA, Reesink HW. Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101. Hepatology 2017; 66:57-68. [PMID: 28295463 PMCID: PMC5850982 DOI: 10.1002/hep.29148] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 02/17/2017] [Accepted: 03/03/2017] [Indexed: 12/17/2022]
Abstract
UNLABELLED MicroRNA-122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG-101, an N-acetylgalactosamine-conjugated anti-microRNA-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. Thirty-two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG-101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG-101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon-γ-induced protein 10 (IP-10) levels declined significantly upon dosing with RG-101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon-γ production decreased after RG-101 dosing. Functional HCV-specific interferon-γ T-cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post-RG-101 injection. No increase in the magnitude of HCV-specific T-cell responses was observed at later time points, including 3 patients who were HCV RNA-negative 76 weeks postdosing. CONCLUSION Dosing with RG-101 is associated with a restoration of NK-cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV-specific T-cell responses did not increase following RG-101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG-101 therapy. (Hepatology 2017;66:57-68).
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Affiliation(s)
- Femke Stelma
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands,Department of Experimental Immunology Academic Medical Center, Amsterdam, The Netherlands
| | - Meike H van der Ree
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands,Department of Experimental Immunology Academic Medical Center, Amsterdam, The Netherlands
| | - Marjan J Sinnige
- Department of Experimental Immunology Academic Medical Center, Amsterdam, The Netherlands
| | - Anthony Brown
- Nuffield department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK
| | - Leo Swadling
- Nuffield department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK
| | - J Marleen L de Vree
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Sophie B Willemse
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Marc van der Valk
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Paul Grint
- Regulus Therapeutics, San Diego, CA, USA
| | | | - Paul Klenerman
- Nuffield department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK
| | - Eleanor Barnes
- Nuffield department of Medicine and the Oxford NIHR BRC, University of Oxford, Oxford, UK
| | - Neeltje A Kootstra
- Department of Experimental Immunology Academic Medical Center, Amsterdam, The Netherlands
| | - Hendrik W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
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Phillips S, Mistry S, Riva A, Cooksley H, Hadzhiolova-Lebeau T, Plavova S, Katzarov K, Simonova M, Zeuzem S, Woffendin C, Chen PJ, Peng CY, Chang TT, Lueth S, De Knegt R, Choi MS, Wedemeyer H, Dao M, Kim CW, Chu HC, Wind-Rotolo M, Williams R, Cooney E, Chokshi S. Peg-Interferon Lambda Treatment Induces Robust Innate and Adaptive Immunity in Chronic Hepatitis B Patients. Front Immunol 2017; 8:621. [PMID: 28611778 PMCID: PMC5446997 DOI: 10.3389/fimmu.2017.00621] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 05/10/2017] [Indexed: 12/15/2022] Open
Abstract
IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses in vivo. We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4+ T cells producing IFN-γ with maintenance of HBV-specific CD8+ T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that in vivo peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8+ T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT01204762.
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Affiliation(s)
- Sandra Phillips
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.,Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Sameer Mistry
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.,Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Antonio Riva
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.,Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Helen Cooksley
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.,Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | | | - Slava Plavova
- Clinic of Gastroenterology and Hepatology, Military Medical Academy, Sofia, Bulgaria
| | - Krum Katzarov
- Clinic of Gastroenterology and Hepatology, Military Medical Academy, Sofia, Bulgaria
| | - Marieta Simonova
- Clinic of Gastroenterology and Hepatology, Military Medical Academy, Sofia, Bulgaria
| | - Stephan Zeuzem
- Johann Wolfgang, Goethe University Medical Center, Frankfurt, Germany
| | - Clive Woffendin
- Oregon Clinical and Translational Research Institute, Portland, OR, United States
| | - Pei-Jer Chen
- National Taiwan University Hospital, Taipei, Taiwan
| | | | | | | | | | | | | | - Michael Dao
- Precision Diagnostic Laboratory, Santa Ana, CA, United States
| | | | | | - Megan Wind-Rotolo
- Research and Development, Bristol-Myers Squibb, Wallingford, CT, United States
| | - Roger Williams
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.,Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | | | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.,Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
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36
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Zhang Y, Chen B, Wang L, Chi J, Song S, Liu M, Zhao Z. HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:263-70. [PMID: 27023755 DOI: 10.17235/reed.2016.3995/2015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as the clinical endpoint. The purpose of the present meta-analysis was to evaluate pegylated interferon alpha (PEG-IFNα) with or without lamivudine (LAM) or adefovir (ADV) combination treatment in HBsAg seroclearance or seroconversion with CHB. METHODS Randomized controlled trials of adults with CHB prior to May 30th 2015, with 48-52 weeks of PEG-IFNα and LAM or ADV combination therapy or monotherapy, were included. Review Manager Software 5.2.0 was used for meta-analysis. RESULTS No statistical difference was noticed in HBsAg seroclearance (9.9% vs 7.1%, OR = 1.47, 95% CI 0.75, 2.90; p = 0.26) or observed in HBsAg seroconversion (4.2% vs 3.7%, OR = 1.17, 95% CI 0.57, 2.37; p = 0.67) between PEG-IFNα + LAM and PEG-IFNα + placebo for 24-26 weeks follow-up after treatment on hepatitis B e antigen (HBeAg)-positive CHB. Statistical difference was not showed in HBsAg disappearance (10.5% vs 6.4%, OR = 1.68, 95% CI 0.75, 3.76; p = 0.21) but was demonstrated in HBsAg seroconversion (6.3% vs 0%, OR = 7.22, 95% CI 1.23, 42.40; p = 0.03) between PEG-IFNα + ADV and PEG-IFNα for 48-52 weeks treatment on HBeAg-positive CHB By systematical evaluation, there were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM for 48-52 weeks treatment on HBeAg-positive CHB. There were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM during 24 weeks to 3 years follow-up after treatment on HBeAg-negative CHB by systematical evaluation. CONCLUSION The combination between PEG-IFNα and LAM or ADV was not superior to monotherapy of PEG-IFNα in terms of HBsAg seroclearance or seroconversion.
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Affiliation(s)
- Yun Zhang
- Changzhi Medical College , Institute of Liver Diseases, China
| | - Bangtao Chen
- First Hospital of Shanxi Medical University, Institute of Liver Diseases, China
| | - Lin Wang
- Beijing Friendship Hospital, Liver Research Center, China
| | | | - Shaojuan Song
- Changzhi Medical College , Institute of Liver Diseases, China
| | - Mingshe Liu
- Changzhi Medical College , Institute of Liver Diseases, China
| | - Zhongfu Zhao
- Shanxi Medical University, Institute of Liver Diseases, China
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Yuan T, Jiang Y, Li M, Li W. Chronic hepatitis B surface antigen seroclearance-related immune factors. Hepatol Res 2017; 47:49-59. [PMID: 27084584 DOI: 10.1111/hepr.12726] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 04/01/2016] [Accepted: 04/12/2016] [Indexed: 12/23/2022]
Abstract
The ultimate aims of the treatment of hepatitis B virus infection are the loss of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody seroconversion. Unfortunately, these goals are rarely reached. Many factors are associated with HBsAg seroconversion, including genetic, immune, and viral factors. However, the mechanism of HBsAg seroclearance, and particularly the immune mechanism, is still difficult to elucidate. The immune factor interferon-α is currently the main antiviral therapy for chronic hepatitis B virus infection. However, a sustained shift from response of HBsAg to hepatitis B surface antibody seroconversion is rarely obtained. Recent studies have revealed that several of the newly identified immune factors are closely related to the removal of HBsAg. In this article, we review recent studies on these immune factors, their influence on hepatitis B progression, and HBsAg seroconversion.
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Affiliation(s)
- Ting Yuan
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yongfang Jiang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mei Li
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Li
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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38
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Shi GY, Pan YJ, Jiang K, Xie JD. Efficacy of different antiviral treatments for chronic hepatitis B patients carrying different genotypes of hepatitis B virus. Shijie Huaren Xiaohua Zazhi 2016; 24:4704-4709. [DOI: 10.11569/wcjd.v24.i35.4704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To compare the efficacy of different antiviral treatments for chronic hepatitis B patients carrying different genotypes of hepatitis B virus (HBV).
METHODS One hundred and twenty hepatitis B patients with liver cirrhosis and 120 patients with chronic hepatitis B were included in the study. Hepatitis B patients with cirrhosis underwent entecavir treatment. Clinical efficacy was compared between patients carrying different genotypes of HBV. Chronic hepatitis B patients were randomly and equally divided into four groups (A, B, C, and D) to receive lamivudine, entecavir, lamivudine combined with adefovir ester, and polyethylene glycol (peg) interferon alpha 2a treatment for 96 wk, respectively. Clinical efficacy was compared between different groups.
RESULTS After treatment, HBV DNA showed an obvious downward trend in hepatitis B associated liver cirrhosis. After 96 wk of treatment, mean HBV DNA level declined to 5.13 copies/mL, and the rate of conversion of HBV DNA to negativity and the rate of recovery of ALT to normal level were 94.17% and 94.17%, respectively. In 84 hepatitis B e antigen (HBeAg) positive liver cirrhosis patients, the rate of conversion of HBeAg to negativity and serum HBeAg conversion rate were 27.38% and 27.38%, respectively. Between liver cirrhosis patients carrying genotypes C/B, the rate of conversion of HBV DNA to negativity, the rate of recovery of ALT to normal level, the rate of conversion of HBeAg to negativity, serum HBeAg conversion rate, and hepatitis B surface antigen quantity had no statistical differences (P > 0.05). The rate of conversion of HBV DNA to negativity, the rate of recovery of ALT to normal level, the rate of conversion of HBeAg to negativity, and serum HBeAg conversion rate differed significantly among groups A-D (P < 0.05). The rate of conversion of HBV DNA to negativity, the rate of recovery of ALT to normal level, the rate of conversion of HBeAg to negativity, and serum HBeAg conversion rate were significantly higher in group C than in the other three groups, but no significant differences were observed among groups A, B and D (P > 0.05).
CONCLUSION Entecavir treatment is effective in patients with hepatitis B associated liver cirrhosis, and the efficacy is not influenced by genotype. Of antiviral treatments tested for chronic hepatitis B, lamivudine combined with adefovir acetate has the best efficacy.
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Shen X, Fu B, Liu Y, Guo C, Ye Y, Sun R, Li J, Tian Z, Wei H. NKp30 + NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B. Sci Rep 2016; 6:38778. [PMID: 27941937 PMCID: PMC5150634 DOI: 10.1038/srep38778] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 11/14/2016] [Indexed: 12/23/2022] Open
Abstract
A pressing need exists for improved therapeutic options for chronic hepatitis B (CHB). Pegylated-interferon-alpha (Peg-IFN-α) achieves sustained off-treatment responses in many cases because of its direct anti-viral effects and regulation of the immune response. However, non-responsiveness to Peg-IFN-α is frequent, and the mechanism is poorly understood. In this study, we found that the frequency and absolute number of NKp30+ natural killer (NK) cells increased markedly, accompanied by enhanced CD107a and IFN-γ production, during Peg-IFN-α-2b monotherapy or combination therapy with adefovir dipivoxil in patients with CHB, especially in responders. The responders and non-responders differed in the frequency of polyfunctional IFN-γ+ CD107+ NK cells. In addition, the increase in NKp30+ NK cells was negatively correlated with the HBV viral load and plasma HBeAg. Moreover, it was found that IL-15 may contribute to the up-regulation of NKp30 on the NK cells, and this up-regulation was not induced in vitro by Peg-IFN-α-2b alone. However, in the non-responders, these NKp30+ NK cells were dysfunctional because of increased NKG2A expression, which partly explains the inactivation of NKp30+ NK cells and the reduced capacity of these cells to produce antiviral cytokines. These findings may provide a new mechanism to explain the variable efficacy of Peg-IFN-α-2b therapy.
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Affiliation(s)
- Xiaokun Shen
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Binqing Fu
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yanyan Liu
- Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University and Chaohu Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Chuang Guo
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Ying Ye
- Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University and Chaohu Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Rui Sun
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Jiabin Li
- Department of Infectious Diseases, First Affiliated Hospital of Anhui Medical University and Chaohu Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhigang Tian
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui 230027, China
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Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice. J Virol 2016; 90:8563-74. [PMID: 27440883 PMCID: PMC5021417 DOI: 10.1128/jvi.01030-16] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 07/12/2016] [Indexed: 12/17/2022] Open
Abstract
In chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8+ T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication. Because of the known stimulatory properties of alpha interferon (IFN-α) and interleukin-15 (IL-15), this study explored the therapeutic potential of liver-directed gene transfer of these cytokines in a murine model of CHB using adeno-associated virus (AAV) delivery. This combination not only resulted in a reduction in the viral load in the liver and the induction of an antibody response but also gave rise to functional and specific CD8+ immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-α- and IL-15-treated animals were transferred to new HBV carriers, partial antiviral immunity was achieved. In contrast to previous observations made using either cytokine alone, markedly attenuated PD-L1 induction in hepatic tissue was observed upon coadministration. An initial study with CHB patient samples also gave promising results. Hence, we demonstrated synergy between two stimulating cytokines, IL-15 and IFN-α, which, given together, constitute a potent approach to significantly enhance the CD8+ T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions. IMPORTANCE With 350 million people affected worldwide and 600,000 annual deaths due to HBV-induced liver cirrhosis and/or hepatocellular carcinoma, chronic hepatitis B (CHB) is a major health problem. However, current treatment options are costly and not very effective and/or need to be administered for life. The unprecedented efficacy of the strategy described in our paper may offer an alternative and is relevant for a broad spectrum of readers because of its clear translational importance to other chronic viral infections in which a hyporesponsive antigen-specific T cell repertoire prevents clearance of the pathogen.
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Gill US, Peppa D, Micco L, Singh HD, Carey I, Foster GR, Maini MK, Kennedy PTF. Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo. PLoS Pathog 2016; 12:e1005788. [PMID: 27487232 PMCID: PMC4972354 DOI: 10.1371/journal.ppat.1005788] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 07/05/2016] [Indexed: 12/16/2022] Open
Abstract
NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg-positive CHB are 'primed' with PegIFNα and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48-weeks of PegIFNα was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Unexpectedly, PegIFNα-expanded NK cells showed further augmentation in their expression of the activating NK cell receptors NKp30 and NKp46 during sequential NUCs. The expansion in proliferating, functional NK cells was more pronounced following sequential NUCs than in comparison cohorts of patients treated with de novo NUCs or PegIFNα only. Reduction in circulating HBsAg concentrations, a key goal in the path towards functional cure of CHB, was only achieved in those patients with enhancement of NK cell IFNγ and cytotoxicity but decrease in their expression of the death ligand TRAIL. In summary, we conclude that PegIFNα priming can expand a population of functional NK cells with an altered responsiveness to subsequent antiviral suppression by NUCs. Patients on sequential NUCs with a distinct NK cell profile show a decline in HBsAg, providing mechanistic insights for the further optimisation of treatment strategies to achieve sustained responses in CHB.
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Affiliation(s)
- Upkar S. Gill
- Hepatology, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, London, United Kingdom
- Department of Hepatology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
| | - Dimitra Peppa
- Division of Infection & Immunity, UCL, London, United Kingdom
| | - Lorenzo Micco
- Division of Infection & Immunity, UCL, London, United Kingdom
| | | | - Ivana Carey
- Institute of Liver Studies, Kings College Hospital, London, United Kingdom
| | - Graham R. Foster
- Hepatology, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, London, United Kingdom
- Department of Hepatology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
| | - Mala K. Maini
- Division of Infection & Immunity, UCL, London, United Kingdom
- * E-mail: (MKM); (PTFK)
| | - Patrick T. F. Kennedy
- Hepatology, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, QMUL, London, United Kingdom
- Department of Hepatology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom
- * E-mail: (MKM); (PTFK)
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42
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Stelma F, Jansen L, Sinnige MJ, van Dort KA, Takkenberg RB, Janssen HLA, Reesink HW, Kootstra NA. HLA-C and KIR combined genotype as new response marker for HBeAg-positive chronic hepatitis B patients treated with interferon-based combination therapy. J Viral Hepat 2016; 23:652-9. [PMID: 26945896 DOI: 10.1111/jvh.12525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 01/20/2016] [Indexed: 12/24/2022]
Abstract
Current treatment for chronic hepatitis B infection (CHB) consists of interferon-based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy.
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Affiliation(s)
- F Stelma
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.,Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
| | - L Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.,Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
| | - M J Sinnige
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
| | - K A van Dort
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
| | - R B Takkenberg
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands
| | - H L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands.,Toronto Centre for Liver Disease, Toronto Western & General Hospital, University Health Network, Toronto, Canada
| | - H W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.,Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
| | - N A Kootstra
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, the Netherlands
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43
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Bruder Costa J, Dufeu-Duchesne T, Leroy V, Bertucci I, Bouvier-Alias M, Pouget N, Brevot-Lutton O, Bourliere M, Zoulim F, Plumas J, Aspord C, ANRS HB06 PEGAN study group. Pegylated Interferon α-2a Triggers NK-Cell Functionality and Specific T-Cell Responses in Patients with Chronic HBV Infection without HBsAg Seroconversion. PLoS One 2016; 11:e0158297. [PMID: 27348813 PMCID: PMC4922676 DOI: 10.1371/journal.pone.0158297] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment.
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Affiliation(s)
- Juliana Bruder Costa
- University Grenoble Alpes, Grenoble, F-38041 France; INSERM, U1209, Immunobiology and Immunotherapy of Chronic Deseases, La Tronche, F-38706 France
- CHU Grenoble, Michallon Hospital, Hepato-gastroenterology unit, Grenoble, F-38043 France
| | - Tania Dufeu-Duchesne
- CHU Grenoble, Michallon Hospital, Hepato-gastroenterology unit, Grenoble, F-38043 France
- University Grenoble Alpes, Grenoble, F-38041 France; INSERM, U1209, Analytic Immunology of chronic pathologies, La Tronche, F-38706 France
| | - Vincent Leroy
- CHU Grenoble, Michallon Hospital, Hepato-gastroenterology unit, Grenoble, F-38043 France
- University Grenoble Alpes, Grenoble, F-38041 France; INSERM, U1209, Analytic Immunology of chronic pathologies, La Tronche, F-38706 France
| | - Inga Bertucci
- ANRS (France REcherche Nord & sud Sida-hiv Hépatites: FRENSH), Paris, France
| | - Magali Bouvier-Alias
- Department of Virology, Henri Mondor Hospital, University Paris-Est and Inserm U955, Creteil, France
| | - Noelle Pouget
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), 75012, Paris, France
| | - Ophelie Brevot-Lutton
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), 75012, Paris, France
| | - Marc Bourliere
- Hepato-gastroenterology department Hospital Saint Joseph, Marseille, 13008 France
| | - Fabien Zoulim
- INSERM U1052—CNRS 5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- Hepatology Department, Hospices Civils de Lyon, Lyon, France
- Université de Lyon, Lyon, France
| | - Joel Plumas
- University Grenoble Alpes, Grenoble, F-38041 France; INSERM, U1209, Immunobiology and Immunotherapy of Chronic Deseases, La Tronche, F-38706 France
- EFS Rhone-Alpes, R&D Laboratory, La Tronche, F-38701 France
- * E-mail: (CA); (JP)
| | - Caroline Aspord
- University Grenoble Alpes, Grenoble, F-38041 France; INSERM, U1209, Immunobiology and Immunotherapy of Chronic Deseases, La Tronche, F-38706 France
- EFS Rhone-Alpes, R&D Laboratory, La Tronche, F-38701 France
- * E-mail: (CA); (JP)
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44
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Zou ZQ, Wang L, Wang K, Yu JG. Innate immune targets of hepatitis B virus infection. World J Hepatol 2016; 8:716-725. [PMID: 27330680 PMCID: PMC4911505 DOI: 10.4254/wjh.v8.i17.716] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/19/2016] [Accepted: 06/01/2016] [Indexed: 02/06/2023] Open
Abstract
Approximately 400 million people are chronically infected with hepatitis B virus (HBV) globally despite the widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.
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Affiliation(s)
- Zhi-Qiang Zou
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Li Wang
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Kai Wang
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
| | - Ji-Guang Yu
- Zhi-Qiang Zou, Li Wang, Ji-Guang Yu, Infectious Disease Hospital of Yantai, Yantai 264001, Shandong Province, China
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45
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Aspord C, Bruder Costa J, Jacob MC, Dufeu-Duchesne T, Bertucci I, Pouget N, Brevot-Lutton O, Zoulim F, Bourliere M, Plumas J, Leroy V, ANRS HB06 PEGAN study group. Remodeling of B-Cell Subsets in Blood during Pegylated IFNα-2a Therapy in Patients with Chronic Hepatitis B Infection. PLoS One 2016; 11:e0156200. [PMID: 27281019 PMCID: PMC4900671 DOI: 10.1371/journal.pone.0156200] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/10/2016] [Indexed: 01/09/2023] Open
Abstract
The ultimate goal of pegylated interferon-alfa-2a (Peg-IFN-α) therapy in chronic hepatitis B (CHB) infection is HBsAg seroconversion. Even though B cells are major mediators of a positive clinical outcome, their modulation during Peg-IFN-α therapy has not yet been described. We investigated here the effects of Peg-IFN-α on eight circulating B-cell subsets thanks to an original multi-gating approach based on CD19, CD27, IgD, CD10, and CD38 markers in patients with CHB treated with nucleos(t)ide analog alone or in combination with Peg-IFN-α. These dynamic changes were analyzed during the 48-weeks of Peg-IFN-α therapy and up to 2 years after the cessation of treatment. The CD19+CD27-IgD+CD10+CD38high transitional B cells and the CD19+CD27+IgD-CD10-CD38high plasmablasts continuously increased, whereas the CD19+CD27-IgD+CD10-CD38low naive, CD19+CD27+IgD+ natural memory, and CD19+CD27+IgD-CD10-CD38low post-germinal center B cells decreased during the course of Peg-IFNα treatment. Such modulations correlated with a sustained increase in sCD30 levels and the decrease in plasma HBsAg. However, no seroconversion occurred and all parameters returned to baseline after the stop of the treatment. Peg-IFN-α therapy mediates a remodeling of B-cell compartmentalization, without clinical relevance. Our study provides new insights into the immunomodulatory effects of Peg-IFN-α on circulating B-cells, and questioned the benefit of the add-on Peg-IFN-α treatment in CHB.
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Affiliation(s)
- Caroline Aspord
- University Joseph Fourier, Grenoble, F-38041, France; INSERM, U823, Immunobiology & Immunotherapy of Cancers, La Tronche, F-38706, France
- EFS Rhone-Alpes, R&D Laboratory, La Tronche, F-38701, France
- * E-mail:
| | - Juliana Bruder Costa
- University Joseph Fourier, Grenoble, F-38041, France; INSERM, U823, Immunobiology & Immunotherapy of Cancers, La Tronche, F-38706, France
- CHU Grenoble, Michallon Hospital, Hepato-gastroenterology unit, Grenoble, F-38043, France
| | - Marie-Christine Jacob
- University Joseph Fourier, Grenoble, F-38041, France; INSERM, U823, CRI/Institut Albert Bonniot, Grenoble, F-38000, France; Department of Immunology, CHU de Grenoble, Grenoble, F-38000, France
| | - Tania Dufeu-Duchesne
- CHU Grenoble, Michallon Hospital, Hepato-gastroenterology unit, Grenoble, F-38043, France
- University Joseph Fourier, Grenoble, F-38041, France; INSERM, U823, Analytic Immunology of chronic pathologies, La Tronche, F-38706, France
| | - Inga Bertucci
- ANRS (France REcherche Nord & sud Sida-hiv Hépatites: FRENSH), Paris, France
| | - Noelle Pouget
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), 75012, Paris, France
| | - Ophelie Brevot-Lutton
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), 75012, Paris, France
| | - Fabien Zoulim
- INSERM U1052—CNRS 5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- Hepatology Department, Hospices Civils de Lyon, Lyon, France
- Université de Lyon, Lyon, France
| | - Marc Bourliere
- Hepato-gastroenterology department, Hospital Saint Joseph, Marseille, 13008, France
| | - Joel Plumas
- University Joseph Fourier, Grenoble, F-38041, France; INSERM, U823, Immunobiology & Immunotherapy of Cancers, La Tronche, F-38706, France
- EFS Rhone-Alpes, R&D Laboratory, La Tronche, F-38701, France
| | - Vincent Leroy
- CHU Grenoble, Michallon Hospital, Hepato-gastroenterology unit, Grenoble, F-38043, France
- University Joseph Fourier, Grenoble, F-38041, France; INSERM, U823, Analytic Immunology of chronic pathologies, La Tronche, F-38706, France
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46
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Maini MK, Gehring AJ. The role of innate immunity in the immunopathology and treatment of HBV infection. J Hepatol 2016; 64:S60-S70. [PMID: 27084038 DOI: 10.1016/j.jhep.2016.01.028] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 01/20/2016] [Accepted: 01/25/2016] [Indexed: 02/06/2023]
Abstract
In this review we give a brief update on sensors recently determined to be capable of detecting HBV, and examine how the virus represses the induction of pro-inflammatory cytokines like type I interferons. We overview cellular components of innate immunity that are present at high frequencies in the liver, and discuss their roles in HBV control and/or pathogenesis. We argue that many innate effectors have adaptive-like features or can exert specific effects on HBV through immunoregulation of T cells. Finally we consider current and possible future strategies to manipulate innate immunity as novel approaches towards a functional cure for HBV.
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Affiliation(s)
- Mala K Maini
- Division of Infection and Immunity and Institute of Immunity and Transplantation, UCL, United Kingdom.
| | - Adam J Gehring
- Molecular Microbiology and Immunology Department, Saint Louis University School of Medicine, United States
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47
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Rosinsky C, Antony PA. A role for pre-mNK cells in tumor progression. J Immunother Cancer 2016; 4:16. [PMID: 26981246 PMCID: PMC4791770 DOI: 10.1186/s40425-016-0120-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 02/19/2016] [Indexed: 11/10/2022] Open
Abstract
The innate and adaptive immune systems have evolved together to fight infection and cancerous tissues. The innate immune system emerges first with the adaptive immune system following, both ostensibly being bridged by dendritic cells (DC). Recently cells have emerged that possess characteristics of both innate and adaptive immune cell qualities, termed interferon-producing killer dendritic cells (IKDCs). These cells have an indistinct origin that is not well understood. They appear to have more NK cell attributes than DC but purportedly can regulate the immune system similar to immunoregulatory NK cells. Because of this, they have been renamed pre-mNK cells (pre-mature NK cells). We argue in this commentary that pre-mNK cells may contribute to cancer recurrence.
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Affiliation(s)
- Carolyn Rosinsky
- Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 USA ; Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201 USA
| | - Paul Andrew Antony
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201 USA ; Department of Microbiology and Immunology, University of Maryland School of Medicine, 10 South Pine Street, 734D MSTF, Baltimore, MD 21201 USA ; Tumor Immunology and Immunotherapy Program, University of Maryland Cancer Center, Baltimore, MD 21201 USA
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48
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de Niet A, Stelma F, Jansen L, Sinnige MJ, Remmerswaal EBM, Takkenberg RB, Kootstra NA, Reesink HW, van Lier RAW, van Leeuwen EMM. Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy. J Hepatol 2016; 64:539-46. [PMID: 26505119 DOI: 10.1016/j.jhep.2015.10.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 09/30/2015] [Accepted: 10/12/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis B virus (HBV) infection is characterized by functional impairment of HBV-specific T cells. Understanding the mechanisms behind T cell dysfunction and restoration is important for the development of optimal treatment strategies. METHODS In this study we have first analysed the phenotype and function of HBV-specific T cells in patients with low viral load (HBV DNA <20,000IU/ml) and spontaneous control over the virus. Subsequently, we assessed HBV-specific T cells in patients with high viral load (HBV DNA >17,182IU/ml) treated with peginterferon/adefovir combination therapy who had various treatment outcomes. RESULTS HBV-specific T cells could be detected directly ex vivo in 7/22 patients with low viral load. These showed an early differentiated memory phenotype with reduced ability to produce IL-2 and cytotoxic molecules such as granzyme B and perforin, but with strong proliferative potential. In a cohort of 28 chronic hepatitis B patients with high viral load treated with peginterferon and adefovir, HBV-specific T cells could not be detected directly ex vivo. However, HBV-specific T cells could be selectively expanded in vitro in patients with therapy-induced HBsAg clearance (HBsAg loss n=7), but not in patients without HBsAg clearance (n=21). Further analysis of HBV-specific T cell function with peptide pools showed broad and efficient antiviral responses after therapy. CONCLUSIONS Our results show that peginterferon based combination therapy can induce HBV-specific T cell restoration. These findings may help to develop novel therapeutic strategies to reconstitute antiviral functions and enhance viral clearance.
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Affiliation(s)
- Annikki de Niet
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands
| | - Femke Stelma
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands
| | - Louis Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands
| | - Marjan J Sinnige
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands
| | - Ester B M Remmerswaal
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands
| | - R Bart Takkenberg
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands
| | - Neeltje A Kootstra
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands
| | - Hendrik W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands.
| | - Rene A W van Lier
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands; Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands
| | - Ester M M van Leeuwen
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands
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49
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Zhang E, Kosinska A, Lu M, Yan H, Roggendorf M. Current status of immunomodulatory therapy in chronic hepatitis B, fifty years after discovery of the virus: Search for the "magic bullet" to kill cccDNA. Antiviral Res 2015; 123:193-203. [PMID: 26476376 DOI: 10.1016/j.antiviral.2015.10.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/09/2015] [Accepted: 10/09/2015] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B (CHB) is currently treated with IFN-α and nucleos(t)ide analogues, which have many clinical benefits, but there is no ultimate cure. The major problem consists in the persistence of cccDNA in infected hepatocytes. Because no antiviral drug has been evaluated which significantly reduces copies of cccDNA, cytolytic and noncytolytic approaches are needed. Effective virus-specific T- and B-cell responses remain crucial in eliminating cccDNA-carrying hepatocytes and for the long-term control of HBV infection. Reduction of viremia by antiviral drugs provides a window for reconstitution of an HBV-specific immune response. Preclinical studies in mice and woodchucks have shown that immunostimulatory strategies, such as prime-boost vaccination and PD-1 blockade, can boost a weak virus-specific T cell response and lead to effective control of HBV infection. Based on data obtained in our preclinical studies, the combination of antiviral drugs and immunomodulators may control HBV viremia during a patient's drug-off period. In this article, we review current immune-modulatory approaches for the treatment of chronic hepatitis B and the elimination of cccDNA in preclinical models. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis".
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Affiliation(s)
- Ejuan Zhang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Anna Kosinska
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Huimin Yan
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Michael Roggendorf
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
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