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Rai P, Mehrotra S, Prajapati VK. Exploring immunotherapy to control human infectious diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 144:389-429. [PMID: 39978973 DOI: 10.1016/bs.apcsb.2024.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Infectious diseases continue to pose significant challenges to global health, especially with the rise of antibiotic resistance and emerging pathogens. Traditional treatments, while effective, are often limited in the face of rapidly evolving pathogens. Immunotherapy, which harnesses and enhances the body's immune response, offers a promising alternative to conventional approaches for the treatment of infectious diseases. By employing use of monoclonal antibodies, vaccines, cytokine therapies, and immune checkpoint inhibitors, immunotherapy has demonstrated considerable potential in overcoming treatment resistance and improving patient outcomes. Key innovations, including the development of mRNA vaccines, use of immune modulators, adoptive cell transfer, and chimeric antigen receptor (CAR)-T cell therapy are paving the way for more targeted pathogen clearance. Further, combining immunotherapy with conventional antibiotic treatment has demonstrated effectiveness against drug-resistant strains, but this chapter explores the evolving field of immunotherapy for the treatment of bacterial, viral, fungal, and parasitic infections. The chapter also explores the recent breakthroughs and ongoing clinical trials in infectious disease immunotherapy.
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Affiliation(s)
- Praveen Rai
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
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Ye X, Chen X, Liu H, Jiang Y, Yang C, Xu T, Chen Z, Wang Y, Chen F, Liu X, Yu H, Yuan Q, Xia N, Chen Y, Luo W. HBsAg and TLR7/8 dual-targeting antibody-drug conjugates induce sustained anti-HBV activity in AAV/HBV mice: a preliminary study. Antib Ther 2024; 7:249-255. [PMID: 39262443 PMCID: PMC11384142 DOI: 10.1093/abt/tbae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/13/2024] [Accepted: 06/28/2024] [Indexed: 09/13/2024] Open
Abstract
UNLABELLED Hepatitis B virus (HBV) infection is a significant global health concern due to elevated immunosuppressive viral antigen levels, the host immune system's inability to manage HBV, and the liver's immunosuppressive conditions. While immunotherapies utilizing broadly reactive HBV neutralizing antibodies present potential due to their antiviral capabilities and Fc-dependent vaccinal effects, they necessitate prolonged and frequent dosing to achieve optimal therapeutic outcomes. Toll-like receptor 7/8 (TLR7/8) agonists have been demonstrated promise for the cure of chronic hepatitis B, but their systemic use often leads to intense side effects. In this study, we introduced immune-stimulating antibody conjugates which consist of TLR7/8 agonists 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-imidazo[4,5-c]quinolin-4-amine (IMDQ) linked to an anti-hepatitis B surface antigen (HBsAg) antibody 129G1, and designated as 129G1-IMDQ. Our preliminary study highlights that 129G1-IMDQ can prompt robust and sustained anti-HBsAg specific reactions with short-term administration. This underscores the conjugate's potential as an effective strategy for HBsAg clearance and seroconversion, offering a fresh perspective for a practical therapeutic approach in the functional cure of CHB. HIGHLIGHTS HBV-neutralizing antibody 129G1 was linked with a TLR7/8 agonist small molecule compound IMDQ.Treatment with 129G1-IMDQ has shown significant promise in lowering HBsAg levels in AAV/HBV mice.129G1-IMDQ were eliciting a strong and lasting anti-HBsAg immune response after short-term treatment in AAV/HBV mice.
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Affiliation(s)
- Xinya Ye
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xiaoqing Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Han Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yichao Jiang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Chengyu Yang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Tao Xu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Ziyou Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yalin Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Fentian Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xue Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Hai Yu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Quan Yuan
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yuanzhi Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Wenxin Luo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, Xiamen University, Xiamen 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China
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Gopalakrishna H, Ghany MG. Perspective on Emerging Therapies to Achieve Functional Cure of Chronic Hepatitis B. CURRENT HEPATOLOGY REPORTS 2024; 23:241-252. [PMID: 38699562 PMCID: PMC11062629 DOI: 10.1007/s11901-024-00652-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/24/2024] [Indexed: 05/05/2024]
Abstract
Purpose of Review Advancements in our understanding of the hepatitis B viral (HBV) life cycle have paved the way for novel approaches to treat HBV infection. This review summarizes the various strategies being pursued to achieve a functional cure, defined as loss of hepatitis B surface antigen (HBsAg) and absence of viral replication 6 months off-therapy. Recent Findings Direct acting antiviral, host targeting antiviral, and immunological approaches are in various stages of development as treatment for chronic HBV infection. Summary Novel treatments are being developed in pursuit of a cure for HBV. Current evidence suggests a single therapeutic agent alone may be insufficient, necessitating the need for combination therapy targeting HBV and the host immune response. Ongoing research focused on identifying the best therapeutic combination holds promise in achieving functional cure for HBV.
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Affiliation(s)
- Harish Gopalakrishna
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9B-16, Bethesda, MD 20892‐1800, USA
| | - Marc G. Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 9B-16, Bethesda, MD 20892‐1800, USA
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Gehring AJ, Salimzadeh L. Current and future use of antibody-based passive immunity to prevent or control HBV/HDV infections. Antiviral Res 2024; 226:105893. [PMID: 38679166 DOI: 10.1016/j.antiviral.2024.105893] [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: 01/01/2024] [Revised: 04/19/2024] [Accepted: 04/22/2024] [Indexed: 05/01/2024]
Abstract
With the increasing momentum and success of monoclonal antibody therapy in conventional medical practices, there is a revived emphasis on the development of monoclonal antibodies targeting the hepatitis B surface antigen (anti-HBs) for the treatment of chronic hepatitis B (HBV) and hepatitis D (HDV). Combination therapies of anti-HBs monoclonal antibodies, and novel anti-HBV compounds and immunomodulatory drugs presenting a promising avenue to enhanced therapeutic outcomes in HBV/HDV cure regimens. In this review, we will cover the role of antibodies in the protection and clearance of HBV infection, the association of anti-HBV surface antigen antibodies (anti-HBs) in protection against HBV and how antibody effector functions, beyond neutralization, are likely necessary. Lastly, we will review clinical data from previous and ongoing clinical trials of passive antibody therapy to provide a state-of-the-are perspective on passive antibody therapies in combinations with additional novel agents.
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Affiliation(s)
- Adam J Gehring
- Schwartz-Reisman Liver Research Centre, University Health Network, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada.
| | - Loghman Salimzadeh
- Schwartz-Reisman Liver Research Centre, University Health Network, Toronto, ON, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
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Janssen HL, Lim YS, Kim HJ, Sowah L, Tseng CH, Coffin CS, Elkhashab M, Ahn SH, Nguyen AH, Chen D, Wallin JJ, Fletcher SP, McDonald C, Yang JC, Gaggar A, Brainard DM, Fung S, Kim YJ, Kao JH, Chuang WL, Brooks AE, Dunbar PR. Safety, pharmacodynamics, and antiviral activity of selgantolimod in viremic patients with chronic hepatitis B virus infection. JHEP Rep 2024; 6:100975. [PMID: 38274492 PMCID: PMC10808922 DOI: 10.1016/j.jhepr.2023.100975] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/24/2023] [Accepted: 11/06/2023] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND & AIMS Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF). METHODS Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.5 mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log10 IU/ml HBsAg decline at W24. RESULTS Sixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events. Most adverse events were grade 1. Alanine aminotransferase flares were not observed up to W48. Four patients experienced alanine aminotransferase and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. Mean HBsAg changes were -0.12, -0.16, and -0.12 log10 IU/ml in the selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo groups, respectively, at W48; HBV DNA declined in all groups by ≥2 log10 IU/ml as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU. CONCLUSIONS Selgantolimod up to 3 mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies. IMPACT AND IMPLICATIONS Novel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a TLR8) when administered with tenofovir alafenamide over 24 weeks in viremic patients with chronic HBV infection. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase levels greater than the upper limit of normal had significantly greater declines compared to those with normal alanine aminotransferase levels (-0.20 vs. -0.03 log10 IU/ml; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways. CLINICAL TRIAL NUMBER NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/.
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Affiliation(s)
- Harry L. Janssen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
- Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Young-Suk Lim
- Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hyung Joon Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea
| | | | - Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Carla S. Coffin
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Sang Hoon Ahn
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | | | - Diana Chen
- Gilead Sciences, Inc., Foster City, CA, USA
| | | | | | | | | | | | | | - Scott Fung
- Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Anna E. Brooks
- School of Biological Sciences, and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand
| | - P. Rod Dunbar
- School of Biological Sciences, and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand
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Kayesh MEH, Kohara M, Tsukiyama-Kohara K. TLR agonists as vaccine adjuvants in the prevention of viral infections: an overview. Front Microbiol 2023; 14:1249718. [PMID: 38179453 PMCID: PMC10764465 DOI: 10.3389/fmicb.2023.1249718] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 12/01/2023] [Indexed: 01/06/2024] Open
Abstract
Tol-like receptor (TLR) agonists, as potent adjuvants, have gained attention in vaccine research for their ability to enhance immune responses. This study focuses on their application in improving vaccine efficacy against key viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and flaviviruses, including West Nile virus, dengue virus, and chikungunya virus. Vaccines are crucial in preventing microbial infections, including viruses, and adjuvants play a vital role in modulating immune responses. However, there are still many diseases for which effective vaccines are lacking or have limited immune response, posing significant threats to human health. The use of TLR agonists as adjuvants in viral vaccine formulations holds promise in improving vaccine effectiveness. By tailoring adjuvants to specific pathogens, such as HBV, HCV, HIV, SARS-CoV-2, influenza virus, and flavivirus, protective immunity against chronic and emerging infectious disease can be elicited.
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Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, Bangladesh
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan
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Asselah T. What is the Path Forward to Treat Hepatitis Delta Virus?: Old Treatments and New Options. Clin Liver Dis 2023; 27:985-995. [PMID: 37778781 DOI: 10.1016/j.cld.2023.05.012] [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] [Indexed: 10/03/2023]
Abstract
HDV use the cell enzymes for its own replication, and the HBsAg as an envelope. There is an urgent need to develop new drugs for chronic hepatitis D (CHD). Pegylated interferon alpha (PEG-IFNα) (direct-antiviral and immune modulator) has been used and recommended by scientific guidelines, although not approved, with moderate efficacy and poor tolerability. There are several drugs in development which target the host: bulevirtide (BLV), lonafarnib (LNF), nucleic acid polymer, and others.
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Affiliation(s)
- Tarik Asselah
- University of Paris-Cité, Hôpital Beaujon, Service d'hépatologie AP-HP & INSERM UMR1149, Clichy, France.
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Rossi M, Vecchi A, Tiezzi C, Barili V, Fisicaro P, Penna A, Montali I, Daffis S, Fletcher SP, Gaggar A, Medley J, Graupe M, Lad L, Loglio A, Soffredini R, Borghi M, Pollicino T, Musolino C, Alfieri A, Brillo F, Laccabue D, Massari M, Boarini C, Abbati G, Pedrazzi G, Missale G, Lampertico P, Ferrari C, Boni C. Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro. Gut 2023; 72:2123-2137. [PMID: 36717219 PMCID: PMC10579518 DOI: 10.1136/gutjnl-2022-327202] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 12/29/2022] [Indexed: 02/01/2023]
Abstract
OBJECTIVE Exhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function. DESIGN HBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients. RESULTS Severely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2. CONCLUSIONS The possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.
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Affiliation(s)
- Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Vecchi
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Camilla Tiezzi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Valeria Barili
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Ilaria Montali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | | | - Anuj Gaggar
- Gilead Sciences Inc, Foster City, California, USA
| | | | | | - Latesh Lad
- Gilead Sciences Inc, Foster City, California, USA
| | - Alessandro Loglio
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Roberta Soffredini
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Marta Borghi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Teresa Pollicino
- Department of Human Pathology, University Hospital of Messina, Messina, Italy
| | - Cristina Musolino
- Department of Human Pathology, University Hospital of Messina, Messina, Italy
| | - Arianna Alfieri
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Federica Brillo
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Diletta Laccabue
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Marco Massari
- Unit of Infectious Diseases, IRCCS, Reggio Emilia, Italy
| | - Chiara Boarini
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
| | - Gianluca Abbati
- Division of Internal Medicine 2 and Center for Hemochromatosis, University of Modena and Reggio Emilia, Modena, Italy
| | - Giuseppe Pedrazzi
- Department of Neuroscience - Biophysics and Medical Physics Unit, University of Parma, Parma, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
- Department of Pathophysiology and Transplantation, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milano, Italy
| | - Carlo Ferrari
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Carolina Boni
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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Michalak TI. The Initial Hepatitis B Virus-Hepatocyte Genomic Integrations and Their Role in Hepatocellular Oncogenesis. Int J Mol Sci 2023; 24:14849. [PMID: 37834296 PMCID: PMC10573506 DOI: 10.3390/ijms241914849] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 09/30/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatitis B virus (HBV) remains a dominant cause of hepatocellular carcinoma (HCC). Recently, it was shown that HBV and woodchuck hepatitis virus (WHV) integrate into the hepatocyte genome minutes after invasion. Retrotransposons and transposable sequences were frequent sites of the initial insertions, suggesting a mechanism for spontaneous HBV DNA dispersal throughout the hepatocyte genome. Several somatic genes were also identified as early insertional targets in infected hepatocytes and woodchuck livers. Head-to-tail joints (HTJs) dominated amongst fusions, indicating their creation by non-homologous end-joining (NHEJ). Their formation coincided with the robust oxidative damage of hepatocyte DNA. This was associated with the activation of poly(ADP-ribose) polymerase 1 (PARP1)-mediated dsDNA repair, as reflected by the augmented transcription of PARP1 and XRCC1; the PARP1 binding partner OGG1, a responder to oxidative DNA damage; and increased activity of NAD+, a marker of PARP1 activation, and HO1, an indicator of cell oxidative stress. The engagement of the PARP1-mediated NHEJ repair pathway explains the HTJ format of the initial merges. The findings show that HBV and WHV are immediate inducers of oxidative DNA damage and hijack dsDNA repair to integrate into the hepatocyte genome, and through this mechanism, they may initiate pro-oncogenic processes. Tracking initial integrations may uncover early markers of HCC and help to explain HBV-associated oncogenesis.
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Affiliation(s)
- Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Science, Faculty of Medicine, Health Science Center, Memorial University of Newfoundland, St. John's, NL A1B 3V6, Canada
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10
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Yi Q, Yang J, Wu Y, Wang Y, Cao Q, Wen W. Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells. Front Immunol 2023; 14:1204524. [PMID: 37539053 PMCID: PMC10395751 DOI: 10.3389/fimmu.2023.1204524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/21/2023] [Indexed: 08/05/2023] Open
Abstract
Cirrhosis is a progressive and diffuse liver disease characterized by liver tissue fibrosis and impaired liver function. This condition is brought about by several factors, including chronic hepatitis, hepatic steatosis, alcohol abuse, and other immunological injuries. The pathogenesis of liver cirrhosis is a complex process that involves the interaction of various immune cells and cytokines, which work together to create the hepatic homeostasis imbalance in the liver. Some studies have indicated that alterations in the immune microenvironment of liver cirrhosis are closely linked to the development and prognosis of the disease. The noteworthy function of mesenchymal stem cells and their paracrine secretion lies in their ability to promote the production of cytokines, which in turn enhance the self-repairing capabilities of tissues. The objective of this review is to provide a summary of the alterations in liver homeostasis and to discuss intercellular communication within the organ. Recent research on MSCs is yielding a blueprint for cell typing and biomarker immunoregulation. Hopefully, as MSCs researches continue to progress, novel therapeutic approaches will emerge to address cirrhosis.
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Affiliation(s)
- Qiuyun Yi
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- International Cooperation Laboratory on Signal Transduction, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Jinxian Yang
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- International Cooperation Laboratory on Signal Transduction, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Ying Wu
- Department of Breast and Thyroid Surgery, Changhai Hospital, Naval Military Medical University, Shanghai, China
| | - Ying Wang
- Department of Laboratory Diagnosis, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Qiqi Cao
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- International Cooperation Laboratory on Signal Transduction, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wen Wen
- National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Laboratory Diagnosis, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, China
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11
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Schlaak JF. Current Therapy of Chronic Viral Hepatitis B, C and D. J Pers Med 2023; 13:964. [PMID: 37373953 DOI: 10.3390/jpm13060964] [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: 03/25/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular carcinoma (HCC). HBV infection is well controlled by the currently available nucleosides as well as nucleotides, and the development of cirrhosis can be prevented. Additionally, it has been shown that HBV-induced liver fibrosis can regress during successful antiviral treatment; however, a "functional cure", i.e., loss of HBsAg, is a rare event when these drugs are used. Therefore, novel therapeutic strategies are aiming at the selective suppression of HBsAg levels in combination with immunostimulation. The development of directly acting antivirals (DAAs) has revolutionized HCV therapy, as almost all patients can be cured via this treatment. Additionally, DAA therapy has few, if any, side effects, and is generally well tolerated by patients. HDV remains the most challenging type of chronic viral hepatitis. Although novel therapeutic options have recently been approved, response rates are still less favorable compared to HBV and HCV. This review discusses current and future options for the treatment of chronic HBV, HCV, and HDV infection.
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Affiliation(s)
- Jörg F Schlaak
- Department of Internal Medicine, Ameos Hospital Oberhausen, Wilhelmstr. 34, 46145 Oberhausen, Germany
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12
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Khan N, Almajed MR, Fitzmaurice MG, Jafri SM. Developments in pharmacotherapeutic agents for hepatitis B - how close are we to a functional cure? Expert Opin Pharmacother 2023; 24:1001-1011. [PMID: 37163255 DOI: 10.1080/14656566.2023.2211259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
INTRODUCTION Hepatitis B virus (HBV) remains a public health concern given its global prevalence and potential complications including hepatocellular carcinoma (HCC). Current therapies, including nucleos(t)ide analogs (NA) and interferons (IFN), are effective in chronic treatment of HBV but rarely provide a functional cure due to inadequate host response and the presence of viral DNA. Therefore, novel therapies that enhance the innate immune response while suppressing DNA transcription may provide definitive treatment of HBV. AREAS COVERED In this review, the authors provide a brief overview of commonly used agents and their efficacy in treatment of HBV. Newer therapies with direct antiviral agents such as bepirovirsen (antisense oligonucleotide (ASO)) and entry inhibitors such as bulevirtide have shown efficacy in reducing viral load but demonstrate further reductions in conjunction with immune modulators such as therapeutic vaccines. EXPERT OPINION Combination therapy is far superior to monotherapy alone, necessitating the need for both immunomodulators and direct antiviral agents in chronic treatment of HBV. Therapies that target covalently closed circular (cccDNA) with immunomodulators like therapeutic vaccines have shown promising results and may ultimately achieve functional cure. However, therapies need to be evaluated in the context of the patient, considering both financial and socioeconomic factors.
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Affiliation(s)
- Naoshin Khan
- Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
| | - Mohamed Ramzi Almajed
- Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
| | - Mary Grace Fitzmaurice
- Pharmacy Department and Transplant Institute, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
| | - Syed-Mohammed Jafri
- Division of Gastroenterology and Hepatology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA
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13
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Pan Y, Xia H, He Y, Zeng S, Shen Z, Huang W. The progress of molecules and strategies for the treatment of HBV infection. Front Cell Infect Microbiol 2023; 13:1128807. [PMID: 37009498 PMCID: PMC10053227 DOI: 10.3389/fcimb.2023.1128807] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/03/2023] [Indexed: 03/17/2023] Open
Abstract
Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis B virus (HBV)-related diseases resulted in approximately 555,000 deaths globally. In view of its high lethality, the treatment of HBV infections has always presented a huge challenge. The World Health Organization (WHO) came up with ambitious targets for the elimination of hepatitis B as a major public health threat by 2030. To accomplish this goal, one of the WHO's strategies is to develop curative treatments for HBV infections. Current treatments in a clinical setting included 1 year of pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both treatments have demonstrated outstanding antiviral effects, it has been difficult to develop a cure for HBV. The reason for this is that covalently closed circular DNA (cccDNA), integrated HBV DNA, the high viral burden, and the impaired host immune responses all hinder the development of a cure for HBV. To overcome these problems, there are clinical trials on a number of antiviral molecules being carried out, all -showing promising results so far. In this review, we summarize the functions and mechanisms of action of various synthetic molecules, natural products, traditional Chinese herbal medicines, as clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), all of which could destroy the stability of the HBV life cycle. In addition, we discuss the functions of immune modulators, which can enhance or activate the host immune system, as well some representative natural products with anti-HBV effects.
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Affiliation(s)
| | | | | | | | | | - Wenhai Huang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
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14
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Gane EJ, Dunbar PR, Brooks AE, Zhang F, Chen D, Wallin JJ, van Buuren N, Arora P, Fletcher SP, Tan SK, Yang JC, Gaggar A, Kottilil S, Tang L. Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression. J Hepatol 2023; 78:513-523. [PMID: 38133554 DOI: 10.1016/j.jhep.2022.09.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 09/08/2022] [Accepted: 09/30/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND & AIMS Selgantolimod (GS-9688) is a Toll-like receptor 8 (TLR8) agonist that suppresses HBV in vitro. In a phase II study, we evaluated the safety and efficacy of weekly selgantolimod treatment in virally suppressed individuals with chronic HBV taking oral antiviral treatment. METHODS Forty-eight patients were randomized into two cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n = 24 each]) to receive oral selgantolimod 3 mg, 1.5 mg, or placebo (2:2:1) once weekly for 24 weeks while maintaining oral antivirals. The primary efficacy endpoint was the percentage of patients with a ≥1 log10 IU/ml decline in hepatitis B surface antigen (HBsAg) from baseline to week 24. Post-treatment, patients continued on oral antivirals for 24 weeks. RESULTS The primary endpoint was reached by one participant, who was HBeAg-negative and received selgantolimod 1.5 mg. In contrast with placebo-treated patients (n = 9), only selgantolimod-treated patients (n = 39 total) had HBsAg declines greater than 0.1 log10 IU/ml at weeks 24 (18%, 7/39) and 48 (26%, 10/39), HBsAg loss (5%, 2/39 through 48 weeks), or HBeAg loss (16%, 3/19 through 48 weeks). The most common adverse events in selgantolimod-treated groups were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders were mostly mild and transient. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40, IFN-γ, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets. CONCLUSION Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in two individuals by week 48. CLINICALTRIALS GOV IDENTIFIER NCT03491553. IMPACT AND IMPLICATIONS The only robust criterion for stopping treatment in chronic hepatitis B is loss of hepatitis B surface antigen (known as functional cure), which is rare during nucleos(t)ide analogue therapy. It is likely that novel antiviral and immunomodulatory therapies will be needed to achieve finite functional cure. Selgantolimod is an oral Toll-like receptor 8 agonist that has shown antiviral activity in vitro as well as safety in a phase I clinical trial with weekly dosing. In this phase II study, selgantolimod therapy was associated with transient increases in serum cytokines, rapid redistribution of circulating immune cell subsets, modest reductions in HBsAg and HBeAg levels, and occasional loss of HBsAg (5%) and HBeAg (16%) among participants with chronic hepatitis B on nucleos(t)ide analogue therapy with viral suppression. Our results support continued development of selgantolimod as a component of a future hepatitis B cure regimen.
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Affiliation(s)
| | - P Rod Dunbar
- School of Biological Sciences, Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand
| | - Anna E Brooks
- School of Biological Sciences, Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand
| | | | - Diana Chen
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | | | | | | | - Jenny C Yang
- Gilead Sciences, Inc., Foster City, California, USA
| | - Anuj Gaggar
- Gilead Sciences, Inc., Foster City, California, USA
| | - Shyamasundaran Kottilil
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Program in Oncology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, USA
| | - Lydia Tang
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Program in Oncology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, USA
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15
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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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16
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Cai J, Li Y, Hu P, Xu R, Yuan H, Zhang W, Feng T, Liu R, Li W, Zhu C. Plerixafor and resatorvid inhibit hepatitis B virus in vitro by upregulating elongation factor Tu GTP-binding domain containing 2. Front Cell Infect Microbiol 2023; 13:1118801. [PMID: 36891156 PMCID: PMC9986551 DOI: 10.3389/fcimb.2023.1118801] [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: 12/08/2022] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Background An increase in the demand for a functional cure has accelerated research on new methods of therapy for chronic hepatitis B, which is mainly focused on restoring antiviral immunity for controlling viral infections. Previously, we had described elongation factor Tu GTP-binding domain containing 2 (EFTUD2) as an innate immune regulator and suggested that it might be an antiviral target. Methods In this study, we generated the Epro-LUC-HepG2 cell model for screening compounds that target EFTUD2. Plerixafor and resatorvid were screened from 261 immunity and inflammation-related compounds due to their ability to highly upregulate EFTUD2. The effects of plerixafor and resatorvid on hepatitis B virus (HBV) were examined in HepAD38 cells and HBV-infected HepG2-NTCP cells. Results The dual-luciferase reporter assays showed that the EFTUD2 promoter hEFTUD2pro-0.5 kb had the strongest activity. In Epro-LUC-HepG2 cells, plerixafor and resatorvid significantly upregulated the activity of the EFTUD2 promoter and the expression of the gene and protein. In HepAD38 cells and HBV-infected HepG2-NTCP cells, treatment with plerixafor and resatorvid strongly inhibited HBsAg, HBV DNA, HBV RNAs, and cccDNA in a dose-dependent manner. Furthermore, the anti-HBV effect was enhanced when entecavir was administered along with either of the previous two compounds, and the effect could be blocked by knocking down EFTUD2. Conclusion We established a convenient model for screening compounds that target EFTUD2 and further identified plerixafor and resatorvid as novel HBV inhibitors in vitro. Our findings provided information on the development of a new class of anti-HBV agents that act on host factors rather than viral enzymes.
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Affiliation(s)
- Jinyuan Cai
- 1Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Infectious Disease, Zhongda Hospital, Southeast University, Nanjing, China
| | - Yuwen Li
- Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pingping Hu
- Department of Infectious Disease, Zhongda Hospital, Southeast University, Nanjing, China
| | - Ruirui Xu
- Department of Infectious Disease, Zhongda Hospital, Southeast University, Nanjing, China
| | - Hui Yuan
- Department of Infectious Disease, Zhongda Hospital, Southeast University, Nanjing, China
| | - Wen Zhang
- Department of Infectious Disease, Zhongda Hospital, Southeast University, Nanjing, China
| | - Tiantong Feng
- Department of Infectious Disease, Zhongda Hospital, Southeast University, Nanjing, China
| | - Rui Liu
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Wenting Li
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Chuanlong Zhu
- 1Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Department of Infectious and Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
- *Correspondence: Chuanlong Zhu,
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17
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Yardeni D, Chang KM, Ghany MG. Current Best Practice in Hepatitis B Management and Understanding Long-term Prospects for Cure. Gastroenterology 2023; 164:42-60.e6. [PMID: 36243037 PMCID: PMC9772068 DOI: 10.1053/j.gastro.2022.10.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 09/25/2022] [Accepted: 10/04/2022] [Indexed: 02/03/2023]
Abstract
The hepatitis B virus (HBV) is a major cause of cirrhosis and hepatocellular carcinoma worldwide. Despite an effective vaccine, the prevalence of chronic infection remains high. Current therapy is effective at achieving on-treatment, but not off-treatment, viral suppression. Loss of hepatitis B surface antigen, the best surrogate marker of off-treatment viral suppression, is associated with improved clinical outcomes. Unfortunately, this end point is rarely achieved with current therapy because of their lack of effect on covalently closed circular DNA, the template of viral transcription and genome replication. Major advancements in our understanding of HBV virology along with better understanding of immunopathogenesis have led to the development of a multitude of novel therapeutic approaches with the prospect of achieving functional cure (hepatitis B surface antigen loss) and perhaps complete cure (clearance of covalently closed circular DNA and integrated HBV DNA). This review will cover current best practice for managing chronic HBV infection and emerging novel therapies for HBV infection and their prospect for cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Kyong-Mi Chang
- Medical Research, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
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18
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Asselah T. Beyond bulevirtide: Alternative therapeutic options for the management of hepatitis delta virus. J Viral Hepat 2022; 30 Suppl 1:33-38. [PMID: 36529713 DOI: 10.1111/jvh.13789] [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: 11/17/2022] [Accepted: 12/08/2022] [Indexed: 01/06/2023]
Abstract
Hepatitis delta virus (HDV) is a small RNA virus which needs Hepatitis B Surface Antigen for its envelope, for entry into hepatocytes and secretion. HDV chronic infection affects around 12 million people worldwide. HDV infection is believed to be the most severe form of viral hepatitis, with a high risk of developing cirrhosis and hepatocellular carcinoma. Pegylated interferons has been used and recommended by guidelines, although not approved, with low efficacy and poor tolerability. Bulevirtide (entry inhibitor) has been recently conditionally approved by the European Medicines Agency. These treatments have many advantages, but they have also limitations since there are non-responders to these previous therapies. There is an urgent need to develop new drugs. In this article, we review antiviral treatments under development for HDV chronic infection (except bulevirtide reviewed in a specific article), including those in the HBV cure programme, outlining their respective mechanisms-of-action.
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Affiliation(s)
- Tarik Asselah
- Université de Paris-Cité, Department of Hepatology, Hôpital Beaujon, AP-HP, CRI, INSERM UMR 1149, Clichy, France
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19
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Sun H, Li Y, Zhang P, Xing H, Zhao S, Song Y, Wan D, Yu J. Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives. Biomark Res 2022; 10:89. [PMID: 36476317 PMCID: PMC9727882 DOI: 10.1186/s40364-022-00436-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are a large family of proteins that are expressed in immune cells and various tumor cells. TLR7/8 are located in the intracellular endosomes, participate in tumor immune surveillance and play different roles in tumor growth. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response in the highly sophisticated process of innate immunity signaling with the recent research advances involving the small molecule activation of TLR 7 and 8. The wide range of expression and clinical significance of TLR7/TLR8 in different kinds of cancers have been extensively explored. TLR7/TLR8 can be used as novel diagnostic biomarkers, progression and prognostic indicators, and immunotherapeutic targets for various tumors. Although the mechanism of action of TLR7/8 in cancer immunotherapy is still incomplete, TLRs on T cells are involved in the regulation of T cell function and serve as co-stimulatory molecules and activate T cell immunity. TLR agonists can activate T cell-mediated antitumor responses with both innate and adaptive immune responses to improve tumor therapy. Recently, novel drugs of TLR7 or TLR8 agonists with different scaffolds have been developed. These agonists lead to the induction of certain cytokines and chemokines that can be applied to the treatment of some diseases and can be used as good adjutants for vaccines. Furthermore, TLR7/8 agonists as potential therapeutics for tumor-targeted immunotherapy have been developed. In this review, we summarize the recent advances in the development of immunotherapy strategies targeting TLR7/8 in patients with various cancers and chronic hepatitis B.
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Affiliation(s)
- Hao Sun
- Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yingmei Li
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Peng Zhang
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Haizhou Xing
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Song Zhao
- Department of Thoracic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yongping Song
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Dingming Wan
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Jifeng Yu
- Department of Hematology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
- Henan International Joint Laboratory of Nuclear Protein Gene Regulation, Henan University College of Medicine, Kaifeng, 475004 Henan China
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20
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Corkum CP, Wiede LL, Ruble CLA, Qiu J, Mulrooney-Cousins PM, Steeves MA, Watson DE, Michalak TI. Identification of antibodies cross-reactive with woodchuck immune cells and activation of virus-specific and global cytotoxic T cell responses by anti-PD-1 and anti-PD-L1 in experimental chronic hepatitis B and persistent occult hepadnaviral infection. Front Microbiol 2022; 13:1011070. [PMID: 36560951 PMCID: PMC9764628 DOI: 10.3389/fmicb.2022.1011070] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022] Open
Abstract
Woodchuck (Marmota monax) infected with woodchuck hepatitis virus (WHV) is the most pathogenically compatible naturally occurring model of human hepatitis B virus (HBV) infection, chronic hepatitis B, and HBV-induced hepatocellular carcinoma. This system plays a crucial role in discovery and preclinical evaluation of anti-HBV therapies. Its utilization remains tempered by the relatively narrow range of validated immunologic and molecular tools. We evaluated commercial antibodies against immune cell phenotypic markers and T cell molecules for cross-reactivity with woodchuck antigenic equivalents. The confirmed antibodies against programed cell death protein-1 (PD-1) and its ligand (PD-L1) were examined for ex vivo ability to activate WHV-specific, global and bystander cytotoxic T cells (CTLs) in chronic hepatitis and asymptomatic infection persisting after self-resolved acute hepatitis. Examination of 65 antibodies led to identification or confirmation of 23 recognizing woodchuck T, regulatory T, B and natural killer cells, T cell-associated PD-1, PD-L1, CTLA-4 and TIM-3 molecules, CD25 and CD69 markers of T cell activation, and interferon gamma (IFNγ). Antibodies against woodchuck PD-1 and PD-L1 triggered in vitro highly individualized WHV-specific and global activation of CTLs in both chronic hepatitis and persistent occult infection. WHV-specific CTLs were more robustly augmented by anti-PD-1 than by anti-PD-L1 in chronic hepatitis, while global IFNγ-positive CTL response was significantly suppressed in chronic hepatitis compared to persistent occult infection. Anti-PD-1 and anti-PD-L1 also occasionally activated CTLs to specificities other than those tested suggesting their potency to trigger side effects. This was particularly apparent when T cells from chronic hepatitis were treated with anti-PD-L1. The current findings indicate that inhibition of the PD-1/PD-L1 pathway could reactivate virus-specific and global T cell responses in both chronic hepatitis and asymptomatic persistent infection. They suggest a mechanism of potential reactivation of clinically silent infection during anti-PD-1/PD-L1 treatment and indicate that this therapy may also subdue occult HBV infection.
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Affiliation(s)
- Christopher P. Corkum
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Louisa L. Wiede
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Cara L.-A. Ruble
- Lilly Research Laboratories, Elli Lilly and Company, Indianapolis, IN, United States
| | - Jiabin Qiu
- Lilly Research Laboratories, Elli Lilly and Company, Indianapolis, IN, United States
| | - Patricia M. Mulrooney-Cousins
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Meredith A. Steeves
- Non-Clinical Safety Assessment, Toxicology, Elli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, United States
| | - David E. Watson
- Lilly Research Laboratories, Elli Lilly and Company, Indianapolis, IN, United States
| | - Tomasz I. Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John’s, NL, Canada,*Correspondence: Tomasz I. Michalak,
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21
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Wang D, Fu B, Wei H. Advances in Immunotherapy for Hepatitis B. Pathogens 2022; 11:1116. [PMID: 36297173 PMCID: PMC9612046 DOI: 10.3390/pathogens11101116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/26/2023] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus with the potential to cause chronic infection, and it is one of the common causes of liver disease worldwide. Chronic HBV infection leads to liver cirrhosis and, ultimately, hepatocellular carcinoma (HCC). The persistence of covalently closed circular DNA (cccDNA) and the impaired immune response in patients with chronic hepatitis B (CHB) has been studied over the past few decades. Despite advances in the etiology of HBV and the development of potent virus-suppressing regimens, a cure for HBV has not been found. Both the innate and adaptive branches of immunity contribute to viral eradication. However, immune exhaustion and evasion have been demonstrated during CHB infection, although our understanding of the mechanism is still evolving. Recently, the successful use of an antiviral drug for hepatitis C has greatly encouraged the search for a cure for hepatitis B, which likely requires an approach focused on improving the antiviral immune response. In this review, we discuss our current knowledge of the immunopathogenic mechanisms and immunobiology of HBV infection. In addition, we touch upon why the existing therapeutic approaches may not achieve the goal of a functional cure. We also propose how combinations of new drugs, and especially novel immunotherapies, contribute to HBV clearance.
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Affiliation(s)
- Dongyao Wang
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230001, China
- Anhui Provincial Key Laboratory of Blood Research and Applications, Hefei 230001, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu 233030, China
| | - Binqing Fu
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230001, China
| | - Haiming Wei
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
- Blood and Cell Therapy Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei 230001, China
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22
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Suresh M, Menne S. Recent Drug Development in the Woodchuck Model of Chronic Hepatitis B. Viruses 2022; 14:v14081711. [PMID: 36016334 PMCID: PMC9416195 DOI: 10.3390/v14081711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/24/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is responsible for the increasing global hepatitis burden, with an estimated 296 million people being carriers and living with the risk of developing chronic liver disease and cancer. While the current treatment options for chronic hepatitis B (CHB), including oral nucleos(t)ide analogs and systemic interferon-alpha, are deemed suboptimal, the path to finding an ultimate cure for this viral disease is rather challenging. The lack of suitable laboratory animal models that support HBV infection and associated liver disease progression is one of the major hurdles in antiviral drug development. For more than four decades, experimental infection of the Eastern woodchuck with woodchuck hepatitis virus has been applied for studying the immunopathogenesis of HBV and developing new antiviral therapeutics against CHB. There are several advantages to this animal model that are beneficial for performing both basic and translational HBV research. Previous review articles have focused on the value of this animal model in regard to HBV replication, pathogenesis, and immune response. In this article, we review studies of drug development and preclinical evaluation of direct-acting antivirals, immunomodulators, therapeutic vaccines, and inhibitors of viral entry, gene expression, and antigen release in the woodchuck model of CHB since 2014 until today and discuss their significance for clinical trials in patients.
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23
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Bhat S, Kazim SN. HBV cccDNA-A Culprit and Stumbling Block for the Hepatitis B Virus Infection: Its Presence in Hepatocytes Perplexed the Possible Mission for a Functional Cure. ACS OMEGA 2022; 7:24066-24081. [PMID: 35874215 PMCID: PMC9301636 DOI: 10.1021/acsomega.2c02216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Hepatitis B virus infection (HBV) is still a big health problem across the globe. It has been linked to the development of liver cirrhosis and hepatocellular carcinoma and can trigger different types of liver damage. Existing medicines are unable to disable covalently closed circular DNA (cccDNA), which may result in HBV persistence and recurrence. The current therapeutic goal is to achieve a functional cure, which means HBV-DNA no longer exists when treatment stops and the absence of HBsAg seroclearance. However, due to the presence of integrated HBV DNA and cccDNA functional treatment is now regarded to be difficult. In order to uncover pathways for potential therapeutic targets and identify medicines that could result in large rates of functional cure, a thorough understanding of the virus' biology is required. The proteins of the virus and episomal cccDNA are thought to be critical for the management and support of the HBV replication cycle as they interact directly with the host proteome to establish the best atmosphere for the virus while evading immune detection. The breakthroughs of host dependence factors, cccDNA transcription, epigenetic regulation, and immune-mediated breakdown have all produced significant progress in our understanding of cccDNA biology during the past decade. There are some strategies where cccDNA can be targeted either in a direct or indirect way and are presently at the point of discovery or preclinical or early clinical advancement. Editing of genomes, techniques targeting host dependence factors or epigenetic gene maintenance, nucleocapsid modulators, miRNA, siRNA, virion secretory inhibitors, and immune-mediated degradation are only a few examples. Though cccDNA approaches for direct targeting are still in the early stages of development, the assembly of capsid modulators and immune-reliant treatments have made it to the clinic. Clinical trials are currently being conducted to determine their efficiency and safety in patients, as well as their effect on viral cccDNA. The influence of recent breakthroughs in the development of new treatment techniques on cccDNA biology is also summarized in this review.
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Affiliation(s)
- Sajad
Ahmad Bhat
- Jamia Millia Islamia Central University, Centre for Interdisciplinary Research in Basic Sciences, New Delhi 110025, India
| | - Syed Naqui Kazim
- Jamia Millia Islamia Central University, Centre for Interdisciplinary Research in Basic Sciences, New Delhi 110025, India
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24
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Fung S, Choi HSJ, Gehring A, Janssen HLA. Getting to HBV cure: The promising paths forward. Hepatology 2022; 76:233-250. [PMID: 34990029 DOI: 10.1002/hep.32314] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Chronic HBV infection is a global public health burden estimated to impact nearly 300 million persons worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve because of the persistence of covalently closed circular DNA (cccDNA), HBV-DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain level of viral suppression. The success of direct-acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though an HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (Toll-like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing toward clinical development. The future of the HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs and discusses the limitations and unanswered questions on the journey to an HBV cure.
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Affiliation(s)
- Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Adam Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
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25
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Wildum S, Korolowicz KE, Suresh M, Steiner G, Dai L, Li B, Yon C, De Vera Mudry MC, Regenass-Lechner F, Huang X, Hong X, Murreddu MG, Kallakury BV, Young JAT, Menne S. Toll-Like Receptor 7 Agonist RG7854 Mediates Therapeutic Efficacy and Seroconversion in Woodchucks With Chronic Hepatitis B. Front Immunol 2022; 13:884113. [PMID: 35677037 PMCID: PMC9169629 DOI: 10.3389/fimmu.2022.884113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 04/22/2022] [Indexed: 01/04/2023] Open
Abstract
Conventional treatment of chronic hepatitis B (CHB) is rarely curative due to the immunotolerant status of patients. RG7854 is an oral double prodrug of a toll-like receptor 7 (TLR7) agonist that is developed for the treatment of CHB. The therapeutic efficacy, host immune response, and safety of RG7854 were evaluated in the woodchuck model of CHB. Monotreatment with the two highest RG7854 doses and combination treatment with the highest RG7854 dose and entecavir (ETV) suppressed viral replication, led to loss of viral antigens, and induced seroconversion in responder woodchucks. Since viral suppression and high-titer antibodies persisted after treatment ended, this suggested that a sustained antiviral response (SVR) was induced by RG7854 in a subset of animals. The SVR rate, however, was comparable between both treatment regimens, suggesting that the addition of ETV did not enhance the therapeutic efficacy of RG7854 although it augmented the proliferation of blood cells in response to viral antigens and magnitude of antibody titers. The induction of interferon-stimulated genes in blood by RG7854/ETV combination treatment demonstrated on-target activation of TLR7. Together with the virus-specific blood cell proliferation and the transient elevations in liver enzymes and inflammation, this suggested that cytokine-mediated non-cytolytic and T-cell mediated cytolytic mechanisms contributed to the SVR, in addition to the virus-neutralizing effects by antibody-producing plasma cells. Both RG7854 regimens were not associated with treatment-limiting adverse effects but accompanied by dose-dependent, transient neutropenia and thrombocytopenia. The study concluded that finite, oral RG7854 treatment can induce a SVR in woodchucks that is based on the retrieval of antiviral innate and adaptive immune responses. This supports future investigation of the TLR7 agonist as an immunotherapeutic approach for achieving functional cure in patients with CHB.
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Affiliation(s)
- Steffen Wildum
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Kyle E Korolowicz
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Guido Steiner
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Lue Dai
- Roche Pharma, Research and Early Development, Roche Innovation Center Shanghai, Shanghai, China
| | - Bin Li
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Changsuek Yon
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | | | | | - Xu Huang
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xupeng Hong
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bhaskar V Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC, United States
| | - John A T Young
- Roche Pharma, Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, United States
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26
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Yardeni D, Ghany MG. Review article: hepatitis B-current and emerging therapies. Aliment Pharmacol Ther 2022; 55:805-819. [PMID: 35224760 DOI: 10.1111/apt.16828] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/17/2022] [Accepted: 02/04/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The hepatitis B virus (HBV) affects an estimated 290 million individuals worldwide and is responsible for approximately 900 000 deaths annually, mostly from complications of cirrhosis and hepatocellular carcinoma. Although current treatment is effective at preventing complications of chronic hepatitis B, it is not curative, and often must be administered long term. There is a need for safe, effective, finite duration curative therapy. AIM Our aim was to provide a concise, up to date review of all currently available and emerging treatment options for chronic hepatitis B. METHODS We conducted a search of PubMed, clinicaltrials.gov, major meeting abstracts and pharmaceutical websites for publications and communications on current and emerging therapies for HBV. RESULTS Currently approved treatment options for chronic hepatitis B include peginterferon alpha-2a and nucleos(t)ide analogues. Both options do not offer a 'complete cure' (clearance of covalently closed circular DNA (cccDNA) and integrated HBV DNA) and rarely achieve a 'functional cure' (hepatitis B surface antigen (HBsAg) loss). An improved understanding of the viral lifecycle, immunopathogenesis and recent advances in drug delivery technologies have led to many novel therapeutic approaches that are currently being evaluated in clinical trials including targeting of viral entry, cccDNA, viral transcription, core protein, and release of HBsAg and HBV polymerase. Additionally, novel immunological approaches that include targeting the innate and adaptive immune system and therapeutic vaccination are being pursued. CONCLUSION The breadth and scope of novel therapies in development hold promise for regimen/s that will achieve functional cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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27
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Kim SW, Yoon JS, Lee M, Cho Y. Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus. Clin Mol Hepatol 2022; 28:17-30. [PMID: 34281294 PMCID: PMC8755466 DOI: 10.3350/cmh.2021.0093] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/05/2021] [Accepted: 07/18/2021] [Indexed: 11/09/2022] Open
Abstract
Hepatitis B virus (HBV) affects approximately 250 million patients worldwide, resulting in the progression to cirrhosis and hepatocellular carcinoma, which are serious public health problems. Although universal vaccination programs exist, they are only prophylactic and not curative. In the HBV life cycle, HBV forms covalently closed circular DNA (cccDNA), which is the viral minichromosome, in the nuclei of human hepatocytes and makes it difficult to achieve a complete cure with the current nucleos(t)ide analogs and interferon therapies. Current antiviral therapies rarely eliminate cccDNA; therefore, lifelong antiviral treatment is necessary. Recent trials for antiviral treatment of chronic hepatitis B have been focused on establishing a functional cure, defined by either the loss of hepatitis B surface antigen, undetectable serum HBV DNA levels, and/or seroconversion to hepatitis B surface antibody. Novel therapeutic targets and molecules are in the pipeline for early clinical trials aiming to cure HBV infection. The ideal strategy for achieving a long-lasting functional or complete cure might be using combination therapies targeting different steps of the HBV life cycle and immunomodulators. This review summarizes the current knowledge about novel treatments and combination treatments for a complete HBV cure.
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Affiliation(s)
- Sun Woong Kim
- Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea
| | - Jun Sik Yoon
- Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Minjong Lee
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
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28
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Ayithan N, Ghosh A, Dwivedi A, Wallin JJ, Tan SK, Chen D, Kottilil S, Poonia B. Oral Selective TLR8 Agonist Selgantolimod Induces Multiple Immune Cell Responses in Humans. Viruses 2021; 13:v13122400. [PMID: 34960669 PMCID: PMC8706304 DOI: 10.3390/v13122400] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/18/2022] Open
Abstract
TLR8 agonists have the potential for use as immunomodulatory components in therapeutic modalities for viral infections such as chronic HBV (CHB) and HIV. In this study, using peripheral blood samples from a phase 1a clinical trial, we examined the acute effects of a single oral administration of a selective TLR8 agonist on immune cell phenotypes. Administration of the TLR8 agonist selgantolimod (SLGN) in healthy individuals resulted in alteration in frequencies of peripheral blood monocytes, pDCs, mDCs and MAIT cells. Frequencies of mDCs and lymphoid cells significantly reduced after 8 h of SLGN administration, whereas pDC frequencies significantly increased, with changes possibly reflecting migration of different cell types between peripheral and tissue compartments in response to the agonist. Myeloid cell activation was evident by an upregulated expression of co-stimulatory molecules CD40 and CD86 accompanied by the production of IL-6 and IL-18 from these cells. Concomitantly, there was induction of the early activation marker CD69 on innate and adaptive lymphoid cells, including MAIT and NK cell subsets. Further, these activated lymphoid cells had enhanced expression of the effector molecules granzyme B and perforin. Microarray analysis of isolated lymphocytes and monocytes from baseline and post-SLGN treatment revealed changes in expression of genes involved in cellular response to cytokine stimulus, innate immune response, myeloid cell differentiation and antigen receptor-mediated signaling pathway. In a preliminary analysis of samples from CHB patients treated with selgantolimod, activation of innate and adaptive lymphocytes was evident. In conclusion, this first in-human study shows that selgantolimod administration in humans results in activation of multiple immune cell responses with antiviral potential.
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Affiliation(s)
- Natarajan Ayithan
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
| | - Alip Ghosh
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
| | - Ankit Dwivedi
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Jeffrey J. Wallin
- Gilead Sciences Inc., Foster City, CA 94404, USA; (J.J.W.); (S.K.T.); (D.C.)
| | - Susanna K. Tan
- Gilead Sciences Inc., Foster City, CA 94404, USA; (J.J.W.); (S.K.T.); (D.C.)
| | - Diana Chen
- Gilead Sciences Inc., Foster City, CA 94404, USA; (J.J.W.); (S.K.T.); (D.C.)
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
| | - Bhawna Poonia
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (N.A.); (A.G.); (S.K.)
- Correspondence:
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29
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Lang-Meli J, Neumann-Haefelin C, Thimme R. Immunotherapy and therapeutic vaccines for chronic HBV infection. Curr Opin Virol 2021; 51:149-157. [PMID: 34710645 DOI: 10.1016/j.coviro.2021.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 09/08/2021] [Accepted: 10/07/2021] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a major global health burden causing severe complications like liver cirrhosis or hepatocellular carcinoma. Curative treatment options are lacking. Therefore, there is an urgent need for new therapeutic options. Immunotherapy with the goal to restore dysfunctional HBV-specific T cell immunity is an interesting new therapeutic strategy. Based on current evidence on dysfunction of the HBV-specific CD8+ T cell response in chronic HBV infection, we will review the growing field of immunotherapeutic approaches for treatment of chronic HBV infection. The review will focus on therapies targeting T cells and will cover checkpoint inhibitors, T cell engineering, Toll-like receptor agonists and therapeutic vaccination.
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Affiliation(s)
- Julia Lang-Meli
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany; IMM-PACT Programm, Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Robert Thimme
- Dept. of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany.
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30
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Suresh M, Li B, Huang X, Korolowicz KE, Murreddu MG, Gudima SO, Menne S. Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects. Front Immunol 2021; 12:745802. [PMID: 34671360 PMCID: PMC8521114 DOI: 10.3389/fimmu.2021.745802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/13/2021] [Indexed: 12/11/2022] Open
Abstract
Immune modulation for the treatment of chronic hepatitis B (CHB) has gained more traction in recent years, with an increasing number of compounds designed for targeting different host pattern recognition receptors (PRRs). These agonistic molecules activate the receptor signaling pathway and trigger an innate immune response that will eventually shape the adaptive immunity for control of chronic infection with hepatitis B virus (HBV). While definitive recognition of HBV nucleic acids by PRRs during viral infection still needs to be elucidated, several viral RNA sensing receptors, including toll-like receptors 7/8/9 and retinoic acid inducible gene-I-like receptors, are explored preclinically and clinically as possible anti-HBV targets. The antiviral potential of viral DNA sensing receptors is less investigated. In the present study, treatment of primary woodchuck hepatocytes generated from animals with CHB with HSV-60 or poly(dA:dT) agonists resulted in increased expression of interferon-gamma inducible protein 16 (IFI16) or Z-DNA-binding protein 1 (ZBP1/DAI) and absent in melanoma 2 (AIM2) receptors and their respective adaptor molecules and effector cytokines. Cytosolic DNA sensing receptor pathway activation correlated with a decline in woodchuck hepatitis virus (WHV) replication and secretion in these cells. Combination treatment with HSV-60 and poly(dA:dT) achieved a superior antiviral effect over monotreatment with either agonist that was associated with an increased expression of effector cytokines. The antiviral effect, however, could not be enhanced further by providing additional type-I interferons (IFNs) exogenously, indicating a saturated level of effector cytokines produced by these receptors following agonism. In WHV-uninfected woodchucks, a single poly(dA:dT) dose administered via liver-targeted delivery was well-tolerated and induced the intrahepatic expression of ZBP1/DAI and AIM2 receptors and their effector cytokines, IFN-β and interleukins 1β and 18. Receptor agonism also resulted in increased IFN-γ secretion of peripheral blood cells. Altogether, the effect on WHV replication and secretion following in vitro activation of IFI16, ZBP1/DAI, and AIM2 receptor pathways suggested an antiviral benefit of targeting more than one cytosolic DNA receptor. In addition, the in vivo activation of ZBP1/DAI and AIM2 receptor pathways in liver indicated the feasibility of the agonist delivery approach for future evaluation of therapeutic efficacy against HBV in woodchucks with CHB.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Kyle E Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Severin O Gudima
- Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
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Barili V, Vecchi A, Rossi M, Montali I, Tiezzi C, Penna A, Laccabue D, Missale G, Fisicaro P, Boni C. Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C. Cells 2021; 10:2563. [PMID: 34685543 PMCID: PMC8533840 DOI: 10.3390/cells10102563] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
In chronic hepatitis B and C virus infections persistently elevated antigen levels drive CD8+ T cells toward a peculiar differentiation state known as T cell exhaustion, which poses crucial constraints to antiviral immunity. Available evidence indicates that T cell exhaustion is associated with a series of metabolic and signaling deregulations and with a very peculiar epigenetic status which all together lead to reduced effector functions. A clear mechanistic network explaining how intracellular metabolic derangements, transcriptional and signaling alterations so far described are interconnected in a comprehensive and unified view of the T cell exhaustion differentiation profile is still lacking. Addressing this issue is of key importance for the development of innovative strategies to boost host immunity in order to achieve viral clearance. This review will discuss the current knowledge in HBV and HCV infections, addressing how innate immunity, metabolic derangements, extensive stress responses and altered epigenetic programs may be targeted to restore functionality and responsiveness of virus-specific CD8 T cells in the context of chronic virus infections.
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Affiliation(s)
- Valeria Barili
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
| | - Marzia Rossi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Ilaria Montali
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Camilla Tiezzi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
| | - Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
| | - Diletta Laccabue
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Gabriele Missale
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Paola Fisicaro
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
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Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview. Int J Mol Sci 2021; 22:10462. [PMID: 34638802 PMCID: PMC8508807 DOI: 10.3390/ijms221910462] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health problem. The immunopathology of the disease, especially the interplay between HBV and host innate immunity, is poorly understood. Moreover, inconsistent literature on HBV and host innate immunity has led to controversies. However, recently, there has been an increase in the number of studies that have highlighted the link between innate immune responses, including Toll-like receptors (TLRs), and chronic HBV infection. TLRs are the key sensing molecules that detect pathogen-associated molecular patterns and regulate the induction of pro- and anti-inflammatory cytokines, thereby shaping the adaptive immunity. The suppression of TLR response has been reported in patients with chronic hepatitis B (CHB), as well as in other models, including tree shrews, suggesting an association of TLR response in HBV chronicity. Additionally, TLR agonists have been reported to improve the host innate immune response against HBV infection, highlighting the potential of these agonists as immunomodulators for enhancing CHB treatment. In this study, we discuss the current understanding of host innate immune responses during HBV infection, particularly focusing on the TLR response and TLR agonists as immunomodulators.
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Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal 8210, Bangladesh
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
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33
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Ayithan N, Tang L, Tan SK, Chen D, Wallin JJ, Fletcher SP, Kottilil S, Poonia B. Follicular Helper T (T FH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients. Front Immunol 2021; 12:735913. [PMID: 34512670 PMCID: PMC8428528 DOI: 10.3389/fimmu.2021.735913] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 08/11/2021] [Indexed: 11/21/2022] Open
Abstract
Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (TFH) function leading to improved B cell responses in vitro. We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and TFH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote TFH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced TFH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by TFH cells with enhanced IL-21+BCL-6+ and ICOS+BCL-6+ co-expression. Mechanistically, incubation of isolated naïve CD4+ T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21+ICOS+BCL-6+ TFH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing TFH with autologous naïve B cells led to enhanced memory (CD19+CD27+) and plasma B cell generation (CD19+CD27++CD38+) and IgG production. Importantly, in TFH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated TFH function and may play a role in achieving HBV functional cure.
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Affiliation(s)
- Natarajan Ayithan
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Lydia Tang
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Susanna K Tan
- Clinical Research, Gilead Sciences Inc., Foster City, CA, United States
| | - Diana Chen
- Clinical Research, Gilead Sciences Inc., Foster City, CA, United States
| | - Jeffrey J Wallin
- Clinical Research, Gilead Sciences Inc., Foster City, CA, United States
| | - Simon P Fletcher
- Clinical Research, Gilead Sciences Inc., Foster City, CA, United States
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Bhawna Poonia
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States
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34
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Korolowicz KE, Suresh M, Li B, Huang X, Yon C, Kallakury BV, Lee KP, Park S, Kim YW, Menne S. Combination Treatment with the Vimentin-Targeting Antibody hzVSF and Tenofovir Suppresses Woodchuck Hepatitis Virus Infection in Woodchucks. Cells 2021; 10:2321. [PMID: 34571970 PMCID: PMC8466705 DOI: 10.3390/cells10092321] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Current treatment options for patients infected with hepatitis B virus (HBV) are suboptimal, because the approved drugs rarely induce cure due to the persistence of the viral DNA genome in the nucleus of infected hepatocytes, and are associated with either severe side effects (pegylated interferon-alpha) or require life-long administration (nucleos(t)ide analogs). We report here the evaluation of the safety and therapeutic efficacy of a novel, humanized antibody (hzVSF) in the woodchuck model of HBV infection. hzVSF has been shown to act as a viral entry inhibitor, most likely by suppressing vimentin-mediated endocytosis of virions. Targeting the increased vimentin expression on liver cells by hzVSF after infection with HBV or woodchuck hepatitis virus (WHV) was demonstrated initially. Thereafter, hzVSF safety was assessed in eight woodchucks naïve for WHV infection. Antiviral efficacy of hzVSF was evaluated subsequently in 24 chronic WHV carrier woodchucks by monotreatment with three ascending doses and in combination with tenofovir alafenamide fumarate (TAF). Consistent with the proposed blocking of WHV reinfection, intravenous hzVSF administration for 12 weeks resulted in a modest but transient reduction of viral replication and associated liver inflammation. In combination with oral TAF dosing, the antiviral effect of hzVSF was enhanced and sustained in half of the woodchucks with an antibody response to viral proteins. Thus, hzVSF safely but modestly alters chronic WHV infection in woodchucks; however, as a combination partner to TAF, its antiviral efficacy is markedly increased. The results of this preclinical study support future evaluation of this novel anti-HBV drug in patients.
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Affiliation(s)
- Kyle E. Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Changsuek Yon
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Bhaskar V. Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Kyoung-pil Lee
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Sungman Park
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Yoon-Won Kim
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
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35
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Suresh M, Li B, Murreddu MG, Gudima SO, Menne S. Involvement of Innate Immune Receptors in the Resolution of Acute Hepatitis B in Woodchucks. Front Immunol 2021; 12:713420. [PMID: 34367179 PMCID: PMC8340647 DOI: 10.3389/fimmu.2021.713420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/05/2021] [Indexed: 12/15/2022] Open
Abstract
The antiviral property of small agonist compounds activating pattern recognition receptors (PRRs), including toll-like and RIG-I receptors, have been preclinically evaluated and are currently tested in clinical trials against chronic hepatitis B (CHB). The involvement of other PRRs in modulating hepatitis B virus infection is less known. Thus, woodchucks with resolving acute hepatitis B (AHB) after infection with woodchuck hepatitis virus (WHV) were characterized as animals with normal or delayed resolution based on their kinetics of viremia and antigenemia, and the presence and expression of various PRRs were determined in both outcomes. While PRR expression was unchanged immediately after infection, most receptors were strongly upregulated during resolution in liver but not in blood. Besides well-known PRRs, including TLR7/8/9 and RIG-I, other less-characterized receptors, such as IFI16, ZBP1/DAI, AIM2, and NLRP3, displayed comparable or even higher expression. Compared to normal resolution, a 3-4-week lag in peak receptor expression and WHV-specific B- and T-cell responses were noted during delayed resolution. This suggested that PRR upregulation in woodchuck liver occurs when the mounting WHV replication reaches a certain level, and that multiple receptors are involved in the subsequent induction of antiviral immune responses. Liver enzyme elevations occurred early during normal resolution, indicating a faster induction of cytolytic mechanisms than in delayed resolution, and correlated with an increased expression of NK-cell and CD8 markers and cytolytic effector molecules. The peak liver enzyme level, however, was lower during delayed resolution, but hepatic inflammation was more pronounced and associated with a higher expression of cytolytic markers. Further comparison of PRR expression revealed that most receptors were significantly reduced in woodchucks with established and progressing CHB, and several RNA sensors more so than DNA sensors. This correlated with a lower expression of receptor adaptor and effector molecules, suggesting that persistent, high-level WHV replication interferes with PRR activation and is associated with a diminished antiviral immunity based on the reduced expression of immune cell markers, and absent WHV-specific B- and T-cell responses. Overall, the differential expression of PRRs during resolution and persistence of WHV infection emphasizes their importance in the ultimate viral control during AHB that is impaired during CHB.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G. Murreddu
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Severin O. Gudima
- Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
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Qu B, Brown RJP. Strategies to Inhibit Hepatitis B Virus at the Transcript Level. Viruses 2021; 13:v13071327. [PMID: 34372533 PMCID: PMC8310268 DOI: 10.3390/v13071327] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 12/11/2022] Open
Abstract
Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of effective HBV vaccination. During chronic infection, HBV forms two distinct templates responsible for viral transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host genome-integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription or destabilize viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA. Small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA, while small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrated templates. These antivirals mediate their effects by reducing viral transcripts abundance, some leading to a loss of surface antigen expression, and they can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.
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Affiliation(s)
- Bingqian Qu
- Division of Veterinary Medicine, Paul Ehrlich Institute, 63225 Langen, Germany
- European Virus Bioinformatics Center, 07743 Jena, Germany
- Correspondence: (B.Q.); (R.J.P.B.)
| | - Richard J. P. Brown
- Division of Veterinary Medicine, Paul Ehrlich Institute, 63225 Langen, Germany
- Correspondence: (B.Q.); (R.J.P.B.)
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37
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Amin OE, Colbeck EJ, Daffis S, Khan S, Ramakrishnan D, Pattabiraman D, Chu R, Micolochick Steuer H, Lehar S, Peiser L, Palazzo A, Frey C, Davies J, Javanbakht H, Rosenberg WM, Fletcher SP, Maini MK, Pallett LJ. Therapeutic Potential of TLR8 Agonist GS-9688 (Selgantolimod) in Chronic Hepatitis B: Remodeling of Antiviral and Regulatory Mediators. Hepatology 2021; 74:55-71. [PMID: 33368377 PMCID: PMC8436741 DOI: 10.1002/hep.31695] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 11/13/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS GS-9688 (selgantolimod) is a toll-like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS-9688 has previously been evaluated in vitro in HBV-infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS-9688 to boost responses contributing to viral control and to modulate regulatory mediators. APPROACH AND RESULTS We characterized the effect of GS-9688 on immune cell subsets in vitro in peripheral blood mononuclear cells of healthy controls and patients with CHB. GS-9688 activated dendritic cells and mononuclear phagocytes to produce IL-12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and patients with CHB. GS-9688 increased the frequency of activated natural killer (NK) cells, mucosal-associated invariant T cells, CD4+ follicular helper T cells, and, in about 50% of patients, HBV-specific CD8+ T cells expressing interferon-γ. Moreover, in vitro stimulation with GS-9688 induced NK-cell expression of interferon-γ and TNF-α, and promoted hepatocyte lysis. We also assessed whether GS-9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS-9688 reduced the frequency of CD4+ regulatory T cells and monocytic myeloid-derived suppressor cells (MDSCs). Residual MDSCs expressed higher levels of negative immune regulators, galectin-9 and programmed death-ligand 1. Conversely, GS-9688 induced an expansion of immunoregulatory TNF-related apoptosis-inducing ligand+ NK cells and degranulation of arginase-I+ polymorphonuclear MDSCs. CONCLUSIONS GS-9688 induces cytokines in human peripheral blood mononuclear cells that are able to activate antiviral effector function by multiple immune mediators (HBV-specific CD8+ T cells, CD4+ follicular helper T cells, NK cells, and mucosal-associated invariant T cells). Although reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimize the antiviral efficacy of GS-9688.
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Affiliation(s)
- Oliver E. Amin
- Division of Infection & ImmunityInstitute of Immunity & TransplantationUniversity College LondonLondonUnited Kingdom
| | - Emily J. Colbeck
- Division of Infection & ImmunityInstitute of Immunity & TransplantationUniversity College LondonLondonUnited Kingdom
| | | | | | | | | | - Ruth Chu
- Gilead Sciences Inc.Foster CityCA
| | | | - Sophie Lehar
- Gilead Sciences Inc.Foster CityCA
- Present address:
Genentech Inc.South San FranciscoCA
| | - Leanne Peiser
- Gilead Sciences Inc.Foster CityCA
- Present address:
Bristol Myers SquibbSeattleWA
| | | | - Christian Frey
- Gilead Sciences Inc.Foster CityCA
- Present address:
Ideaya Biosciences Inc.South San FranciscoCA
| | - Jessica Davies
- Division of Infection & ImmunityInstitute of Immunity & TransplantationUniversity College LondonLondonUnited Kingdom
| | - Hassan Javanbakht
- Gilead Sciences Inc.Foster CityCA
- Present address:
SQZ BiotechnologiesWatertownMA
| | | | | | - Mala K. Maini
- Division of Infection & ImmunityInstitute of Immunity & TransplantationUniversity College LondonLondonUnited Kingdom
| | - Laura J. Pallett
- Division of Infection & ImmunityInstitute of Immunity & TransplantationUniversity College LondonLondonUnited Kingdom
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38
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Suresh M, Menne S. Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer. World J Gastrointest Oncol 2021; 13:509-535. [PMID: 34163570 PMCID: PMC8204361 DOI: 10.4251/wjgo.v13.i6.509] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/02/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
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Tsounis EP, Tourkochristou E, Mouzaki A, Triantos C. Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure. World J Gastroenterol 2021; 27:2727-2757. [PMID: 34135551 PMCID: PMC8173382 DOI: 10.3748/wjg.v27.i21.2727] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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40
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Golsaz-Shirazi F, Shokri F. Cross talk between hepatitis B virus and innate immunity of hepatocytes. Rev Med Virol 2021; 32:e2256. [PMID: 34021666 DOI: 10.1002/rmv.2256] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 12/13/2022]
Abstract
Innate immunity plays a major role in controlling viral infections. Recent exploration of sodium taurocholate co-transporting polypeptide receptor as specific hepatitis B virus (HBV) receptor in human hepatocytes has provided appropriate cell culture tools to study the innate immunity of hepatocytes and its cross talk with HBV. In this review, we give a brief update on interaction between HBV and innate immunity using the currently available in vitro cellular models that support the complete life cycle of HBV. We will discuss how HBV can act as a 'stealth' virus to counteract the innate immune responses mediated by the pathogen recognition receptors of hepatocytes and escape the first line of surveillance of the host immune system. We give an overview of the cellular components of innate immunity that present in these in vitro models and discuss how activating these innate immunity components may contribute to the eradication of HBV infection.
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Affiliation(s)
- Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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41
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Chiale C, Marchese AM, Robek MD. Innate immunity and HBV persistence. Curr Opin Virol 2021; 49:13-20. [PMID: 33992859 DOI: 10.1016/j.coviro.2021.04.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) causes chronic infections that are associated with immune dysfunction. Though T cell impairment is perhaps the most prominent immune change contributing to viral persistence, HBV interaction with the innate immune system is also likely key, as the lack of effective innate immunity has functional consequences that promote chronic infection. In addition to an intrinsic ability to fight viral infections, the innate immune system also impacts T cell responses and other adaptive immune mechanisms critical for HBV control. Therefore, it is essential to understand the relationships between HBV and innate immunity, as these interactions may be useful immunotherapeutic targets to manage the infection.
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Affiliation(s)
- Carolina Chiale
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Anthony M Marchese
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
| | - Michael D Robek
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
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Korolowicz KE, Suresh M, Li B, Huang X, Yon C, Leng X, Kallakury BV, Tucker RD, Menne S. Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B. Viruses 2021; 13:v13040648. [PMID: 33918831 PMCID: PMC8069054 DOI: 10.3390/v13040648] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.
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Affiliation(s)
- Kyle E. Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Changsuek Yon
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Xuebing Leng
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Bhaskar V. Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Robin D. Tucker
- Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
- Correspondence: ; Tel.: +1-(202)-687-2949
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Huang X, Zhang X, Lu M. Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics. Expert Opin Drug Discov 2021; 16:869-880. [PMID: 33678093 DOI: 10.1080/17460441.2021.1898369] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Toll-like receptor (TLR) 7 and TLR8 are functionally localized to endosomes and recognize specific RNA sequences. They play crucial roles in initiating innate and adaptive immune responses. TLR7/8 activation protects the host against invading pathogens and enhances immune responses. In contrast, sustained TLR7/8 signaling leads to immune overreaction. Therefore, agonists or antagonists targeting TLR7/8 signaling are favorable drug candidates for the treatment of immune disorders.Areas covered: Basic knowledge about TLR7 and TLR8 and their signaling pathways are briefly reviewed. Various therapeutic agents have been designed to activate or antagonize TLR7/8 signaling pathways, and their safety and efficacy for the treatment of multiple diseases have been investigated in preclinical animal models and clinical trials. TLR7/8 agonists exhibit potent antiviral activity and regulate anti-tumor immune responses. TLR7 agonists have also been used as adjuvants to improve vaccine immunogenicity and generate greater seroprotection. TLR7/8 antagonists are promising candidates for the treatment of autoimmune and inflammatory diseases.Expert opinion: TLR7/8 pathways are favorable targets for immunological therapies. Future research should concentrate on the optimization of drug safety, efficiency, and specificity. Detailed mechanistic studies will contribute to the development of TLR7/8 immunomodulators and novel therapeutic strategies.
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Affiliation(s)
- Xuan Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, Essen, Germany
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Roca Suarez AA, Testoni B, Baumert TF, Lupberger J. Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease. Front Immunol 2021; 11:624034. [PMID: 33613561 PMCID: PMC7892431 DOI: 10.3389/fimmu.2020.624034] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- DNA, Viral/immunology
- Hepacivirus/immunology
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/mortality
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/mortality
- Hepatitis C, Chronic/pathology
- Humans
- Liver Neoplasms/immunology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- RNA, Viral/immunology
- Signal Transduction/immunology
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Affiliation(s)
- Armando Andres Roca Suarez
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Thomas F. Baumert
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
- Institut Universitaire de France (IUF), Paris, France
| | - Joachim Lupberger
- INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
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Bassit L, Ono SK, Schinazi RF. Moving Fast Toward Hepatitis B Virus Elimination. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1322:115-138. [PMID: 34258739 DOI: 10.1007/978-981-16-0267-2_5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Currently, there are two safe and effective therapeutic strategies for chronic hepatitis B treatment, namely, nucleoside analogs and interferon alpha (pegylated or non-pegylated). These treatments can control viral replication and improve survival; however, they do not eliminate the virus and therefore require long-term continued therapy. In addition, there are significant concerns about virus rebound on discontinuation of therapy and the development of fibrosis and hepatocellular carcinoma despite therapy. Therefore, the search for new, more effective, and safer antiviral agents that can cure hepatitis B virus (HBV) continues. Anti-HBV drug discovery and development is fundamentally impacted by our current understanding of HBV replication, disease physiopathology, and persistence of HBV covalently closed circular DNA (cccDNA). Several HBV replication targets are the basis for novel anti-HBV drug development strategies. Many of them are already in clinical trial phase 1 or 2, while others with promising results are still in preclinical stages. As research intensifies, potential HBV curative therapies and modalities in the pipeline are now on the horizon.
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Affiliation(s)
- Leda Bassit
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Suzane Kioko Ono
- Department of Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, SP, Brazil
| | - Raymond F Schinazi
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA, USA.
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Zheng J, Balsitis S, Santos R, Smith BJ, Subramanian R. Characterization of Seasonal Pharmacokinetic Variability in Woodchucks. Drug Metab Dispos 2020; 48:1199-1209. [PMID: 32892154 DOI: 10.1124/dmd.120.000140] [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: 06/16/2020] [Accepted: 08/24/2020] [Indexed: 11/22/2022] Open
Abstract
The eastern woodchuck (Marmota monax) is a hibernating species extensively used as an in vivo efficacy model for chronic human hepatitis B virus infection. Under laboratory conditions, woodchucks develop a pseudohibernation condition; thus, the pharmacokinetics (PK) of small-molecule therapeutics may be affected by the seasonal change. The seasonal PK of four probe compounds were characterized over 12 months in seven male and nine female laboratory-maintained woodchucks. These compounds were selected to study changes in oxidative metabolism [antipyrine (AP)], glucuronidation [raltegravir (RTG)], renal clearance [lamivudine (3TC)], and hepatic function [indocyanine green (ICG)]. Seasonal changes in physiologic parameters and PK were determined. Seasonal body weight increases were ≥30%. Seasonal changes in body temperature and heart rate were <10%. The mean AP exposure remained unchanged from April to August 2017, followed by a significant increase (≥1.0-fold) from August to December and subsequent decrease to baseline at the end of study. A similar trend was observed in RTG and 3TC exposures. The ICG exposure remained unchanged. No significant sex difference in PK was observed, although female woodchucks appeared to be less susceptible to seasonal PK and body weight changes. Significant seasonal PK changes for AP, RTG, and 3TC indicate decreases in oxidative metabolism, phase II glucuronidation, and renal clearance during pseudohibernation. The lack of seasonal change in ICG exposure suggests there are no significant changes in hepatic function. This information can be used to optimize the scheduling of woodchuck studies to avoid seasonally driven variation in drug PK. SIGNIFICANCE STATEMENT: Woodchuck is a hibernating species and is commonly used as a nonclinical model of hepatitis B infection. Investigation of seasonal PK changes is perhaps of greater interest to pharmaceutical industry scientists, who use the woodchuck model to optimize the scheduling of woodchuck studies to avoid seasonally driven variation in drug PK and/or toxicity. This information is also valuable to drug metabolism and veterinary scientists in understanding woodchuck's seasonal metabolism and behavior under the pseudohibernation condition.
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Affiliation(s)
- Jim Zheng
- Gilead Sciences, Inc., Foster City, California
| | | | - Rex Santos
- Gilead Sciences, Inc., Foster City, California
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Rybicka M, Bielawski KP. Recent Advances in Understanding, Diagnosing, and Treating Hepatitis B Virus Infection. Microorganisms 2020; 8:E1416. [PMID: 32942584 PMCID: PMC7565763 DOI: 10.3390/microorganisms8091416] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects 292 million people worldwide and is associated with a broad range of clinical manifestations including cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Despite the availability of an effective vaccine HBV still causes nearly 900,000 deaths every year. Current treatment options keep HBV under control, but they do not offer a cure as they cannot completely clear HBV from infected hepatocytes. The recent development of reliable cell culture systems allowed for a better understanding of the host and viral mechanisms affecting HBV replication and persistence. Recent advances into the understanding of HBV biology, new potential diagnostic markers of hepatitis B infection, as well as novel antivirals targeting different steps in the HBV replication cycle are summarized in this review article.
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Affiliation(s)
- Magda Rybicka
- Department of Molecular Diagnostics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland;
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Abstract
Abstract
Purpose of Review
Chronic Hepatitis B Virus (HBV) Infection is a major global health burden. Currently, a curative therapy does not exist; thus, there is an urgent need for new therapeutical options. Viral elimination in the natural course of infection results from a robust and multispecific T and B cell response that, however, is dysfunctional in chronically infected patients. Therefore, immunomodulatory therapies that strengthen the immune responses are an obvious approach trying to control HBV infection. In this review, we summarize the rationale and current options of immunological cure of chronic HBV infection.
Recent Findings
Recently, among others, drugs that stimulate the innate immune system or overcome CD8+ T cell exhaustion by checkpoint blockade, and transfer of HBV-specific engineered CD8+ T cells emerged as promising approaches.
Summary
HBV-specific immunity is responsible for viral control, but also for immunopathogenesis. Thus, the development of immunomodulatory therapies is a difficult process on a thin line between viral control and excessive immunopathology. Some promising agents are under investigation. Nevertheless, further research is indispensable in order to optimally orchestrate immunostimulation.
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49
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Michalak TI. Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B. Front Immunol 2020; 11:853. [PMID: 32536912 PMCID: PMC7267019 DOI: 10.3389/fimmu.2020.00853] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances.
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Affiliation(s)
- Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada
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50
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Mackman RL, Mish M, Chin G, Perry JK, Appleby T, Aktoudianakis V, Metobo S, Pyun P, Niu C, Daffis S, Yu H, Zheng J, Villasenor AG, Zablocki J, Chamberlain J, Jin H, Lee G, Suekawa-Pirrone K, Santos R, Delaney WE, Fletcher SP. Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B. J Med Chem 2020; 63:10188-10203. [DOI: 10.1021/acs.jmedchem.0c00100] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Richard L. Mackman
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Michael Mish
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Gregory Chin
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Jason K. Perry
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Todd Appleby
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | | | - Sammy Metobo
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Peter Pyun
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Congrong Niu
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Stephane Daffis
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Helen Yu
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Jim Zheng
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Armando G. Villasenor
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Jeff Zablocki
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Jason Chamberlain
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Haolun Jin
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Gary Lee
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | | | - Rex Santos
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - William E. Delaney
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
| | - Simon P. Fletcher
- Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
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