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Yu F, Zhu Y, Li S, Hao L, Li N, Ye F, Jiang Z, Hu X. Dysfunction and regulatory interplay of T and B cells in chronic hepatitis B: immunotherapy and emerging antiviral strategies. Front Cell Infect Microbiol 2024; 14:1488527. [PMID: 39717542 PMCID: PMC11663751 DOI: 10.3389/fcimb.2024.1488527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/20/2024] [Indexed: 12/25/2024] Open
Abstract
In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity. Humoral immunity, mediated by B-cell subpopulations, and cellular immunity, dominated by T-cell subpopulations show varying degrees of dysfunction during chronic hepatitis B (CHB). Notably, not all T- and B-cells produce positive immune responses. This review examine the most recent developments in the mutual regulation of T-B cells during chronic HBV infection. Our focus is on the prevailing immunotherapeutic strategies, such as T cell engineering, HBV-related vaccines, PD-1 inhibitors, and Toll-like receptor agonists. While nucleos(t)ide analogues (NUCs) and interferons have notable limitations, including inadequate viral suppression, drug resistance, and adverse reactions, several HBV entry inhibitors have shown promising clinical efficacy. To overcome the challenges posed by NUCs or monotherapy, the combination of immunotherapy and novel antiviral agents presents a promising avenue for future CHB treatment and potential cure.
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Affiliation(s)
- Fei Yu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yue Zhu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Na Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Fanghang Ye
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhi Jiang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Daly MB, Dinh C, Holder A, Rudolph D, Ruone S, Swaims-Kohlmeier A, Khalil G, Sharma S, Mitchell J, Condrey J, Kim D, Pan Y, Curtis K, Williams P, Spreen W, Heneine W, García-Lerma JG. SHIV remission in macaques with early treatment initiation and ultra long-lasting antiviral activity. Nat Commun 2024; 15:10550. [PMID: 39632836 PMCID: PMC11618496 DOI: 10.1038/s41467-024-54783-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 11/21/2024] [Indexed: 12/07/2024] Open
Abstract
Studies in SIV-infected macaques show that the virus reservoir is particularly refractory to conventional suppressive antiretroviral therapy (ART). We posit that optimized ART regimens designed to have robust penetration in tissue reservoirs and long-lasting antiviral activity may be advantageous for HIV or SIV remission. Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia. We document full suppression in all animals during treatment (4-12 months) and no virus rebound after treatment discontinuation (1.5-2 years of follow up) despite CD8 + T cell depletion. We show efficient multidrug penetration in virus reservoirs and persisting rilpivirine in plasma for 2 years after the last dose. Our results document a type of virus remission that is achieved through early treatment initiation and provision of ultra long-lasting antiviral activity that persists after treatment cessation.
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Affiliation(s)
- Michele B Daly
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Chuong Dinh
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Angela Holder
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Donna Rudolph
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Susan Ruone
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Alison Swaims-Kohlmeier
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA
| | - George Khalil
- Quantitative Sciences and Data Management Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
- Office of Informatics and Data Management, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Sunita Sharma
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - James Mitchell
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Jillian Condrey
- Comparative Medicine Branch, Division of Scientific Resources, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Daniel Kim
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Yi Pan
- Quantitative Sciences and Data Management Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Kelly Curtis
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | | | | | - Walid Heneine
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - J Gerardo García-Lerma
- Laboratory Branch, Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA.
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Shigeno S, Kodama T, Murai K, Motooka D, Fukushima A, Nishio A, Hikita H, Tatsumi T, Okamoto T, Kanto T, Takehara T. Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B. Cell Mol Gastroenterol Hepatol 2024; 19:101412. [PMID: 39349249 PMCID: PMC11609393 DOI: 10.1016/j.jcmgh.2024.101412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 09/21/2024] [Accepted: 09/23/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND & AIMS Targeting exhausted immune systems would be a promising therapeutic strategy to achieve a functional cure for HBV infection in patients with chronic hepatitis B (CHB). However, animal models recapitulating the immunokinetics of CHB are very limited. We aimed to develop an immunocompetent mouse model of CHB for intrahepatic immune profiling. METHODS CHB mice were created by intrahepatic delivery of the Sleeping Beauty transposon vector tandemly expressing the hepatitis B virus (HBV) genome and fumarylacetoacetate hydrolase (FAH) cDNA into C57BL/6J congenic FAH knockout mice via hydrodynamic tail vein injection. We profiled the viral and intrahepatic immune kinetics in CHB mice with or without treatment with recombinant IFNα or the hepatotropic Toll-like receptor 7 agonist SA-5 using single-cell RNA-seq. RESULTS CHB mice exhibited sustained HBV viremia and persistent hepatitis. They showed intrahepatic expansion of exhausted CD8+ T (Tex) cells, the frequency of which was positively associated with viral load. Recruited macrophages increased in number but impaired inflammatory responses in the liver. The cytotoxicity of mature natural killer (NK) cells also increased in CHB mice. IFNα and SA-5 treatment both resulted in viral suppression with mild hepatic flares in CHB mice. Although both treatments activated NK cells, SA-5 had the capacity to revitalize the impaired function of Tex cells and liver-recruited macrophages. CONCLUSIONS Our novel CHB mouse model recapitulated the intrahepatic exhausted antiviral immunity in patients with CHB, which might be able to be reinvigorated by a hepatotropic TLR7 agonist.
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Affiliation(s)
- Satoshi Shigeno
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuhiro Murai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Daisuke Motooka
- Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | | | - Akira Nishio
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Toru Okamoto
- Institute for Advanced Co-Creation Studies, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
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Chen J, Duan Y, Che J, Zhu J. Dysfunction of dendritic cells in tumor microenvironment and immunotherapy. Cancer Commun (Lond) 2024; 44:1047-1070. [PMID: 39051512 PMCID: PMC11492303 DOI: 10.1002/cac2.12596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/10/2024] [Accepted: 07/13/2024] [Indexed: 07/27/2024] Open
Abstract
Dendritic cells (DCs) comprise diverse cell populations that play critical roles in antigen presentation and triggering immune responses in the body. However, several factors impair the immune function of DCs and may promote immune evasion in cancer. Understanding the mechanism of DC dysfunction and the diverse functions of heterogeneous DCs in the tumor microenvironment (TME) is critical for designing effective strategies for cancer immunotherapy. Clinical applications targeting DCs summarized in this report aim to improve immune infiltration and enhance the biological function of DCs to modulate the TME to prevent cancer cells from evading the immune system. Herein, factors in the TME that induce DC dysfunction, such as cytokines, hypoxic environment, tumor exosomes and metabolites, and co-inhibitory molecules, have been described. Furthermore, several key signaling pathways involved in DC dysfunction and signal-relevant drugs evaluated in clinical trials were identified. Finally, this review provides an overview of current clinical immunotherapies targeting DCs, especially therapies with proven clinical outcomes, and explores future developments in DC immunotherapies.
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Affiliation(s)
- Jie Chen
- Jecho Institute Co., LtdShanghaiP. R. China
| | - Yuhang Duan
- Engineering Research Center of Cell & Therapeutic AntibodyMinistry of EducationBeijingP. R. China
- Shanghai Jiao Tong University, School of PharmacyShanghaiP. R. China
| | - Junye Che
- Jecho Institute Co., LtdShanghaiP. R. China
| | - Jianwei Zhu
- Jecho Institute Co., LtdShanghaiP. R. China
- Engineering Research Center of Cell & Therapeutic AntibodyMinistry of EducationBeijingP. R. China
- Shanghai Jiao Tong University, School of PharmacyShanghaiP. R. China
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Assefa A, Getie M, Getie B, Yazie T, Enkobahry A. Molecular epidemiology of hepatitis B virus (HBV) in Ethiopia: A review article. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2024; 122:105618. [PMID: 38857639 DOI: 10.1016/j.meegid.2024.105618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 06/12/2024]
Abstract
Hepatitis B virus (HBV) belongs to the family Hepadnaviridae and is the smallest human DNA virus, with a genome that is only 3200 nucleotides long. The absence of proofreading function in HBV reverse transcriptase provides a wide range of genetic variants for targeted outgrowth at different stages of infection. A number of sub genotypes and ten HBV genotypes (A through J) have been identified through analyses of the divergence of HBV genomic sequences. Numerous clinical outcomes, including the emergence of chronicity, the course of the disease, the effectiveness of treatment, and the response to vaccination, have been related to differences in genotype between HBV isolates. There are just seven studies that have been done in Ethiopia that examine the molecular epidemiology of HBV. Moreover, these studies haven't been compiled and reviewed yet. In this review, we looked at the genetic diversity and molecular epidemiology of HBV, the relationship between HBV genotypes and clinical outcomes, the immunopathogenesis of HBV, and finally the molecular epidemiology of HBV in Ethiopia. PubMed, Embase, and Google Scholar search engines were used to find relevant articles for the review. By using HBV genotyping, clinicians can better tailor vaccination decisions and antiviral therapy for patients with chronic hepatitis B who are more likely to experience the disease's progression.
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Affiliation(s)
- Ayenew Assefa
- Unit of Immunology, Department of Medical Laboratory Science, Debre Tabor University, Debre Tabor, Ethiopia.
| | - Molla Getie
- College of Medicine and Health Science, Medical Laboratory Science Department, Injibara University, Injibara, Ethiopia
| | - Birhanu Getie
- Unit of Medical Microbiology, Department of Medical Laboratory Science, Debre Tabor University, Debre Tabor, Ethiopia
| | - Takilosimeneh Yazie
- College of Health Science, Department of Pharmacy, Debre Tabor University, Debre Tabor, Ethiopia
| | - Aklesya Enkobahry
- College of Medicine and Health Science, Department of Biomedical Science, Injibara University, Injibara, Ethiopia
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Li H, Huang Y, Yang Q, Zhang Z, Shen S, Guo H, Wei W. Pharmacological activation of TLR7 exerts inhibition on the replication of EV-D68 in respiratory cells. J Virol 2024; 98:e0043424. [PMID: 38690875 PMCID: PMC11237570 DOI: 10.1128/jvi.00434-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 04/04/2024] [Indexed: 05/03/2024] Open
Abstract
The globally reemerging respiratory pathogen enterovirus D68 (EV-D68) is implicated in outbreaks of severe respiratory illness and associated with acute flaccid myelitis. However, there remains a lack of effective treatments for EV-D68 infection. In this work, we found that the host Toll-like receptor 7 (TLR7) proteins, which function as powerful innate immune sensors, were selectively elevated in expression in response to EV-D68 infection. Subsequently, we investigated the impact of Vesatolimod (GS-9620), a Toll-like receptor 7 agonist, on EV-D68 replication. Our findings revealed that EV-D68 infection resulted in increased mRNA levels of TLR7. Treatment with Vesatolimod significantly inhibited EV-D68 replication [half maximal effective concentration (EC50) = 0.1427 µM] without inducing significant cytotoxicity at virucidal concentrations. Although Vesatolimod exhibited limited impact on EV-D68 attachment, it suppressed RNA replication and viral protein synthesis after virus entry. Vesatolimod broadly inhibited the replication of circulating isolated strains of EV-D68. Furthermore, our findings demonstrated that treatment with Vesatolimod conferred resistance to both respiratory and neural cells against EV-D68 infection. Overall, these results present a promising strategy for drug development by pharmacologically activating TLR7 to initiate an antiviral state in EV-D68-infected cells selectively.IMPORTANCEConventional strategies for antiviral drug development primarily focus on directly targeting viral proteases or key components, as well as host proteins involved in viral replication. In this study, based on our intriguing discovery that enterovirus D68 (EV-D68) infection specifically upregulates the expression of immune sensor Toll-like receptor 7 (TLR7) protein, which is either absent or expressed at low levels in respiratory cells, we propose a potential antiviral approach utilizing TLR7 agonists to activate EV-D68-infected cells into an anti-viral defense state. Notably, our findings demonstrate that pharmacological activation of TLR7 effectively suppresses EV-D68 replication in respiratory tract cells through a TLR7/MyD88-dependent mechanism. This study not only presents a promising drug candidate and target against EV-D68 dissemination but also highlights the potential to exploit unique alterations in cellular innate immune responses induced by viral infections, selectively inducing a defensive state in infected cells while safeguarding uninfected normal cells from potential adverse effects associated with therapeutic interventions.
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Affiliation(s)
- Huili Li
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Yuehan Huang
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Qingran Yang
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Zhe Zhang
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Siyu Shen
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Haoran Guo
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
| | - Wei Wei
- Institute of Virology and AIDS Research, First Hospital, Jilin University, Changchun, Jilin, China
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, First Hospital, Jilin University, Changchun, Jilin, China
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Peters MG, Yuen MF, Terrault N, Fry J, Lampertico P, Gane E, Hwang C, Stamm LM, Leus M, Maini MK, Mendez P, Lonjon-Domanec I, Berg T, Wang S, Mishra P, Donaldson E, Buchholz S, Miller V, Lenz O. Chronic Hepatitis B Finite Treatment: Similar and Different Concerns With New Drug Classes. Clin Infect Dis 2024; 78:983-990. [PMID: 37633256 PMCID: PMC11006103 DOI: 10.1093/cid/ciad506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/09/2023] [Accepted: 08/22/2023] [Indexed: 08/28/2023] Open
Abstract
Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed.
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Affiliation(s)
- Marion G Peters
- Department of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine & State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Norah Terrault
- Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - John Fry
- Aligos Therapeutics, Clinical Development Consultant, San Francisco, California, USA
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, CRC “A. M. and A. Migliavacca” Center for Liver Disease, University of Milan, Milan, Italy
| | - Ed Gane
- Department of Medicine, University of Auckland, Auckland, New Zealand
| | - Carey Hwang
- Vir Biotechnology, San Francisco, California, USA
| | - Luisa M Stamm
- Assembly Biosciences, South San Francisco, California, USA
| | - Mitchell Leus
- Forum for Collaborative Research, University of California, Berkeley School of Public Health, Washington, DC, USA
| | - Mala K Maini
- Institute of Immunity and Transplantation, University College London, London, United Kingdom
| | | | | | - Thomas Berg
- Department of Medicine, Leipzig University Medical Center, Leipzig, Germany
| | - Su Wang
- Cooperman Barnabas Medical Center, RWJBarnabas-Rutgers Medical Group, Livingston, New Jersey, USA
| | - Poonam Mishra
- Division of Antivirals, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Eric Donaldson
- Division of Antivirals, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Stephanie Buchholz
- Department 32 Infectiology, Dermatology and Allergology, Federal Institute for Drugs and Medical Devices, Germany
| | - Veronica Miller
- Forum for Collaborative Research, University of California, Berkeley School of Public Health, Washington, DC, USA
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Su X, Wang Z, Li J, Gao S, Fan Y, Wang K. Hypermethylation of the glutathione peroxidase 4 gene promoter is associated with the occurrence of immune tolerance phase in chronic hepatitis B. Virol J 2024; 21:72. [PMID: 38515187 PMCID: PMC10958902 DOI: 10.1186/s12985-024-02346-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 03/19/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a public health problem that seriously threatens human health. This study aimed to investigate the clinical significance of glutathione peroxidase 4(GPX4) in the occurrence and development of chronic hepatitis B (CHB). METHODS A total of 169 participants including 137 patients with CHB and 32 healthy controls (HCs) were recruited. We detected the expression of GPX4 and stimulator of interferon genes (STING) in peripheral blood mononuclear cells (PBMCs) by real-time quantitative polymerase chain reaction (RT-qPCR). The methylation level of GPX4 gene promoter in PBMCs was detected by TaqMan probe-based quantitative methylation-specific PCR (MethyLight). Enzyme-linked immunosorbent assay (ELISA) was performed to detect the serum levels of GPX4, IFN-β, oxidative stress (OS) related molecules, and pro-inflammatory cytokines. RESULTS The expression levels of GPX4 in PBMCs and serum of CHB patients were lower than those of HCs, but the methylation levels of GPX4 promoter were higher than those of HCs, especially in patients at the immune tolerance phase. STING mRNA expression levels in PBMCs and serum IFN-β levels of patients at the immune activation phase and reactivation phase of CHB were higher than those at other clinical phases of CHB and HCs. GPX4 mRNA expression level and methylation level in PBMCs from patients with CHB had a certain correlation with STING and IFN-β expression levels. In addition, the methylation level of the GPX4 promoter in PBMCs from patients with CHB was correlated with molecules associated with OS and inflammation. CONCLUSIONS GPX4 may play an important role in the pathogenesis and immune tolerance of CHB, which may provide new ideas for the functional cure of CHB.
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Affiliation(s)
- Xing Su
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012, Jinan City, Shandong Province, China
| | - Zhaohui Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012, Jinan City, Shandong Province, China
| | - Jihui Li
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012, Jinan City, Shandong Province, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012, Jinan City, Shandong Province, China
- Hepatology Institute of Shandong University, 250012, Jinan, Shandong, China
| | - Yuchen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012, Jinan City, Shandong Province, China
- Hepatology Institute of Shandong University, 250012, Jinan, Shandong, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, 250012, Jinan City, Shandong Province, China.
- Hepatology Institute of Shandong University, 250012, Jinan, Shandong, China.
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Ide M, Tabata N, Yonemura Y, Murai K, Wang Y, Ishida A, Honda M, Kaneko S, Ito S, Yanagawa H. Hepatitis B virus evades the immune system by suppressing the NF-κB signaling pathway with DENND2A. Microbiol Spectr 2024; 12:e0378523. [PMID: 38240571 PMCID: PMC10913737 DOI: 10.1128/spectrum.03785-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/08/2023] [Indexed: 03/06/2024] Open
Abstract
Overcoming hepatitis B virus (HBV) is a challenging problem because HBV deceives the host immune system. We have found that DENN domain-containing 2A (DENND2A) was essential for HBV maintenance, although its role remains unclear. In this study, we elucidate its function by screening a novel DENND2A-binding peptide, DENP4-3S. DENP4-3S exhibits homology to SAM and SH3 domain-containing protein 1 (SASH1), a scaffold protein involved in Toll-like receptor signaling that promotes proinflammatory cytokine production. We confirmed that DENND2A interacts with SASH1 specifically. Overexpression and knockdown experiments showed that overexpression of DENND2A suppressed the transcriptional activity of NF-κB, and the knockdown of DENND2A promoted it and the production of cytokines and interferons. Here, we constructed a fusion protein (10M-DEN3SN) consisting of an anti-asialoglycoprotein receptor antibody and DENP4-3S to deliver the peptide to hepatocytes specifically. 10M-DEN3SN inhibited the interaction between DENND2A and SASH1, and rescued SASH1 trapped by DENND2A, leading to the upregulation of NF-κB and its downstream signaling. In addition, 10M-DEN3SN suppressed HBV proliferation in PXB chimeric mice. These results with the DENND2A-binding peptide delivered into hepatocytes suggested the involvement of DENND2A, SASH, and NF-κB signaling pathway in the HBV infection and onset of hepatitis. In conclusion, this study indicates that HBV utilizes DENND2A and SASH1 to evade the immune system.IMPORTANCEHepatitis B virus (HBV) is a serious liver infection with no established cure, causing an abnormal host immune response. Here, we identified a novel peptide that interacts with DENN domain-containing 2A (DENND2A), a host factor essential for HBV maintenance. The resulting peptide showed sequence homology, revealing an interaction between DENND2A and the immune system regulator SASH1. This study suggests that DENND2A contributes to HBV infection by suppressing the cellular immune system by inhibiting SASH1. The DENND2A-binding peptide, incorporated into our hepatocyte-specific peptide delivery system, inhibited the DENND2A-SASH1 interaction and promoted the production of cytokines and interferons in cultured hepatocytes. As a consequence, the peptide suppressed HBV proliferation in humanized mice. We report new insights into the role of DENND2A and SASH1 in HBV maintenance and highlight the importance of the immune system.
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Affiliation(s)
- Mayuko Ide
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Noriko Tabata
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Yuko Yonemura
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Kazuhisa Murai
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
| | - Ying Wang
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
| | - Atsuya Ishida
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
| | - Masao Honda
- Department of Clinical Laboratory Medicine, Kanazawa University Graduate School of Health Medicine, Kanazawa, Ishikawa, Japan
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan
| | - Satoru Ito
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
| | - Hiroshi Yanagawa
- Research Department, Purotech Bio Inc, Yokohama, Kanagawa, Japan
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10
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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: 0] [Impact Index Per Article: 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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11
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Hu JL, Huang AL. Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics. Virol Sin 2024; 39:9-23. [PMID: 38110037 PMCID: PMC10877440 DOI: 10.1016/j.virs.2023.12.005] [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: 01/29/2023] [Accepted: 12/13/2023] [Indexed: 12/20/2023] Open
Abstract
The achievement of a functional cure for chronic hepatitis B (CHB) remains limited to a minority of patients treated with currently approved drugs. The primary objective in developing new anti-HBV drugs is to enhance the functional cure rates for CHB. A critical prerequisite for the functional cure of CHB is a substantial reduction, or even eradication of covalently closed circular DNA (cccDNA). Within this context, the changes in cccDNA levels during treatment become as a pivotal concern. We have previously analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics. In this review, we employ a systems thinking perspective to elucidate the fundamental aspects of the HBV replication cycle and to rationalize the classification of treatment strategies according to their impact on the dynamic equilibrium of cccDNA. Building upon this foundation, we categorize current anti-HBV strategies into two distinct groups and advocate for their combined use to significantly reduce cccDNA levels within a well-defined timeframe.
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Affiliation(s)
- Jie-Li Hu
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
| | - Ai-Long Huang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
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12
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Korkmaz P, Asan A, Karakeçili F, Tekin S, Demirtürk N. New Treatment Options in Chronic Hepatitis B: How Close Are We to Cure? INFECTIOUS DISEASES & CLINICAL MICROBIOLOGY 2023; 5:267-280. [PMID: 38633851 PMCID: PMC10986727 DOI: 10.36519/idcm.2023.265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/18/2023] [Indexed: 04/19/2024]
Abstract
Hepatitis B virus (HBV) infection is the leading cause of chronic liver disease worldwide. HBV-infected patients are at a lifetime risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). Today, pegylated interferon (Peg-IFN) and nucleos(t)ide analogs (NAs) are used in the treatment of patients with chronic hepatitis B (CHB). Both treatment options have limitations. Despite effective viral suppression, NAs have little effect on covalently closed circular DNA (cccDNA), the stable episomal form of the HBV genome in hepatocytes. Therefore, the cure rate with NAs is low, and long-term treatment is required. Although the cure rate is better with Peg-IFN, it is difficult to tolerate due to drug side effects. Therefore, new treatment options are needed in the treatment of HBV infection. We can group new treatments under two headings: those that interfere with the viral life cycle and spread and those that modulate the immune response. Clinical studies show that combinations of treatments that directly target the viral life cycle and treatments that regulate the host immune system will be among the important treatment strategies in the future. As new direct-acting antiviral (DAA) and immunomodulatory therapies continue to emerge and evolve, functional cures in HBV treatment may be an achievable goal.
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Affiliation(s)
- Pınar Korkmaz
- Department of Infectious Diseases and Clinical Microbiology, Kütahya Health Sciences University School of Medicine, Kütahya, Türkiye
| | - Ali Asan
- Department of Infectious Diseases and Clinical Microbiology, Bursa Health Sciences University School of Medicine, Bursa, Türkiye
| | - Faruk Karakeçili
- Department of Infectious Diseases and Clinical Microbiology, Erzincan Binali Yıldırım University School of Medicine, Erzincan, Türkiye
| | - Süda Tekin
- Department of Infectious Diseases and Clinical Microbiology, Koç University School of Medicine, İstanbul, Türkiye
| | - Neşe Demirtürk
- Department of Infectious Diseases and Clinical Microbiology, Afyonkarahisar Health Sciences University, School of Medicine, Afyonkarahisar, Türkiye
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13
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Ogunnaike M, Das S, Raut SS, Sultana A, Nayan MU, Ganesan M, Edagwa BJ, Osna NA, Poluektova LY. Chronic Hepatitis B Infection: New Approaches towards Cure. Biomolecules 2023; 13:1208. [PMID: 37627273 PMCID: PMC10452112 DOI: 10.3390/biom13081208] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/27/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection leads to the development of cirrhosis and hepatocellular carcinoma. Lifelong treatment with nucleotides/nucleoside antiviral agents is effective at suppressing HBV replication, however, adherence to daily therapy can be challenging. This review discusses recent advances in the development of long-acting formulations for HBV treatment and prevention, which could potentially improve adherence. Promising new compounds that target distinct steps of the virus life cycle are summarized. In addition to treatments that suppress viral replication, curative strategies are focused on the elimination of covalently closed circular DNA and the inactivation of the integrated viral DNA from infected hepatocytes. We highlight promising long-acting antivirals and genome editing strategies for the elimination or deactivation of persistent viral DNA products in development.
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Affiliation(s)
- Mojisola Ogunnaike
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Srijanee Das
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Samiksha S. Raut
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Ashrafi Sultana
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Mohammad Ullah Nayan
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Murali Ganesan
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Benson J. Edagwa
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
| | - Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Larisa Y. Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.O.); (S.D.); (S.S.R.); (A.S.); (M.U.N.); (M.G.)
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14
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Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
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Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
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15
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Yu H, Deng W, Chen S, Qin B, Yao Y, Zhou C, Guo M. Strongylocentrotus nudus egg polysaccharide (SEP) suppresses HBV replication via activation of TLR4-induced immune pathway. Int J Biol Macromol 2023:125539. [PMID: 37355064 DOI: 10.1016/j.ijbiomac.2023.125539] [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: 01/29/2023] [Revised: 06/17/2023] [Accepted: 06/21/2023] [Indexed: 06/26/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide public health problem that causes significant liver-related morbidity and mortality. In our previous study, Strongylocentrotus nudus eggs polysaccharide (SEP), extracted from sea urchins, had immunomodulatory and antitumor effects. Whether SEP has anti-HBV activity is still obscure. This study demonstrated that SEP decreased the secretion of hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), as well as the replication and transcription of HBV both in vitro and in vivo. Immunofluorescence and immunohistochemistry results showed that the level of HBV core antigen (HBcAg) was clearly reduced by SEP treatment. Mechanistically, RT-qPCR, western blot, and confocal microscopy analysis showed that SEP significantly increased the expression of toll-like receptor 4 (TLR4) and co-localization with TLR4. The downstream molecules of TLR4, including NF-κb and IRF3, were activated and the expression of IFN-β, TNF-α, IL-6, OAS, and MxA were also increased, which could suppress HBV replication. Moreover, SEP inhibited other genotypes of HBV and hepatitis C virus (HCV) replication in vitro. In summary, SEP could be investigated as a potential anti-HBV drug capable of modulating the innate immune.
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Affiliation(s)
- Haifei Yu
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China
| | - Wanyu Deng
- College of life science, Shangrao Normal University, Shangrao 334001, Jiangxi province, China
| | - Shuo Chen
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China
| | - Bo Qin
- Shaoxing Women and Children's Hospital, Shaoxing 312000, Zhejiang, China
| | - Yongxuan Yao
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children Medical Center, Guangzhou 510623, China.
| | - Changlin Zhou
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China.
| | - Min Guo
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China.
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16
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Salama II, Sami SM, Salama SI, Abdel-Latif GA, Shaaban FA, Fouad WA, Abdelmohsen AM, Raslan HM. Current and novel modalities for management of chronic hepatitis B infection. World J Hepatol 2023; 15:585-608. [PMID: 37305370 PMCID: PMC10251278 DOI: 10.4254/wjh.v15.i5.585] [Citation(s) in RCA: 6] [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: 11/19/2022] [Revised: 03/13/2023] [Accepted: 04/12/2023] [Indexed: 05/24/2023] Open
Abstract
Over 296 million people are estimated to have chronic hepatitis B viral infection (CHB), and it poses unique challenges for elimination. CHB is the result of hepatitis B virus (HBV)-specific immune tolerance and the presence of covalently closed circular DNA as mini chromosome inside the nucleus and the integrated HBV. Serum hepatitis B core-related antigen is the best surrogate marker for intrahepatic covalently closed circular DNA. Functional HBV "cure" is the durable loss of hepatitis B surface antigen (HBsAg), with or without HBsAg seroconversion and undetectable serum HBV DNA after completing a course of treatment. The currently approved therapies are nucleos(t)ide analogues, interferon-alpha, and pegylated-interferon. With these therapies, functional cure can be achieved in < 10% of CHB patients. Any variation to HBV or the host immune system that disrupts the interaction between them can lead to reactivation of HBV. Novel therapies may allow efficient control of CHB. They include direct acting antivirals and immunomodulators. Reduction of the viral antigen load is a crucial factor for success of immune-based therapies. Immunomodulatory therapy may lead to modulation of the host immune system. It may enhance/restore innate immunity against HBV (as toll-like-receptors and cytosolic retinoic acid inducible gene I agonist). Others may induce adaptive immunity as checkpoint inhibitors, therapeutic HBV vaccines including protein (HBsAg/preS and hepatitis B core antigen), monoclonal or bispecific antibodies and genetically engineered T cells to generate chimeric antigen receptor-T or T-cell receptor-T cells and HBV-specific T cells to restore T cell function to efficiently clear HBV. Combined therapy may successfully overcome immune tolerance and lead to HBV control and cure. Immunotherapeutic approaches carry the risk of overshooting immune responses causing uncontrolled liver damage. The safety of any new curative therapies should be measured in relation to the excellent safety of currently approved nucleos(t)ide analogues. Development of novel antiviral and immune modulatory therapies should be associated with new diagnostic assays used to evaluate the effectiveness or to predict response.
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Affiliation(s)
- Iman Ibrahim Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt.
| | - Samia M Sami
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Somaia I Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Ghada A Abdel-Latif
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Fatma A Shaaban
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Walaa A Fouad
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Aida M Abdelmohsen
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Hala M Raslan
- Department of Internal Medicine, National Research Centre, Giza 12411, Dokki, Egypt
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17
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Yang M, Vanderwert E, Kimchi ET, Staveley-O’Carroll KF, Li G. The Important Roles of Natural Killer Cells in Liver Fibrosis. Biomedicines 2023; 11:1391. [PMID: 37239062 PMCID: PMC10216436 DOI: 10.3390/biomedicines11051391] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/05/2023] [Accepted: 05/07/2023] [Indexed: 05/28/2023] Open
Abstract
Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If liver fibrosis is uncontrolled, it may lead to cirrhosis and even liver cancer, primarily hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as prostaglandin E receptor 3 (EP3) can regulate the cytotoxic function of NK cells. In addition, treatments such as alcohol dehydrogenase 3 (ADH3) inhibitors, microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of liver fibrosis.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Ethan Vanderwert
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
| | - Eric T. Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (M.Y.)
- NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA
- Department of Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO 65212, USA
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18
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Bhat S, Ahanger IA, Kazim SN. Forthcoming Developments in Models to Study the Hepatitis B Virus Replication Cycle, Pathogenesis, and Pharmacological Advancements. ACS OMEGA 2023; 8:14273-14289. [PMID: 37125123 PMCID: PMC10134252 DOI: 10.1021/acsomega.2c07154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/08/2023] [Indexed: 05/03/2023]
Abstract
Hepatitis, liver cirrhosis, and hepatocellular carcinoma are all manifestations of chronic hepatitis B. Its pathogenesis and molecular mechanism remain mysterious. As medical science progresses, different models are being used to study the disease from the physiological and molecular levels. Animal models have played an unprecedented role in achieving in-depth knowledge of the disease while posing no risk of harming humans throughout the study. The scarcity of acceptable animal models has slowed progress in hepatitis B virus (HBV) research and preclinical testing of antiviral medicines since HBV has a narrow species tropism and exclusively infects humans and higher primates. The development of human chimeric mice was supported by a better understanding of the obstacles to interspecies transmission, which has substantially opened the way for HBV research in vivo and the evaluation of possible chronic hepatitis B therapeutics. Animal models are cumbersome to handle, not accessible, and expensive. Hence, it is herculean to investigate the HBV replication cycle in animal models. Therefore, it becomes essential to build a splendid in vitro cell culture system to demonstrate the mechanisms attained by the HBV for its multiplication and sustenance. We also addressed the advantages and caveats associated with different models in examining HBV.
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Affiliation(s)
- Sajad
Ahmad Bhat
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ishfaq Ahmad Ahanger
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
- Clinical
Biochemistry University of Kashmir, Srinagar, India
| | - Syed Naqui Kazim
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
- Phone: +91 9953621758.
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Omer I, Abuthiyab N, Al-Omari B, Aletani T, Betar M, Alzaid N, Hakami AY. Efficacy and safety of vesatolimod in chronic hepatitis B: A systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e33609. [PMID: 37083786 PMCID: PMC10118312 DOI: 10.1097/md.0000000000033609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 04/03/2023] [Indexed: 04/22/2023] Open
Abstract
BACKGROUND Vesatolimod is a toll-like receptor (TLR) agonist that is thought to suppress chronic hepatitis B (HBV) infection. This systematic review aimed to assess the safety and efficacy of vesatolimod in treating chronic hepatitis B. METHODS We included randomized clinical trials (RCTs) that assessed vesatolimod in patients with hepatitis B infection without hepatocellular carcinoma or liver transplantation and with reported levels of hepatitis B surface antigen (HBsAg) or liver transaminases post-intervention. We searched MEDLINE, SCOPUS, Springer, Google Scholar, ClinicalTrials.gov, and Cochrane Central Register of Clinical Trials for all related articles during May 2022. Two independent authors screened articles for inclusion, and discrepancies were resolved by consensus and a third reviewer. Two independent reviewers assessed studies included in this systematic review using the Critical Appraisal Skills Programme checklist for RCTs. RESULTS AND CONCLUSION Only 4 were considered eligible from 391 articles identified through our search. All eligible studies did not report any clinically significant outcomes following the use of vesatolimod, as evidenced by the persistence of HBsAg. However, vesatolimod was associated with induction of interferon-stimulated genes (ISGs) and only mild side effects, warranting further studies to evaluate its potential for future use as a safe, tolerable anti-HBV medication. No significant differences were noted amongst trials included in either of Vesatolimod doses (Vesatolimod 1 mg, RR = 0.99, 95% CI 0.76-1.30, P = .95, I2 = 0%; Vesatolimod 2 mg, RR = 1.06, 95% CI 0.82-1.37, P = .66, I2 = 0%; Vesatolimod 4 mg, RR = 1.06, 95% CI 0.82-1.37, P = .66, I2 = 0%;), further suggesting its comparable safety in comparison to oral antiviral agents.
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Affiliation(s)
- Ibrahim Omer
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Noorah Abuthiyab
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Basil Al-Omari
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Tala Aletani
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Manar Betar
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Nura Alzaid
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Alqassem Y. Hakami
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
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20
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Nevola R, Beccia D, Rosato V, Ruocco R, Mastrocinque D, Villani A, Perillo P, Imbriani S, Delle Femine A, Criscuolo L, Alfano M, La Montagna M, Russo A, Marfella R, Cozzolino D, Sasso FC, Rinaldi L, Marrone A, Adinolfi LE, Claar E. HBV Infection and Host Interactions: The Role in Viral Persistence and Oncogenesis. Int J Mol Sci 2023; 24:7651. [PMID: 37108816 PMCID: PMC10145402 DOI: 10.3390/ijms24087651] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/14/2023] [Accepted: 04/19/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatitis B virus (HBV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Despite the advent of vaccines and potent antiviral agents able to suppress viral replication, recovery from chronic HBV infection is still an extremely difficult goal to achieve. Complex interactions between virus and host are responsible for HBV persistence and the risk of oncogenesis. Through multiple pathways, HBV is able to silence both innate and adaptive immunological responses and become out of control. Furthermore, the integration of the viral genome into that of the host and the production of covalently closed circular DNA (cccDNA) represent reservoirs of viral persistence and account for the difficult eradication of the infection. An adequate knowledge of the virus-host interaction mechanisms responsible for viral persistence and the risk of hepatocarcinogenesis is necessary for the development of functional cures for chronic HBV infection. The purpose of this review is, therefore, to analyze how interactions between HBV and host concur in the mechanisms of infection, persistence, and oncogenesis and what are the implications and the therapeutic perspectives that follow.
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Affiliation(s)
- Riccardo Nevola
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Domenico Beccia
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Valerio Rosato
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
| | - Rachele Ruocco
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Davide Mastrocinque
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
| | - Angela Villani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Pasquale Perillo
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
| | - Simona Imbriani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Augusto Delle Femine
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Livio Criscuolo
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Maria Alfano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Marco La Montagna
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Antonio Russo
- Department of Mental Health and Public Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Domenico Cozzolino
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (D.B.); (R.R.); (A.V.); (S.I.); (A.D.F.); (L.C.); (M.A.); (M.L.M.); (R.M.); (D.C.); (F.C.S.); (L.R.); (A.M.); (L.E.A.)
| | - Ernesto Claar
- Liver Unit, Ospedale Evangelico Betania, 80147 Naples, Italy; (V.R.); (D.M.); (P.P.); (E.C.)
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21
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Yuen MF, Balabanska R, Cottreel E, Chen E, Duan D, Jiang Q, Patil A, Triyatni M, Upmanyu R, Zhu Y, Canducci F, Gane EJ. TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind, placebo-controlled, phase 1 trial. THE LANCET. INFECTIOUS DISEASES 2023; 23:496-507. [PMID: 36509100 DOI: 10.1016/s1473-3099(22)00727-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Toll-like receptor 7 (TLR7) agonists augment immune activity and have potential for the treatment of chronic hepatitis B virus (HBV) infection. We aimed to assess the safety and tolerability of RO7020531 (also called RG7854), a prodrug of the TLR7 agonist RO7011785, in healthy volunteers and patients with chronic HBV infection. METHODS This randomised, observer-blind, placebo-controlled, phase 1 study was done in two parts. Part 1 was done at one site in New Zealand and part 2 was done at 12 sites in Bulgaria, Hong Kong, Italy, New Zealand, the Netherlands, Taiwan, Thailand, and the UK. In part 1, healthy volunteers were randomly assigned (4:1) within one of eight dose cohorts (3 mg, 10 mg, 20 mg, 40 mg, 60 mg, 100 mg, 140 mg, or 170 mg) to receive a single RO7020531 dose or placebo or randomly assigned (4:1) within one of three dose cohorts (100 mg, 140 mg, or 170 mg) to receive either RO7020531 or placebo every other day for 13 days. In part 2, nucleoside or nucleotide analogue-suppressed patients with chronic HBV infection were randomly assigned (4:1) within cohorts 1-3 (150 mg, 150 mg, or 170 mg) to receive either RO7020531 or placebo and treatment-naive patients with chronic HBV infection were randomly assigned (3:1) in cohort 4 to receive either 150 mg of RO7020531 or placebo. Patients were treated every other day for 6 weeks. Study medication was administered orally to participants after they had fasted. Study participants and investigational staff were masked to treatment allocation. The primary outcome was the safety and tolerability of RO7020531, as measured by the incidence and severity of adverse events and the incidence of laboratory, vital sign, and electrocardiogram abnormalities, and was analysed in all participants who received at least one dose of the study medication. This trial is registered with ClinicalTrials.gov, NCT02956850, and the study is complete. FINDINGS Between Dec 12, 2016, and March 21, 2021, 340 healthy volunteers were screened in part 1, of whom 80 were randomly assigned in the single ascending dose study (eight assigned RO7020531 in each cohort and 16 assigned placebo) and 30 were randomly assigned in the multiple ascending dose study (eight assigned RO7020531 in each cohort and six assigned placebo), and 110 patients were screened in part 2, of whom 30 were randomly assigned in cohorts 1-3 (16 assigned RO7020531 150 mg, eight assigned RO7020531 170 mg, and six assigned placebo) and 20 were randomly assigned in cohort 4 (15 assigned RO7020531 and five assigned placebo). All randomly assigned participants received at least one dose of a study drug and were included in the safety analysis. All tested doses of RO7020531 were safe and had acceptable tolerability in healthy volunteers and patients. The most frequent treatment-related adverse events among the total study population were headache (15 [9%] of 160 participants), influenza-like illness (seven [4%] of 160 participants), and pyrexia (ten [6%] of 160 participants). Most adverse events were mild and transient. There were no severe or serious adverse events in healthy volunteers. In the patient cohorts, there was one severe adverse event (influenza-like illness with 170 mg of RO7020531) and one serious adverse event (moderate influenza-like illness with a 3-day hospitalisation in a treatment-naive patient receiving RO7020531). There were no treatment-related deaths. INTERPRETATION Due to acceptable safety and tolerability, RO7020531 should continue to be developed for the treatment of patients with chronic HBV infection. FUNDING F Hoffmann-La Roche.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, School of Clinical Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Rozalina Balabanska
- Clinic of Gastroenterology, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria
| | - Emmanuelle Cottreel
- Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Ethan Chen
- Roche Pharma Product Development China, Shanghai, China
| | - Dan Duan
- Roche Pharma Research and Early Development, Roche Innovation Center, Shanghai, China
| | - Qiudi Jiang
- Roche Pharma Research and Early Development, Roche Innovation Center, Shanghai, China
| | - Avinash Patil
- Product Development Data Science Department, Roche Products, Welwyn, UK
| | - Miriam Triyatni
- Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland
| | - Ruchi Upmanyu
- Product Development Data Science Department, Roche Products, Welwyn, UK
| | - Yonghong Zhu
- Roche Pharma Research and Early Development, Roche Innovation Center, Shanghai, China
| | - Filippo Canducci
- Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.
| | - Edward J Gane
- Faculty of Medicine, University of Auckland, Auckland, New Zealand
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22
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Jeng WJ, Lok AS. What will it take to cure hepatitis B? Hepatol Commun 2023; 7:e0084. [PMID: 36972391 PMCID: PMC10043561 DOI: 10.1097/hc9.0000000000000084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 12/02/2022] [Indexed: 03/29/2023] Open
Abstract
The current treatment of chronic HBV infection, pegylated interferon-α (pegIFNα) and nucleos(t)ide analog (NA), can suppress HBV replication, reverse liver inflammation and fibrosis and reduce the risks of cirrhosis, HCC, and HBV-related deaths, but relapse is common when the treatment is stopped before HBsAg loss. There have been major efforts to develop a cure for HBV, defined as sustained HBsAg loss after a finite course of therapy. This requires the suppression of HBV replication and viral protein production and the restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. Immune modulatory therapies to stimulate adaptive or innate immunity and/or to remove immune blockade are being tested. NAs are included in most and pegIFNα in some regimens. Despite the combination of 2 or more therapies, HBsAg loss remains rare in part because HbsAg can be derived not only from the covalently closed circular DNA but also from the integrated HBV DNA. Achievement of a functional HBV cure will require therapies to eliminate or silence covalently closed circular DNA and integrated HBV DNA. In addition, assays to differentiate the source of circulating HBsAg and to determine HBV immune recovery, as well as standardization and improvement of assays for HBV RNA and hepatitis B core-related antigen, surrogate markers for covalently closed circular DNA transcription, are needed to accurately assess response and to target treatments according to patient/disease characteristics. Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Anna S.F. Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
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23
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Abstract
Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.
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Affiliation(s)
- Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - George V Papatheodoridis
- Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
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Dihydromyricetin inhibits Hepatitis B virus replication by activating NF-κB, MAPKs, and autophagy in HepG2.2.15 cells. Mol Biol Rep 2023; 50:1403-1414. [PMID: 36474061 DOI: 10.1007/s11033-022-07971-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/21/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a severe global health problem, and there has been no effective method to eliminate HBV. This study was designed to explore the pharmacological mechanism of Dihydromyricetin (DHM) treatment on HBV replication in vitro. METHODS AND RESULTS DHM is a flavonoid compound from Ampelopsis grossedentata. Using HepG2.2.15 cells, which can stably express HBV in vitro, we demonstrated that DHM treatment dramatically reduced HBV replication and secretions of HBsAg and HBeAg. Meanwhile, DHM inhibited mRNA expression of HBV RNAs in HepG2.2.15 cells, including Total HBV RNA, HBV pregenomic RNA (pgRNA), and HBV precore mRNA (pcRNA). Also, DHM elevated the mRNA expressions of inflammatory cytokines and antiviral effectors. In contrast, DHM decreased the mRNA level of HNF4α, which positively correlated with HBV replication. Further studies show that the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway played a critical role in DHM-initiated inhibition of HBV replication in HepG2.2.15 cells. Besides, activated autophagy was another contributor that may accelerate the clearance of HBV components. CONCLUSION In summary, DHM could suppress HBV replication by activating NF-κB, MAPKs, and autophagy in HepG2.2.15 cells. Our studies shed light on the future application of DHM for the clinical treatment of HBV infection.
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Wu LS, Hu Y, Gane EJ, Slaets L, De Creus A, Ding Y, Niu J, Schwabe C, Goeyvaerts N, Xu Z, Huo D, Tuefferd M, Verbrugge I, Van Remoortere P, Schwertschlag U, Vandenbossche J. Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants. Antivir Ther 2023; 28:13596535231151626. [PMID: 36691849 DOI: 10.1177/13596535231151626] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND JNJ-4964 is a TLR7 agonist, which, via a type I interferon (IFN)-dependent mechanism, may enhance host immunity suppressed by persistent exposure to hepatitis B antigens in chronic hepatitis B. METHODS PK and PD data were pooled from 2 studies involving 90 participants (n = 74 JNJ-4964, dose range 0.2-1.8 mg; n = 16 placebo) in a fasted state. Food effects on PK were studied in 24 participants (1.2 or 1.25 mg). A population PK model and PK/PD models were developed to characterize the effect of JNJ-4964 plasma levels on the time course of IFN-α, IFN-γ-inducible protein 10 (IP-10 or CXCL10), IFN-stimulated gene 15 (ISG15), neopterin and lymphocytes following single and weekly dosing in healthy adults. Covariate effects, circadian rhythms and negative feedback were incorporated in the models. RESULTS A 3-compartment linear PK model with transit absorption adequately described JNJ-4964 PK. Bioavailability was 44.2% in fed state relative to fasted conditions. Indirect response models with maximum effect (Emax) stimulation on production rate constant (kin) described IFN-α, IP-10, ISG15 and neopterin, while a precursor-dependent indirect response model with inhibitory effect described the transient lymphocyte reduction. Emax, EC50 and γ (steepness) estimates varied according to PD markers, with EC50 displaying substantial between-subject variability. Female and Asian race exhibited lower EC50, suggesting higher responsiveness. CONCLUSIONS PK/PD models well characterized the time course of immune system markers in healthy adults. Our results supported sex and race as covariates on JNJ-4964 responsiveness, as well as circadian rhythms and negative feedback as homeostatic mechanisms that are relevant in TLR7-induced type I IFN responses.
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Affiliation(s)
| | - Yue Hu
- 117971The First Hospital of Jilin University, Department of Hepatology, Changchun, Jilin, China
| | - Edward J Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital and University of Auckland, Auckland, New Zealand
| | - Leen Slaets
- Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium
| | - An De Creus
- Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium
| | - Yanhua Ding
- 117971The First Hospital of Jilin University, Department of Hepatology, Changchun, Jilin, China
| | - Junqi Niu
- 117971The First Hospital of Jilin University, Department of Hepatology, Changchun, Jilin, China
| | - Christian Schwabe
- Auckland Clinical Studies, New Zealand Clinical Research, Auckland, New Zealand
| | - Nele Goeyvaerts
- Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium
| | - Zhongnan Xu
- Chia Tai-Tianqing Pharmaceutical Group Co., Ltd, Nanjing, Jiangsu, China
| | - Dandan Huo
- Chia Tai-Tianqing Pharmaceutical Group Co., Ltd, Nanjing, Jiangsu, China
| | - Marianne Tuefferd
- Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium
| | - Inge Verbrugge
- Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium
| | | | | | - Joris Vandenbossche
- Janssen Research & Development, 50148Janssen Pharmaceutica NV, Beerse, Belgium
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The scientific basis of combination therapy for chronic hepatitis B functional cure. Nat Rev Gastroenterol Hepatol 2023; 20:238-253. [PMID: 36631717 DOI: 10.1038/s41575-022-00724-5] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2022] [Indexed: 01/13/2023]
Abstract
Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available.
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27
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Wang L, Zhang G, Sun Y, Wu Z, Ren C, Zhang Z, Peng X, Zhang Y, Zhao Y, Li C, Gao L, Liang X, Sun H, Cui J, Ma C. Enhanced Delivery of TLR7/8 Agonists by Metal-Organic Frameworks for Hepatitis B Virus Cure. ACS APPLIED MATERIALS & INTERFACES 2022; 14:46176-46187. [PMID: 36206454 DOI: 10.1021/acsami.2c11203] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Hepatitis B virus (HBV) infection remains a major challenge to global health due to unsatisfactory treatment efficacy, side effects of current therapies, and immune tolerance. Toll-like receptors 7/8 (TLR7/8) agonists have shown great potential in chronic hepatitis B (CHB) cure, but systemic administration often induces severe side effects due to rapid dispersion into the microvasculature. Herein, we encapsulate an imidazoquinoline-based TLR7/8 agonist (IMDQ) into zeolitic imidazolate framework 8 nanoparticles (IMDQ@ZIF-8 NPs) for HBV immunotherapy. Compared with free IMDQ, IMDQ@ZIF-8 NPs efficiently accumulate in the liver and are selectively taken up by antigen-presenting cells (APCs), leading to enhanced APC activation and efficient viral elimination in HBV-infected models. Strikingly, MDQ@ZIF-8 NP treatment results in the obvious production of anti-HBs antibody and seroconversion in HBV-infected mice. Overall, this study on the convergence of a facile assembly approach and efficient therapeutic effects represents a promising strategy for HBV treatment.
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Affiliation(s)
- Liyuan Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
- Department of Microbiology, Weifang Medical University, Weifang, Shandong 261042, China
| | - Guiqiang Zhang
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
- Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, Shandong 250117, China
| | - Yang Sun
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
| | - Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
| | - Caiyue Ren
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
| | - Zhaoying Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
| | - Xueqi Peng
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
| | - Yankun Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
| | - Ying Zhao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
| | - Chunyang Li
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
- Key Laboratory of Infection and Immunity of Shandong Province, Shandong University, Jinan, Shandong 250012, China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
- Key Laboratory of Infection and Immunity of Shandong Province, Shandong University, Jinan, Shandong 250012, China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
- Key Laboratory of Infection and Immunity of Shandong Province, Shandong University, Jinan, Shandong 250012, China
| | - Haifeng Sun
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
| | - Jiwei Cui
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong 250012, China
- Key Laboratory of Infection and Immunity of Shandong Province, Shandong University, Jinan, Shandong 250012, China
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28
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Contribution of T- and B-cell intrinsic toll-like receptors to the adaptive immune response in viral infectious diseases. Cell Mol Life Sci 2022; 79:547. [PMID: 36224474 PMCID: PMC9555683 DOI: 10.1007/s00018-022-04582-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 11/03/2022]
Abstract
Toll-like receptors (TLRs) comprise a class of highly conserved molecules that recognize pathogen-associated molecular patterns and play a vital role in host defense against multiple viral infectious diseases. Although TLRs are highly expressed on innate immune cells and play indirect roles in regulating antiviral adaptive immune responses, intrinsic expression of TLRs in adaptive immune cells, including T cells and B cells, cannot be ignored. TLRs expressed in CD4 + and CD8 + T cells play roles in enhancing TCR signal-induced T-cell activation, proliferation, function, and survival, serving as costimulatory molecules. Gene knockout of TLR signaling molecules has been shown to diminish antiviral adaptive immune responses and affect viral clearance in multiple viral infectious animal models. These results have highlighted the critical role of TLRs in the long-term immunological control of viral infection. This review summarizes the expression and function of TLR signaling pathways in T and B cells, focusing on the in vitro and vivo mechanisms and effects of intrinsic TLR signaling in regulating T- and B-cell responses during viral infection. The potential clinical use of TLR-based immune regulatory drugs for viral infectious diseases is also explored.
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29
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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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30
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Gehring AJ, Mendez P, Richter K, Ertl H, Donaldson EF, Mishra P, Maini M, Boonstra A, Lauer G, de Creus A, Whitaker K, Martinez SF, Weber J, Gainor E, Miller V. Immunological biomarker discovery in cure regimens for chronic hepatitis B virus infection. J Hepatol 2022; 77:525-538. [PMID: 35259469 DOI: 10.1016/j.jhep.2022.02.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 01/26/2022] [Accepted: 02/16/2022] [Indexed: 12/16/2022]
Abstract
There have been unprecedented advances in the identification of new treatment targets for chronic hepatitis B that are being developed with the goal of achieving functional cure in patients who would otherwise require lifelong nucleoside analogue treatment. Many of the new investigational therapies either directly target the immune system or are anticipated to impact immunity indirectly through modulation of the viral lifecycle and antigen production. While new viral biomarkers (HBV RNA, HBcAg, small, middle, large HBs isoforms) are proceeding through validation steps in clinical studies, immunological biomarkers are non-existent outside of clinical assays for antibodies to HBs, HBc and HBe. To develop clinically applicable immunological biomarkers to measure mechanisms of action, inform logical combination strategies, and guide clinical management for use and discontinuation of immune-targeting drugs, immune assays must be incorporated into phase I/II clinical trials. This paper will discuss the importance of sample collection, the assays available for immunological analyses, their advantages/disadvantages and suggestions for their implementation in clinical trials. Careful consideration must be given to ensure appropriate immunological studies are included as a primary component of the trial with deeper immunological analysis provided by ancillary studies. Standardising immunological assays and data obtained from clinical trials will identify biomarkers that can be deployed in the clinic, independently of specialised immunology laboratories.
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Affiliation(s)
- Adam J Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
| | - Patricia Mendez
- Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
| | - Kirsten Richter
- F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacher Strasse 124, CH-4070 Basel, Switzerland
| | | | - Eric F Donaldson
- Division of Antivirals, Center for Drug Evaluation and Research, US Food and Drug Administration, USA
| | - Poonam Mishra
- Division of Antivirals, Center for Drug Evaluation and Research, US Food and Drug Administration, USA
| | - Mala Maini
- Division of Infection and Immunity, University College London, London, UK
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Georg Lauer
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Kathleen Whitaker
- Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health, US Food and Drug Administration, USA
| | - Sara Ferrando Martinez
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, US; NeoImmuneTech, LLC 2400 Research Blvd, Suite 250 Rockville, MD 20850, USA
| | - Jessica Weber
- Forum for Collaborative Research, University of California, Berkeley, USA
| | - Emily Gainor
- Forum for Collaborative Research, University of California, Berkeley, USA
| | - Veronica Miller
- Forum for Collaborative Research, University of California, Berkeley, USA
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31
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Du Y, Wu J, Liu J, Zheng X, Yang D, Lu M. Toll-like receptor-mediated innate immunity orchestrates adaptive immune responses in HBV infection. Front Immunol 2022; 13:965018. [PMID: 35967443 PMCID: PMC9372436 DOI: 10.3389/fimmu.2022.965018] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/30/2022] [Indexed: 12/03/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains to be a substantial global burden, especially for end-stage liver diseases. It is well accepted that HBV-specific T and B cells are essential for controlling HBV infection. Toll-like receptors (TLRs) represent one of the major first-line antiviral defenses through intracellular signaling pathways that induce antiviral inflammatory cytokines and interferons, thereby shaping adaptive immunity. However, HBV has evolved strategies to counter TLR responses by suppressing the expression of TLRs and blocking the downstream signaling pathways, thus limiting HBV-specific adaptive immunity and facilitating viral persistence. Recent studies have stated that stimulation of the TLR signaling pathway by different TLR agonists strengthens host innate immune responses and results in suppression of HBV replication. In this review, we will discuss how TLR-mediated responses shape HBV-specific adaptive immunity as demonstrated in different experimental models. This information may provide important insight for HBV functional cure based on TLR agonists as immunomodulators.
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Affiliation(s)
- Yanqin Du
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Mengji Lu,
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32
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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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33
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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: 88] [Impact Index Per Article: 29.3] [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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34
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Watanabe T, Hayashi S, Tanaka Y. Drug Discovery Study Aimed at a Functional Cure for HBV. Viruses 2022; 14:1393. [PMID: 35891374 PMCID: PMC9321005 DOI: 10.3390/v14071393] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/19/2022] [Accepted: 06/23/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis B virus (HBV) causes acute and, most importantly, chronic hepatitis B worldwide. Antiviral treatments have been developed to reduce viral loads but few patients with chronic hepatitis B (CHB) achieve a functional cure. The development of new therapeutic agents is desirable. Recently, many novel agents have been developed, including drugs targeting HBV-DNA and HBV-RNA. This review provides an overview of the developmental status of these drugs, especially direct acting antiviral agents (DAAs). Serological biomarkers of HBV infection are essential for predicting the clinical course of CHB. It is also important to determine the amount and activity of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. Hepatitis B core-associated antigen (HBcrAg) is a new HBV marker that has an important role in reflecting cccDNA in CHB, because it is associated with hepatic cccDNA, as well as serum HBV DNA. The highly sensitive HBcrAg (iTACT-HBcrAg) assay could be a very sensitive HBV activation marker and an alternative to HBV DNA testing for monitoring reactivation. Many of the drugs currently in clinical trials have shown efficacy in reducing hepatitis B surface antigen (HBsAg) levels. Combination therapies with DAAs and boost immune response are also under development; finding the best combinations will be important for therapeutic development.
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Affiliation(s)
| | | | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (T.W.); (S.H.)
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35
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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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36
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Wong GLH, Gane E, Lok ASF. How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development? J Hepatol 2022; 76:1249-1262. [PMID: 35589248 DOI: 10.1016/j.jhep.2021.11.024] [Citation(s) in RCA: 142] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 12/20/2022]
Abstract
Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.
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Affiliation(s)
- Grace L H Wong
- Medical Data Analytics Centre, Department of Medicine and Therapeutics, and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Ed Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, University of Auckland, New Zealand
| | - Anna S F Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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37
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Mikhail AS, Mauda-Havakuk M, Negussie AH, Hong N, Hawken NM, Carlson CJ, Owen JW, Franco-Mahecha O, Wakim PG, Lewis AL, Pritchard WF, Karanian JW, Wood BJ. Evaluation of immune-modulating drugs for use in drug-eluting microsphere transarterial embolization. Int J Pharm 2022; 616:121466. [PMID: 35065205 PMCID: PMC9139086 DOI: 10.1016/j.ijpharm.2022.121466] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 12/30/2022]
Abstract
Cancer immunotherapy has yet to reach its full potential due in part to limited response rates and side effects inherent to systemic delivery of immune-modulating drugs. Local administration of immunotherapy using drug-eluting embolic (DEE) microspheres as drug delivery vehicles for direct infusion into tumor-feeding arteries might increase and prolong tumor drug concentrations and reduce systemic drug exposure, potentially improving the risk-to-benefit ratio of these agents. The purpose of this study was to evaluate the ability of four immune modulators affecting two different immune pathways to potentiate replication of immune cells from a woodchuck model of hepatocellular carcinoma. DSR 6434, a Toll-like receptor agonist, and BMS-202, a PD-L1 checkpoint inhibitor, induced immune cell replication and were successfully loaded into radiopaque DEE microspheres in high concentrations. Release of DSR 6434 from the DEE microspheres was rapid (t99% = 0.4 h) upon submersion in a physiologic saline solution while BMS-202 demonstrated a more sustained release profile (t99% = 17.9 h). These findings demonstrate the feasibility of controlled delivery of immune-modulating drugs via a local DEE microsphere delivery paradigm.
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Affiliation(s)
- Andrew S Mikhail
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
| | - Michal Mauda-Havakuk
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Ayele H Negussie
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Natalie Hong
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Natalie M Hawken
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Camella J Carlson
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Joshua W Owen
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Olga Franco-Mahecha
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Paul G Wakim
- Biostatistics and Clinical Epidemiology Service, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Andrew L Lewis
- Biocompatibles UK Ltd (a BTG International Group Company), Lakeview, Riverside Way, Watchmoor Park, Camberley, Surrey, UK
| | - William F Pritchard
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - John W Karanian
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Bradford J Wood
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
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Hui RWH, Mak LY, Seto WK, Yuen MF. RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin Mol Hepatol 2022; 28:408-424. [PMID: 35172540 PMCID: PMC9293617 DOI: 10.3350/cmh.2022.0012] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 02/16/2022] [Indexed: 11/26/2022] Open
Abstract
Chronic hepatitis B (CHB) is a major cause of liver-related morbidity and mortality. Functional cure of CHB, defined as sustainable hepatitis B surface antigen (HBsAg) seroclearance, is associated with improved clinical outcomes. However, functional cure is rarely attainable by current treatment modalities. RNA interference (RNAi) by small-interfering RNA (siRNA) and anti-sense oligonucleotide (ASO) has been studied as a novel treatment strategy for CHB. RNAi targets post-transcriptional messenger RNAs and pregenomic RNAs to reduce hepatitis B virus (HBV) antigen production and viral replication. By reducing viral antigens, host immune reconstitution against HBV may also be attained. Phase I/II trials on siRNAs have demonstrated them to be safe and well-tolerated. siRNA is effective when given in monthly doses with different total number of doses according to different trial design, and can lead to sustainable dose-dependent mean HBsAg reduction by 2–2.5 log. Incidences of HBsAg seroclearance after siRNA therapy have also been reported. ASOs have also been studied in early phase trials, and a phase Ib study using frequent dosing regimen within 4 weeks could achieve similar HBsAg reduction of 2 log from baseline. Given the established efficacy and safety of nucleos(t) ide analogues (NAs), future RNAi regimens will likely include NA backbone. While the current evidence on RNAi appears promising, it remains undetermined whether the potent HBsAg reduction by RNAi can result in a high rate of HBsAg seroclearance with durability. Data on RNAi from phase IIb/III trials are keenly anticipated.
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Affiliation(s)
- Rex Wan-Hin Hui
- Department of Medicine, The University of Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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Abstract
Chronic hepatitis B virus (HBV) infection remains a global health burden. Timely and effective antiviral therapy is beneficial for patients with HBV infection. With existing antiviral drugs, including nucleos(t)ide analogs and interferon-alfa, patients can achieve viral suppression with improved prognosis. However, the rate of hepatitis B surface antigen loss is low. To achieve a functional cure and even complete cure in chronic hepatitis B patients, new antivirals need to be developed. In this review, we summarized the advantages and disadvantages of existing antiviral drugs and focused on new antivirals including direct-acting antiviral drugs and immunotherapeutic approaches.
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40
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Humoral immunity in hepatitis B virus infection: Rehabilitating the B in HBV. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100398. [PMID: 35059620 PMCID: PMC8760517 DOI: 10.1016/j.jhepr.2021.100398] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/15/2022]
Abstract
Insights into the immunopathogenesis of chronic HBV infections are fundamental in the quest for novel treatment approaches aimed at a functional cure. While much is known about the ineffective HBV-specific T-cell responses that characterise persistent HBV replication, B cells have been left largely understudied. However, an important role for humoral immunity during the natural history of HBV infections, as well as after functional cure, has been inadvertently revealed by the occurrence of HBV flares following B cell-depleting treatments. Herein, we review our current understanding of the role of the humoral immune response in chronic HBV, both at the level of HBV-specific antibody production and at the phenotypic and broader functional level of B cells. The recent development of fluorescently labelled HBV proteins has given us unprecedented insights into the phenotype and function of HBsAg- and HBcAg-specific B cells. This should fuel novel research into the mechanisms behind dysfunctional HBsAg-specific and fluctuating, possibly pathogenic, HBcAg-specific B-cell responses in chronic HBV. Finally, novel immunomodulatory treatments that partly target B cells are currently in clinical development, but a detailed assessment of their impact on HBV-specific B-cell responses is lacking. We plead for a rehabilitation of B-cell studies related to both the natural history of HBV and treatment development programmes.
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Wei L, Zhao T, Zhang J, Mao Q, Gong G, Sun Y, Chen Y, Wang M, Tan D, Gong Z, Li B, Niu J, Li S, Gong H, Zou L, Zhou W, Jia Z, Tang Y, Fei L, Hu Y, Shang X, Han J, Zhang B, Wu Y. Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis B: A randomized clinical trial. Hepatology 2022; 75:182-195. [PMID: 34396571 DOI: 10.1002/hep.32109] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/28/2021] [Accepted: 07/31/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB. APPROACH AND RESULTS A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo. CONCLUSIONS Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).
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Affiliation(s)
- Lai Wei
- Peking University People's Hospital, Peking University Hepatology institute, Beijing, China
| | - Tingting Zhao
- Chongqing International Institute for Immunology, Chongqing, China
| | - Ji Zhang
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Qing Mao
- Infectious Diseases Institute of PLA, Southwest Hospital, Army Medical University, Chongqing, China
| | - Guozhong Gong
- Infectious Diseases Department, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yongtao Sun
- Infectious Diseases Department, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yongping Chen
- Infectious Diseases Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Maorong Wang
- Infectious Diseases Department, The 81th Hospital of PLA, Nanjing, China
| | - Deming Tan
- Infectious Diseases Department, Xiangya Hospital of Central South University, Changsha, China
| | - Zuojiong Gong
- Infectious Diseases Department, Renmin Hospital of Wuhan University, Wuhan, China
| | - Baosen Li
- Infectious Diseases Department, 302 Military Hospital, Beijing, China
| | - Junqi Niu
- Infectious Diseases Department, The First Hospital of Jilin University, Changchun, China
| | - Shuchen Li
- Infectious Diseases Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huanyu Gong
- Infectious Diseases Department, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Liyun Zou
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Wei Zhou
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Zhengcai Jia
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Yan Tang
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Lei Fei
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Yang Hu
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Xiaoyun Shang
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Junfeng Han
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Bei Zhang
- Department of Immunology, Medical College of Qingdao University, Qingdao, China
| | - Yuzhang Wu
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
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González Grande R, Santaella Leiva I, López Ortega S, Jiménez Pérez M. Present and future management of viral hepatitis. World J Gastroenterol 2021; 27:8081-8102. [PMID: 35068856 PMCID: PMC8704279 DOI: 10.3748/wjg.v27.i47.8081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/08/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis can result in important morbidity and mortality, with its impact on health conditioned by the specific type of hepatitis, the geographical region of presentation and the development and access to new drugs, among other factors. Most acute presentation forms are self-limiting and may even go unnoticed, with just a small percentage of cases leading to acute liver failure that may necessitate transplantation or even cause the death of the patient. However, when they become chronic, as in the case of hepatitis B virus and C virus, unless they are diagnosed and treated adequately they may have severe consequences, like cirrhosis or hepatocarcinoma. Understanding of the mechanisms of transmission, the pathogenesis, the presence of vaccinations and the development over recent years of new highly-efficient, potent drugs have meant that we are now faced with a new scenario in the management of viral hepatitis, particularly hepatitis B virus and hepatitis C virus. The spectacular advances in hepatitis C virus treatment have led the World Health Organization to propose the objective of its eradication by 2030. The key aspect to achieving this goal is to ensure that these treatments reach all the more vulnerable population groups, in whom the different types of viral hepatitis have a high prevalence and constitute a niche that may perpetuate infection and hinder its eradication. Accordingly, micro-elimination programs assume special relevance at the present time.
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Affiliation(s)
- Rocío González Grande
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
| | - Inmaculada Santaella Leiva
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
| | - Susana López Ortega
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
| | - Miguel Jiménez Pérez
- UGC de Aparato Digestivo. Unidad de Hepatología-Trasplante Hepático, Hospital Regional Universitario de Málaga, Málaga 29010, Spain
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Gao F, Wang H, Li X, Guo F, Yuan Y, Wang X, Zhang Y, Bai G. Alteration of the Immune Microenvironment in HBsAg and HBeAg Dual-Positive Pregnant Women Presenting a High HBV Viral Load. J Inflamm Res 2021; 14:5619-5632. [PMID: 34764667 PMCID: PMC8573211 DOI: 10.2147/jir.s337561] [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: 09/03/2021] [Accepted: 10/14/2021] [Indexed: 12/17/2022] Open
Abstract
Purpose The aim of this study was to compare the differences in the immune microenvironment between HBV-infected pregnant women with a high HBV viral load and healthy pregnant women, with an emphasis on T cell subset alteration. Patients and Methods We compared the differences of cellular and molecular signatures between HBV-infected and healthy pregnant women by performing single-cell RNA and T cell receptor sequencing of peripheral blood mononuclear cells from 51,836 women in the mid-trimester pregnancy stage. Specific trajectories of the different T clusters throughout the course of T cell differentiation were investigated. Flow cytometry was used to validate the proportion of different T cell subtypes. Results We identified nine cellular subtypes and found an increased proportion of effector/memory CD8+ T cells in HBV-infected pregnant women. Both CD4+ and CD8+ effector/memory T cells in HBV-related samples expressed higher levels of metallothionein (MT)-related genes (MT2A, MTIE, MTIF, MTIX), metal ion pathways, and multiple inflammatory responses. Among CD8+ T cell clusters, we identified a particular subset of effector/memory CD8+ T cells (CD8-cluster 2) with MTs as the top-ranking genes, which may be enriched in HBV-related samples. These cells showed an increased clonal expansion in HBV infection. Moreover, we found more active immune responses, according to cellular interaction patterns, between immune cell subsets in HBV-infected samples. Conclusion This study shows significant differences between HBV-infected and healthy samples, including cell clusters, dominant gene sets, T cell function, clonal expansion, and V/J gene usage of T cell clonotypes, and identifies a distinct CD8+ T cell cluster with immune-active and antiviral properties. These findings pave the way for a deeper understanding of the impact of HBV infection on the immune microenvironment during pregnancy.
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Affiliation(s)
- Fan Gao
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Hongyan Wang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Xia Li
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Fanfan Guo
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Yufei Yuan
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Xiaona Wang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Yidan Zhang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Guiqin Bai
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
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44
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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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45
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Feng Y, Xie H, Shi F, Chen D, Xie A, Li J, Fang C, Wei H, Huang H, Pan X, Tang X, Huang J. Roles of TLR7 in Schistosoma japonicum Infection-Induced Hepatic Pathological Changes in C57BL/6 Mice. Front Cell Infect Microbiol 2021; 11:754299. [PMID: 34692568 PMCID: PMC8531751 DOI: 10.3389/fcimb.2021.754299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
S. japonicum infection can induce granulomatous inflammation in the liver of the host. Granulomatous inflammation limits the spread of infection and plays a role in host protection. Toll-like receptor 7 (TLR7) is an endosomal TLR that recognizes single-stranded RNA (ssRNA). In this study, the role of TLR7 in S. japonicum infection-induced hepatitis was investigated in both normal and TLR7 knockout (KO) C57BL/6 mice. The results indicated that TLR7 KO could aggravate S. japonicum infection-induced damage in the body, with less granuloma formation in the tissue, lower WBCs in blood, and decreased ALT and AST in the serum. Then, the expression of TLR7 was detected in isolated hepatic lymphocytes. The results indicated that the percentage of TLR7+ cells was increased in the infected mice. Hepatic macrophages, DCs, and B cells could express TLR7, and most of the TLR7-expressing cells in the liver of infected mice were macrophages. The percentage of TLR7-expressing macrophages was also increased after infection. Moreover, macrophages, T cells, and B cells showed significant changes in the counts, activation-associated molecule expression, and cytokine secretion between S. japonicum-infected WT and TLR7 KO mice. Altogether, this study indicated that TLR7 could delay the progression of S. japonicum infection-induced hepatitis mainly through macrophages. DCs, B cells, and T cells were involved in the TLR7-mediated immune response.
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Affiliation(s)
- Yuanfa Feng
- Department of Infectious Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Hongyan Xie
- China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Feihu Shi
- Department of Infectious Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Dianhui Chen
- Department of Infectious Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Anqi Xie
- China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Jiajie Li
- China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Chao Fang
- China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Haixia Wei
- China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - He Huang
- China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Xingfei Pan
- Department of Infectious Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoping Tang
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jun Huang
- China Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
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46
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Cheng Z, Lin P, Cheng N. HBV/HIV Coinfection: Impact on the Development and Clinical Treatment of Liver Diseases. Front Med (Lausanne) 2021; 8:713981. [PMID: 34676223 PMCID: PMC8524435 DOI: 10.3389/fmed.2021.713981] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/23/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a common contributor to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Approximately 10% of people with human immunodeficiency virus (HIV) also have chronic HBV co-infection, owing to shared transmission routes. HIV/HBV coinfection accelerates the progression of chronic HBV to cirrhosis, end-stage liver disease, or hepatocellular carcinoma compared to chronic HBV mono-infection. HBV/HIV coinfection alters the natural history of hepatitis B and renders the antiviral treatment more complex. In this report, we conducted a critical review on the epidemiology, natural history, and pathogenesis of liver diseases related to HBV/HIV coinfection. We summarized the novel therapeutic options for these coinfected patients.
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Affiliation(s)
- Zhimeng Cheng
- Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Panpan Lin
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Nansheng Cheng
- Department of Bile Duct Surgery, West China Hospital, Sichuan University, Chengdu, China
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Jiao Q, Xu W, Guo X, Liu H, Liao B, Zhu X, Chen C, Yang F, Wu L, Xie C, Peng L. NLRX1 can counteract innate immune response induced by an external stimulus favoring HBV infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Sci Prog 2021; 104:368504211058036. [PMID: 34825857 PMCID: PMC10461377 DOI: 10.1177/00368504211058036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION This study is aimed at the determination of the effect of the immune-regulatory factor NLRX1 on the antiviral activity of hepatocytes against an external stimuli favoring hepatitis B virus infection, and to explore its mechanism of action. METHODS A HepG2-NTCP model was established using the LV003 lentivirus. Cells were transfected using an overexpression vector and NLRX1 siRNA to achieve overexpression and interference of NLRX1 expression (OV-NLRX1, si-NLRX1). Levels of HBsAg and HBcAg were determined using Western blotting analysis and immunohistochemical analysis. The levels of hepatitis B virus DNA and hepatitis B virus cccDNA were determined by real-time quantitative polymerase chain reaction. The expression and transcriptional activity of IFN-α, IFN-β, and IL-6 were measured using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and promoter-luciferase reporter plasmids. Co-immunoprecipitation was used to determine the effect of NLRX1 on the interaction between MAVS and RIG-1. Western blotting was used to obtain the phosphorylation of essential proteins in the MAVS-RLRs signaling pathways. RESULTS NLRX1 promoted HepG2-NTCP cell hepatitis B virus infection. Compared to the control group, the levels of HBsAg, HBcAg, hepatitis B virus cccDNA, and hepatitis B virus DNA increased in the OV-NLRX1 group and decreased in the si-NLRX1. Co-immunoprecipitation results showed that NLRX1 competitively inhibited the interaction between MAVS and RIG-1, and inhibited the phosphorylation of p65, IRF3, and IRF7. Additionally, NLRX1 reduced the transcription activity and expression levels of the final products: IFN-α, IFN-β, and IL-6. CONCLUSIONS NLRX1 can counteract innate immune response induced by an external stimuli favoring hepatitis B virus infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Inhibition of the MAVS-RLR-mediated signaling pathways leads to a decline in the expression levels of I-IFN and IL-6.
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Affiliation(s)
- Qian Jiao
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
- Infectious Disease Center, Guangzhou Eighth People’s
Hospital, Guangzhou Medical University, China
| | - Wenxiong Xu
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
| | - Xiaoyan Guo
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
| | - Huiyuan Liu
- Infectious Disease Center, Guangzhou Eighth People’s
Hospital, Guangzhou Medical University, China
| | - Baolin Liao
- Infectious Disease Center, Guangzhou Eighth People’s
Hospital, Guangzhou Medical University, China
| | - Xiang Zhu
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
| | - Chuming Chen
- Department of Infectious Diseases, Third People’s Hospital of
Shenzhen, China
| | - Fangji Yang
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
| | - Lina Wu
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
| | - Chan Xie
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
| | - Liang Peng
- Department of Infectious Diseases,
Third Affiliated Hospital, Sun Yat-sen University, China
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48
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Abstract
Chronic hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, estimated to be globally responsible for ∼800,000 deaths annually. Although effective vaccines are available to prevent new HBV infection, treatment of existing chronic hepatitis B (CHB) is limited, as the current standard-of-care antiviral drugs can only suppress viral replication without achieving cure. In 2016, the World Health Organization called for the elimination of viral hepatitis as a global public health threat by 2030. The United States and other nations are working to meet this ambitious goal by developing strategies to cure CHB, as well as prevent HBV transmission. This review considers recent research progress in understanding HBV pathobiology and development of therapeutics for the cure of CHB, which is necessary for elimination of hepatitis B by 2030.
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Affiliation(s)
- Timothy M Block
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz VA Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Doylestown, Pennsylvania 18902, USA;
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Akbar SMF, Al Mahtab M, Cesar Aguilar J, Uddin MH, Khan MSI, Yoshida O, Penton E, Gerardo GN, Hiasa Y. Exploring evidence-based innovative therapy for the treatment of chronic HBV infection: experimental and clinical. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/03/2021] [Indexed: 01/02/2025] Open
Abstract
With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.
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Affiliation(s)
- Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 1000, Bangladesh
| | - Julio Cesar Aguilar
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Md. Sakirul Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
| | - Eduardo Penton
- Center for Genetic Engineering and Biotechnology, Havana, Havana 10600, Cuba
| | | | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime 7910295, Japan
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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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