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Bertoletti A. The immune response in chronic HBV infection. J Viral Hepat 2024; 31 Suppl 2:43-55. [PMID: 38845402 DOI: 10.1111/jvh.13962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 05/14/2024] [Indexed: 12/06/2024]
Abstract
Hepatitis B virus (HBV) is an ancient virus that has evolved unique strategies to persist as a chronic infection in humans. Here, I summarize the innate and adaptive features of the HBV-host interaction, and I discuss how different profiles of antiviral immunity cannot be predicted only on the basis of virological and clinical parameters.
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Affiliation(s)
- Antonio Bertoletti
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
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2
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Lok J, Guerra Veloz MF, Agarwal K. Overview of New Targets for Hepatitis B Virus: Immune Modulators, Interferons, Bifunctional Peptides, Therapeutic Vaccines and Beyond. Clin Liver Dis 2023; 27:857-876. [PMID: 37778774 DOI: 10.1016/j.cld.2023.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Nucleos(t)ide analogs are the cornerstone of treatment against hepatitis B virus; however, they have no direct effect on its transcriptional template (ie, covalently closed circular DNA) and so functional cure is rarely achieved. Over recent years, there has been a significant improvement in our understanding of the viral life cycle and its mechanisms of immune evasion. In this review article, we will explore novel therapeutic targets, discuss the latest data from clinical trials, and highlight future research priorities.
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Affiliation(s)
- James Lok
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK.
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Li F, Song B, Zhou WF, Chu LJ. Toll-Like Receptors 7/8: A Paradigm for the Manipulation of Immunologic Reactions for Immunotherapy. Viral Immunol 2023; 36:564-578. [PMID: 37751284 DOI: 10.1089/vim.2023.0077] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023] Open
Abstract
The innate immune system recognizes conserved features of viral and microbial pathogens through pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are one type of PRR used by the innate immune system to mediate the secretion of proinflammatory cytokines and promote innate and adaptive immune responses. TLR family members TLR7 and TLR8 (referred to as TLR7/8 from herein) are endosomal transmembrane receptors that recognize purine-rich single-stranded RNA (ssRNA) and bacterial DNA, eliciting an immunologic reaction to pathogens. TLR7/8 were discovered to mediate the secretion of proinflammatory cytokines by activating immune cells. In addition, accumulating evidence has indicated that TLR7/8 may be closely related to numerous immune-mediated disorders, specifically several types of cancer, autoimmune disease, and viral disease. TLR7/8 agonists and antagonists, which are used as drugs or adjuvants, have been identified in preclinical studies and clinical trials as promising immune stimulators for the immunotherapy of these immune-mediated disorders. These results provided reasoning to further explore immunotherapy for the treatment of immune-mediated disorders. Nevertheless, numerous needs remain unmet, and the therapeutic effects of TLR7/8 agonists and antagonists are poor and exert strong immune-related toxicities. The present review aimed to provide an overview of the TLR family members, particularly TLR7/8, and address the underlying molecular mechanisms and clinical implications of TLR7/8 in immune-mediated disorders. The aim of the work is to discuss the underlying molecular mechanisms and clinical implications of TLR7/8 in immune-mediated disorders.
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Affiliation(s)
- Fang Li
- Department of Clinical Medicine, Anhui Medical College, Hefei, China
| | - Biao Song
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei-Feng Zhou
- Department of Clinical Medicine, Anhui Medical College, Hefei, China
| | - Li-Jin Chu
- Department of Clinical Medicine, Anhui Medical College, Hefei, China
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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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5
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Pan Y, Xia H, He Y, Zeng S, Shen Z, Huang W. The progress of molecules and strategies for the treatment of HBV infection. Front Cell Infect Microbiol 2023; 13:1128807. [PMID: 37009498 PMCID: PMC10053227 DOI: 10.3389/fcimb.2023.1128807] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/03/2023] [Indexed: 03/17/2023] Open
Abstract
Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis B virus (HBV)-related diseases resulted in approximately 555,000 deaths globally. In view of its high lethality, the treatment of HBV infections has always presented a huge challenge. The World Health Organization (WHO) came up with ambitious targets for the elimination of hepatitis B as a major public health threat by 2030. To accomplish this goal, one of the WHO's strategies is to develop curative treatments for HBV infections. Current treatments in a clinical setting included 1 year of pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both treatments have demonstrated outstanding antiviral effects, it has been difficult to develop a cure for HBV. The reason for this is that covalently closed circular DNA (cccDNA), integrated HBV DNA, the high viral burden, and the impaired host immune responses all hinder the development of a cure for HBV. To overcome these problems, there are clinical trials on a number of antiviral molecules being carried out, all -showing promising results so far. In this review, we summarize the functions and mechanisms of action of various synthetic molecules, natural products, traditional Chinese herbal medicines, as clustered regularly interspaced short palindromic repeats and their associated proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), all of which could destroy the stability of the HBV life cycle. In addition, we discuss the functions of immune modulators, which can enhance or activate the host immune system, as well some representative natural products with anti-HBV effects.
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Affiliation(s)
| | | | | | | | | | - Wenhai Huang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China
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6
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Jiang X, Song Y, Fang J, Yang X, Mu S, Zhang J. Neuroprotective effect of Vesatolimod in an experimental autoimmune encephalomyelitis mice model. Int Immunopharmacol 2023; 116:109717. [PMID: 36738672 DOI: 10.1016/j.intimp.2023.109717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/27/2022] [Accepted: 01/08/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Multiple sclerosis is a chronic demyelinating autoimmune disease accompanied by inflammation and loss of axons and neurons. Toll-like receptors play crucial roles in the innate immune system and inflammation. However, few studies have explored the specific effects of toll-like receptor 7 signaling pathway in multiple sclerosis. To explore underlying effects to develop a new therapeutic target, we use Vesatolimod, a safe and well-tolerated agonist of toll-like receptor 7, to assess the possible effects in Experimental autoimmune encephalomyelitis (EAE) animal model. METHODS EAE animal model was induced by injection of MOG35-55 and monitored daily for clinical symptoms, and the treatment group was given Vesatolimod at the onset of illness. The therapeutic effects of Vesatolimod on EAE inflammation, demyelination, CD107b cells and T cells infiltration, and microglia activation was evaluated. Autophagy within the spinal cords of EAE mice was also preliminarily assessed. RESULTS Treatment with Vesatolimod significantly alleviated clinical symptoms of EAE from day 18 post-immunization and decreased the expression levels of inflammatory cytokines, particularly Eotaxin and IL-12 (P40), in peripheral blood. It also inhibited demyelination in spinal cords. Moreover, VES treatment reduced activation of microglia, infiltration of CD3 + T cells and CD107b + cells, as well as inhibited the autophagy-related proteins expression in the spinal cords of EAE mice. CONCLUSION Our results indicate that Vesatolimod exhibits protective effects on EAE mice and is promising for treatment of MS.
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Affiliation(s)
- Xian Jiang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518055, Guangdong, China
| | - Yifan Song
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518055, Guangdong, China
| | - Jie Fang
- School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518055, Guangdong, China
| | - Xiaosheng Yang
- School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518055, Guangdong, China
| | - Shuhua Mu
- School of Psychology, Shenzhen University, Shenzhen 518060, Guangdong, China.
| | - Jian Zhang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518055, Guangdong, China.
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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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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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Obermann HL, Lederbogen II, Steele J, Dorna J, Sander LE, Engelhardt K, Bakowsky U, Kaufmann A, Bauer S. RNA-Cholesterol Nanoparticles Function as Potent Immune Activators via TLR7 and TLR8. Front Immunol 2022; 12:658895. [PMID: 35126343 PMCID: PMC8814444 DOI: 10.3389/fimmu.2021.658895] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 12/27/2021] [Indexed: 12/30/2022] Open
Abstract
The innate immune system senses viral and bacterial ribonucleic acid (RNA) via pattern recognition receptors (PRR) leading to subsequent activation of the immune system. One group of RNA sensors is formed by endosomal/lysosomal Toll-like receptors (TLR) such as TLR7 and TLR8. During viral or bacterial infection, immunostimulatory RNA is part of the pathogen reaching the endosomal/lysosomal compartment after cellular uptake. Synthetic single-stranded or double-stranded oligoribonucleotides (ORN) can mimic RNA from pathogens and are widely used as activating ligands for TLR7 and TLR8. However, one limitation in the use of synthetic ORN driven immune stimulation is the need for transfection reagents for RNA delivery into cells. Here we demonstrate that the conjugation of cholesterol to a double-stranded version of immunostimulatory RNA40 strongly enhanced RNA uptake into monocytes and plasmacytoid dendritic cells when compared to naked RNA. Cholesterol-conjugated RNA (RNA-chol) formed nanoparticles that were superior to RNA-liposomes complexes in regard to induction of type I interferon from human and murine plasmacytoid dendritic cells as well as proinflammatory cytokine production (e.g. TNF-α, IL12p70 or IL-6) in human monocytes. Furthermore, the RNA40-chol induced cytokines in human monocyte cultures supported TH1 and TFH cell differentiation underscoring a strong adjuvant function of RNA-chol nanoparticles for adaptive immune responses. In summary, cholesterol-conjugated immunostimulatory RNA forms nanoparticles and functions as a potent immune adjuvant in human and murine immune cells. It further simplifies the use of immunostimulatory RNA by avoiding the need for liposomal transfection reagents.
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Affiliation(s)
| | - Ines I Lederbogen
- Institute for Immunology, Philipps-University Marburg, Marburg, Germany
| | - Jenny Steele
- Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jens Dorna
- Institute for Immunology, Philipps-University Marburg, Marburg, Germany
| | - Leif Erik Sander
- Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Konrad Engelhardt
- Department of Pharmaceutics and Biopharmaceutics, Philipps-University Marburg, Marburg, Germany
| | - Udo Bakowsky
- Department of Pharmaceutics and Biopharmaceutics, Philipps-University Marburg, Marburg, Germany
| | - Andreas Kaufmann
- Institute for Immunology, Philipps-University Marburg, Marburg, Germany
| | - Stefan Bauer
- Institute for Immunology, Philipps-University Marburg, Marburg, Germany
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Suresh M, Li B, Huang X, Korolowicz KE, Murreddu MG, Gudima SO, Menne S. Agonistic Activation of Cytosolic DNA Sensing Receptors in Woodchuck Hepatocyte Cultures and Liver for Inducing Antiviral Effects. Front Immunol 2021; 12:745802. [PMID: 34671360 PMCID: PMC8521114 DOI: 10.3389/fimmu.2021.745802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/13/2021] [Indexed: 12/11/2022] Open
Abstract
Immune modulation for the treatment of chronic hepatitis B (CHB) has gained more traction in recent years, with an increasing number of compounds designed for targeting different host pattern recognition receptors (PRRs). These agonistic molecules activate the receptor signaling pathway and trigger an innate immune response that will eventually shape the adaptive immunity for control of chronic infection with hepatitis B virus (HBV). While definitive recognition of HBV nucleic acids by PRRs during viral infection still needs to be elucidated, several viral RNA sensing receptors, including toll-like receptors 7/8/9 and retinoic acid inducible gene-I-like receptors, are explored preclinically and clinically as possible anti-HBV targets. The antiviral potential of viral DNA sensing receptors is less investigated. In the present study, treatment of primary woodchuck hepatocytes generated from animals with CHB with HSV-60 or poly(dA:dT) agonists resulted in increased expression of interferon-gamma inducible protein 16 (IFI16) or Z-DNA-binding protein 1 (ZBP1/DAI) and absent in melanoma 2 (AIM2) receptors and their respective adaptor molecules and effector cytokines. Cytosolic DNA sensing receptor pathway activation correlated with a decline in woodchuck hepatitis virus (WHV) replication and secretion in these cells. Combination treatment with HSV-60 and poly(dA:dT) achieved a superior antiviral effect over monotreatment with either agonist that was associated with an increased expression of effector cytokines. The antiviral effect, however, could not be enhanced further by providing additional type-I interferons (IFNs) exogenously, indicating a saturated level of effector cytokines produced by these receptors following agonism. In WHV-uninfected woodchucks, a single poly(dA:dT) dose administered via liver-targeted delivery was well-tolerated and induced the intrahepatic expression of ZBP1/DAI and AIM2 receptors and their effector cytokines, IFN-β and interleukins 1β and 18. Receptor agonism also resulted in increased IFN-γ secretion of peripheral blood cells. Altogether, the effect on WHV replication and secretion following in vitro activation of IFI16, ZBP1/DAI, and AIM2 receptor pathways suggested an antiviral benefit of targeting more than one cytosolic DNA receptor. In addition, the in vivo activation of ZBP1/DAI and AIM2 receptor pathways in liver indicated the feasibility of the agonist delivery approach for future evaluation of therapeutic efficacy against HBV in woodchucks with CHB.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Kyle E Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G Murreddu
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Severin O Gudima
- Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
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11
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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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12
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Kayesh MEH, Kohara M, Tsukiyama-Kohara K. Toll-Like Receptor Response to Hepatitis B Virus Infection and Potential of TLR Agonists as Immunomodulators for Treating Chronic Hepatitis B: An Overview. Int J Mol Sci 2021; 22:10462. [PMID: 34638802 PMCID: PMC8508807 DOI: 10.3390/ijms221910462] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major global health problem. The immunopathology of the disease, especially the interplay between HBV and host innate immunity, is poorly understood. Moreover, inconsistent literature on HBV and host innate immunity has led to controversies. However, recently, there has been an increase in the number of studies that have highlighted the link between innate immune responses, including Toll-like receptors (TLRs), and chronic HBV infection. TLRs are the key sensing molecules that detect pathogen-associated molecular patterns and regulate the induction of pro- and anti-inflammatory cytokines, thereby shaping the adaptive immunity. The suppression of TLR response has been reported in patients with chronic hepatitis B (CHB), as well as in other models, including tree shrews, suggesting an association of TLR response in HBV chronicity. Additionally, TLR agonists have been reported to improve the host innate immune response against HBV infection, highlighting the potential of these agonists as immunomodulators for enhancing CHB treatment. In this study, we discuss the current understanding of host innate immune responses during HBV infection, particularly focusing on the TLR response and TLR agonists as immunomodulators.
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Affiliation(s)
- Mohammad Enamul Hoque Kayesh
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
- Department of Microbiology and Public Health, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal 8210, Bangladesh
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
| | - Kyoko Tsukiyama-Kohara
- Transboundary Animal Diseases Centre, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima 890-0065, Japan;
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13
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Korolowicz KE, Suresh M, Li B, Huang X, Yon C, Kallakury BV, Lee KP, Park S, Kim YW, Menne S. Combination Treatment with the Vimentin-Targeting Antibody hzVSF and Tenofovir Suppresses Woodchuck Hepatitis Virus Infection in Woodchucks. Cells 2021; 10:2321. [PMID: 34571970 PMCID: PMC8466705 DOI: 10.3390/cells10092321] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Current treatment options for patients infected with hepatitis B virus (HBV) are suboptimal, because the approved drugs rarely induce cure due to the persistence of the viral DNA genome in the nucleus of infected hepatocytes, and are associated with either severe side effects (pegylated interferon-alpha) or require life-long administration (nucleos(t)ide analogs). We report here the evaluation of the safety and therapeutic efficacy of a novel, humanized antibody (hzVSF) in the woodchuck model of HBV infection. hzVSF has been shown to act as a viral entry inhibitor, most likely by suppressing vimentin-mediated endocytosis of virions. Targeting the increased vimentin expression on liver cells by hzVSF after infection with HBV or woodchuck hepatitis virus (WHV) was demonstrated initially. Thereafter, hzVSF safety was assessed in eight woodchucks naïve for WHV infection. Antiviral efficacy of hzVSF was evaluated subsequently in 24 chronic WHV carrier woodchucks by monotreatment with three ascending doses and in combination with tenofovir alafenamide fumarate (TAF). Consistent with the proposed blocking of WHV reinfection, intravenous hzVSF administration for 12 weeks resulted in a modest but transient reduction of viral replication and associated liver inflammation. In combination with oral TAF dosing, the antiviral effect of hzVSF was enhanced and sustained in half of the woodchucks with an antibody response to viral proteins. Thus, hzVSF safely but modestly alters chronic WHV infection in woodchucks; however, as a combination partner to TAF, its antiviral efficacy is markedly increased. The results of this preclinical study support future evaluation of this novel anti-HBV drug in patients.
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Affiliation(s)
- Kyle E. Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Changsuek Yon
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
| | - Bhaskar V. Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Kyoung-pil Lee
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Sungman Park
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Yoon-Won Kim
- ImmuneMed, Inc., Chuncheon BioTown, Soyanggang ro 32, Chuncheon-si 24232, Gangwon-do, Korea; (K.-p.L.); (S.P.); (Y.-W.K.)
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.)
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Abstract
PURPOSE OF REVIEW Antiviral therapy for chronic hepatitis B infection is rarely curative, thus research in HBV cure strategies is a priority. Drug development and testing has been hampered by the lack of robust cell culture systems and small animal models. This review summarizes existing models for HBV cure research and focuses on recent developments since 2017 until today. RECENT FINDINGS The field has progressed in the development of cell culture and animal models to study HBV. Although early cell culture systems relied on transfection of HBV genomes in hepatoma cell lines, novel models expressing the entry receptor for HBV are susceptible to infection. Improved culture conditions for primary human hepatocytes, the primary target of HBV, have enabled the screening and validation of novel antivirals. Mouse models grafted with partially humanized livers are suitable for testing viral entry inhibitors or direct acting antivirals, and can be reconstituted with human immune cells to analyze immunotherapies. Other immunocompetent models include mice transduced with HBV genomes or woodchucks infected with their native hepatitis virus. SUMMARY Model systems for HBV research have helped lay the groundwork for the development and optimization of antiviral and immune-based therapeutic approaches that are now moving to clinical trials.
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15
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Bhagchandani S, Johnson JA, Irvine DJ. Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: From antiviral formulations to vaccine adjuvants. Adv Drug Deliv Rev 2021; 175:113803. [PMID: 34058283 PMCID: PMC9003539 DOI: 10.1016/j.addr.2021.05.013] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/04/2021] [Accepted: 05/15/2021] [Indexed: 02/07/2023]
Abstract
Imidazoquinoline derivatives (IMDs) and related compounds function as synthetic agonists of Toll-like receptors 7 and 8 (TLR7/8) and one is FDA approved for topical antiviral and skin cancer treatments. Nevertheless, these innate immune system-activating drugs have potentially much broader therapeutic utility; they have been pursued as antitumor immunomodulatory agents and more recently as candidate vaccine adjuvants for cancer and infectious disease. The broad expression profiles of TLR7/8, poor pharmacokinetic properties of IMDs, and toxicities associated with systemic administration, however, are formidable barriers to successful clinical translation. Herein, we review IMD formulations that have advanced to the clinic and discuss issues related to biodistribution and toxicity that have hampered the further development of these compounds. Recent strategies aimed at enhancing safety and efficacy, particularly through the use of bioconjugates and nanoparticle formulations that alter pharmacokinetics, biodistribution, and cellular targeting, are described. Finally, key aspects of the biology of TLR7 signaling, such as TLR7 tolerance, that may need to be considered in the development of new IMD therapeutics are discussed.
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Affiliation(s)
- Sachin Bhagchandani
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Jeremiah A Johnson
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
| | - Darrell J Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
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16
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Suresh M, Li B, Murreddu MG, Gudima SO, Menne S. Involvement of Innate Immune Receptors in the Resolution of Acute Hepatitis B in Woodchucks. Front Immunol 2021; 12:713420. [PMID: 34367179 PMCID: PMC8340647 DOI: 10.3389/fimmu.2021.713420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 07/05/2021] [Indexed: 12/15/2022] Open
Abstract
The antiviral property of small agonist compounds activating pattern recognition receptors (PRRs), including toll-like and RIG-I receptors, have been preclinically evaluated and are currently tested in clinical trials against chronic hepatitis B (CHB). The involvement of other PRRs in modulating hepatitis B virus infection is less known. Thus, woodchucks with resolving acute hepatitis B (AHB) after infection with woodchuck hepatitis virus (WHV) were characterized as animals with normal or delayed resolution based on their kinetics of viremia and antigenemia, and the presence and expression of various PRRs were determined in both outcomes. While PRR expression was unchanged immediately after infection, most receptors were strongly upregulated during resolution in liver but not in blood. Besides well-known PRRs, including TLR7/8/9 and RIG-I, other less-characterized receptors, such as IFI16, ZBP1/DAI, AIM2, and NLRP3, displayed comparable or even higher expression. Compared to normal resolution, a 3-4-week lag in peak receptor expression and WHV-specific B- and T-cell responses were noted during delayed resolution. This suggested that PRR upregulation in woodchuck liver occurs when the mounting WHV replication reaches a certain level, and that multiple receptors are involved in the subsequent induction of antiviral immune responses. Liver enzyme elevations occurred early during normal resolution, indicating a faster induction of cytolytic mechanisms than in delayed resolution, and correlated with an increased expression of NK-cell and CD8 markers and cytolytic effector molecules. The peak liver enzyme level, however, was lower during delayed resolution, but hepatic inflammation was more pronounced and associated with a higher expression of cytolytic markers. Further comparison of PRR expression revealed that most receptors were significantly reduced in woodchucks with established and progressing CHB, and several RNA sensors more so than DNA sensors. This correlated with a lower expression of receptor adaptor and effector molecules, suggesting that persistent, high-level WHV replication interferes with PRR activation and is associated with a diminished antiviral immunity based on the reduced expression of immune cell markers, and absent WHV-specific B- and T-cell responses. Overall, the differential expression of PRRs during resolution and persistence of WHV infection emphasizes their importance in the ultimate viral control during AHB that is impaired during CHB.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Marta G. Murreddu
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
| | - Severin O. Gudima
- Department of Microbiology, Molecular Genetics & Immunology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC, United States
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17
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Suresh M, Menne S. Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer. World J Gastrointest Oncol 2021; 13:509-535. [PMID: 34163570 PMCID: PMC8204361 DOI: 10.4251/wjgo.v13.i6.509] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/02/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.
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Affiliation(s)
- Manasa Suresh
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
| | - Stephan Menne
- Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, United States
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18
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Tsounis EP, Tourkochristou E, Mouzaki A, Triantos C. Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure. World J Gastroenterol 2021; 27:2727-2757. [PMID: 34135551 PMCID: PMC8173382 DOI: 10.3748/wjg.v27.i21.2727] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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Grippo JF, Folitar I, Passe S, Jiang Q, Rodriguez I, Fettner SH, Calleja E. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a TLR7 agonist prodrug RO6870868 in healthy volunteers. Clin Transl Sci 2021; 14:1524-1534. [PMID: 33742764 PMCID: PMC8301559 DOI: 10.1111/cts.13016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 12/13/2022] Open
Abstract
RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B.
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Affiliation(s)
| | | | - Sharon Passe
- Roche Innovation Center, New York, New York, USA
| | - Qiudi Jiang
- Roche Innovation Center Shanghai, Shanghai, China
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20
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Korolowicz KE, Suresh M, Li B, Huang X, Yon C, Leng X, Kallakury BV, Tucker RD, Menne S. Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B. Viruses 2021; 13:v13040648. [PMID: 33918831 PMCID: PMC8069054 DOI: 10.3390/v13040648] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.
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Affiliation(s)
- Kyle E. Korolowicz
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Manasa Suresh
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Bin Li
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Xu Huang
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Changsuek Yon
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Xuebing Leng
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
| | - Bhaskar V. Kallakury
- Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Robin D. Tucker
- Division of Comparative Medicine, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Stephan Menne
- Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA; (K.E.K.); (M.S.); (B.L.); (X.H.); (C.Y.); (X.L.)
- Correspondence: ; Tel.: +1-(202)-687-2949
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21
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Huang X, Zhang X, Lu M. Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics. Expert Opin Drug Discov 2021; 16:869-880. [PMID: 33678093 DOI: 10.1080/17460441.2021.1898369] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Toll-like receptor (TLR) 7 and TLR8 are functionally localized to endosomes and recognize specific RNA sequences. They play crucial roles in initiating innate and adaptive immune responses. TLR7/8 activation protects the host against invading pathogens and enhances immune responses. In contrast, sustained TLR7/8 signaling leads to immune overreaction. Therefore, agonists or antagonists targeting TLR7/8 signaling are favorable drug candidates for the treatment of immune disorders.Areas covered: Basic knowledge about TLR7 and TLR8 and their signaling pathways are briefly reviewed. Various therapeutic agents have been designed to activate or antagonize TLR7/8 signaling pathways, and their safety and efficacy for the treatment of multiple diseases have been investigated in preclinical animal models and clinical trials. TLR7/8 agonists exhibit potent antiviral activity and regulate anti-tumor immune responses. TLR7 agonists have also been used as adjuvants to improve vaccine immunogenicity and generate greater seroprotection. TLR7/8 antagonists are promising candidates for the treatment of autoimmune and inflammatory diseases.Expert opinion: TLR7/8 pathways are favorable targets for immunological therapies. Future research should concentrate on the optimization of drug safety, efficiency, and specificity. Detailed mechanistic studies will contribute to the development of TLR7/8 immunomodulators and novel therapeutic strategies.
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Affiliation(s)
- Xuan Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, Essen, Germany
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22
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Xu J, Zhan Q, Fan Y, Yu Y, Zeng Z. Human genetic susceptibility to hepatitis B virus infection. INFECTION GENETICS AND EVOLUTION 2020; 87:104663. [PMID: 33278635 DOI: 10.1016/j.meegid.2020.104663] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection is still a serious health threat worldwide. The outcomes of HBV infection consist of spontaneous HBV clearance and chronic HBV infection. Multiple factors contribute to the disparity of HBV infection outcomes, including host factors, viral factors and environmental factors. The present review comprehends the current researches mainly focusing on the relationships between genetic determinants, including single nucleotide polymorphisms (SNPs) and haplotypes, and susceptibility of HBV infection, namely chronic (persistent) HBV infection and HBV clearance. A number of determinants in the chromosomes, including mutations in human leukocyte antigens (HLAs), cytokines genes, toll-like receptors (TLRs), and other genes are related to the human susceptibility to HBV infection. Among the above variants, some of those in HLAs have been studied and replicated in multiple-ethnic populations and came to consistent conclusions, while some others are novel and need to be evaluated further.
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Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China
| | - Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China
| | - Yanan Fan
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China.
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Peking University Health Science Center, Beijing 100034, China.
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23
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Kieffer ME, Patel AM, Hollingsworth SA, Seganish WM. Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 - 2020. Expert Opin Ther Pat 2020; 30:825-845. [PMID: 33052748 DOI: 10.1080/13543776.2020.1825687] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Toll-like receptors 7 and 8 (TLR7 and TLR8) are endosomal immune receptors that initiate an innate immune response and can facilitate activation of the adaptive immune system. Both preclinical and clinical studies have shown the downstream inflammatory response from TLR7 and TLR8 agonism results in preliminary efficacy for the treatment of cancer, viral infections, and for use as a vaccine adjuvant. AREAS COVERED This patent review covers recent developments in small molecule TLR7 and TLR8 agonists published between January 2014 - February 2020. We summarize relevant chemical scaffolds, observed structure-activity relationships, and where available, preliminary animal models, and clinical data. EXPERT OPINION In the last 6 years, there has been significant progress in the optimization of novel TLR7 and TLR8 small molecule agonists. These novel compounds are currently being evaluated in the clinic for multiple antiviral and oncology indications. Clinical data from these trials will provide a clearer outlook on 1) the TLR7/8 engagement necessary to obtain the desired immune response, 2) safety margin improvement using directed delivery, and 3) potential synergistic effects with checkpoint inhibitor combination therapies.
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Affiliation(s)
- Madeleine E Kieffer
- Department of Discovery Chemistry, Merck & Co., Inc , South San Francisco, California, USA
| | - Akash M Patel
- Department of Discovery Chemistry, Merck & Co., Inc , South San Francisco, California, USA
| | - Scott A Hollingsworth
- Department of Discovery Chemistry, Merck & Co., Inc , South San Francisco, California, USA
| | - W Michael Seganish
- Department of Discovery Chemistry, Merck & Co., Inc , South San Francisco, California, USA
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24
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Michalak TI. Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B. Front Immunol 2020; 11:853. [PMID: 32536912 PMCID: PMC7267019 DOI: 10.3389/fimmu.2020.00853] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 04/14/2020] [Indexed: 12/15/2022] Open
Abstract
Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances.
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Affiliation(s)
- Tomasz I Michalak
- Molecular Virology and Hepatology Research Group, Division of BioMedical Sciences, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, Canada
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25
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Menne S, Wildum S, Steiner G, Suresh M, Korolowicz K, Balarezo M, Yon C, Murreddu M, Hong X, Kallakury BV, Tucker R, Yang S, Young JAT, Javanbakht H. Efficacy of an Inhibitor of Hepatitis B Virus Expression in Combination With Entecavir and Interferon-α in Woodchucks Chronically Infected With Woodchuck Hepatitis Virus. Hepatol Commun 2020; 4:916-931. [PMID: 32490326 PMCID: PMC7262289 DOI: 10.1002/hep4.1502] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 02/13/2020] [Accepted: 02/18/2020] [Indexed: 12/16/2022] Open
Abstract
RG7834 is a small‐molecule inhibitor of hepatitis B virus (HBV) gene expression that significantly reduces the levels of hepatitis B surface antigen (HBsAg) and HBV DNA in a humanized liver HBV mouse model. In the current study, we evaluated the potency of RG7834 in the woodchuck model of chronic HBV infection, alone and in combination with entecavir (ETV) and/or woodchuck interferon‐α (wIFN‐α). RG7834 reduced woodchuck hepatitis virus (WHV) surface antigen (WHsAg) by a mean of 2.57 log10 from baseline and WHV DNA by a mean of 1.71 log10. ETV + wIFN‐α reduced WHsAg and WHV DNA by means of 2.40 log10 and 6.70 log10, respectively. The combination of RG7834, ETV, and wIFN‐α profoundly reduced WHsAg and WHV DNA levels by 5.00 log10 and 7.46 log10, respectively. However, both viral parameters rebounded to baseline after treatment was stopped and no antibody response against WHsAg was observed. Effects on viral RNAs were mainly seen with the triple combination treatment, reducing both pregenomic RNA (pgRNA) and WHsAg RNA, whereas RG7834 mainly reduced WHsAg RNA and ETV mainly affected pgRNA. When WHsAg was reduced by the triple combination, peripheral blood mononuclear cells (PBMCs) proliferated significantly in response to viral antigens, but the cellular response was diminished after WHsAg returned to baseline levels during the off‐treatment period. Consistent with this, Pearson correlation revealed a strong negative correlation between WHsAg levels and PBMC proliferation in response to peptides covering the entire WHsAg and WHV nucleocapsid antigen. Conclusion: A fast and robust reduction of WHsAg by combination therapy reduced WHV‐specific immune dysfunction in the periphery. However, the magnitude and/or duration of the induced cellular response were not sufficient to achieve a sustained antiviral response.
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Affiliation(s)
- Stephan Menne
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Steffen Wildum
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
| | - Guido Steiner
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
| | - Manasa Suresh
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Kyle Korolowicz
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Maria Balarezo
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Changsuek Yon
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Marta Murreddu
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | - Xupeng Hong
- Department of Microbiology and Immunology Georgetown University Medical Center Washington DC
| | | | - Robin Tucker
- Department of Pharmacology Georgetown University Medical Center Washington DC
| | - Song Yang
- Roche Pharma Research and Early Development Roche Innovation Center Shanghai Shanghai China
| | - John A T Young
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
| | - Hassan Javanbakht
- Roche Pharma Research and Early Development Roche Innovation Center Basel Basel Switzerland
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26
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Akkina R, Barber DL, Bility MT, Bissig KD, Burwitz BJ, Eichelberg K, Endsley JJ, Garcia JV, Hafner R, Karakousis PC, Korba BE, Koshy R, Lambros C, Menne S, Nuermberger EL, Ploss A, Podell BK, Poluektova LY, Sanders-Beer BE, Subbian S, Wahl A. Small Animal Models for Human Immunodeficiency Virus (HIV), Hepatitis B, and Tuberculosis: Proceedings of an NIAID Workshop. Curr HIV Res 2020; 18:19-28. [PMID: 31870268 PMCID: PMC7403688 DOI: 10.2174/1570162x18666191223114019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 11/27/2019] [Accepted: 12/11/2019] [Indexed: 12/21/2022]
Abstract
The main advantage of animal models of infectious diseases over in vitro studies is the gain in the understanding of the complex dynamics between the immune system and the pathogen. While small animal models have practical advantages over large animal models, it is crucial to be aware of their limitations. Although the small animal model at least needs to be susceptible to the pathogen under study to obtain meaningful data, key elements of pathogenesis should also be reflected when compared to humans. Well-designed small animal models for HIV, hepatitis viruses and tuberculosis require, additionally, a thorough understanding of the similarities and differences in the immune responses between humans and small animals and should incorporate that knowledge into the goals of the study. To discuss these considerations, the NIAID hosted a workshop on 'Small Animal Models for HIV, Hepatitis B, and Tuberculosis' on May 30, 2019. Highlights of the workshop are outlined below.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Brigitte E. Sanders-Beer
- Address correspondence to this author at the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5601 Fishers Lane, Bethesda, MD 20892-9830, USA; Tel: (240) 627-3209; E-mail:
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