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Baig S, Berikkara A, Khalid R, Subhan SA, Abbas T, Abidi SH. In silico analysis of the effect of HCV genotype-specific polymorphisms in Core, NS3, NS5A, and NS5B proteins on T-cell epitope processing and presentation. Front Microbiol 2025; 15:1498069. [PMID: 39881992 PMCID: PMC11774985 DOI: 10.3389/fmicb.2024.1498069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/20/2024] [Indexed: 01/31/2025] Open
Abstract
Background HCV genotypes are 30-35% polymorphic at the nucleotide level, while subtypes within the same genotype differ by nearly 20%. Although previous studies have shown the immune escape potential of several mutations within the HCV proteins, little is known about the effect of genotype/subtype-specific gene polymorphism on T-cell immunity. Therefore, this study employed several in silico methods to examine the impact of genotype/subtype-specific polymorphisms in Core, NS3, NS5A, and NS5B sequences on T cell epitope processing and HLA-epitope interactions. Methods For this study, 8,942, 17,700, 14,645, and 3,277 HCV Core, NS3, NS5A, and NS5B sequences, respectively, from eight genotypes and 21 subtypes were retrieved from the Los Alamos HCV Database. Next, the NetCTL tool was employed to predict Cytotoxic T Lymphocyte (CTL) epitopes based on combined proteasomal cleavage, TAP efficacy, and HLA class I receptor binding scores. PEP-FOLD was used to model selected epitopes, followed by peptide-HLA docking using HPEPDOCK. Finally, molecular dynamics simulations were conducted for 200 ns using Desmond software to analyze differences in HLA-epitope (from different HCV genotypes) interaction kinetics and dynamics. Results A total of 3,410, 8,054, 6,532, and 14,015 CTL epitopes were observed in the HCV Core, NS3, NS5A, and NS5B sequences, respectively. Significant genotype/subtype-specific variations in CTL values and docking scores were observed among NS3, NS5A, and NS5B proteins. In silico results reveal that epitopes from genotype 6b (NS3), 6d/r (NS5B), 6o and 6 k (NS5A) exhibit higher immunogenicity than other genotypes, forming more energetically stable complexes with host receptors. These epitopes, compared to those from the same positions but different genotypes, showed binding energies of -144.24 kcal/mol, -85.30 kcal/mol, and - 43 kcal/mol, respectively. Over a 200 ns MD simulation, GT 6b and 6d/r epitopes displayed up to a 40% stronger binding energy with the HLA receptor. These findings suggest that patients infected with GT 6 may experience enhanced T cell responsiveness and broader immunogenicity. Conclusion Our study suggests that genotype/subtype-specific polymorphism in HCV may result in altered immune responses by modulating T-cell epitope processing and interaction with HLA receptors. Further experimental studies can be performed to confirm the effect of genotype/subtype-specific polymorphisms on T cell-mediated immune response.
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Affiliation(s)
- Samina Baig
- Department of Microbiology, University of Karachi, Karachi, Pakistan
- Dow Institute of Medical Technology, Dow University of Health Sciences, Karachi, Pakistan
| | - Assel Berikkara
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Ramsha Khalid
- Department of Biochemistry, University of Karachi, Karachi, Pakistan
| | - Syed A. Subhan
- Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Tanveer Abbas
- Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Syed Hani Abidi
- Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan
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2
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Ludwig SD, Meksiriporn B, Tan J, Kureshi R, Mishra A, Kaeo KJ, Zhu A, Stavrakis G, Lee SJ, Schodt DJ, Wester MJ, Kumar D, Lidke KA, Cox AL, Dooley HM, Nimmagadda S, Spangler JB. Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1. Cell Chem Biol 2024; 31:904-919.e11. [PMID: 38547863 PMCID: PMC11102303 DOI: 10.1016/j.chembiol.2024.02.014] [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: 08/12/2023] [Revised: 12/28/2023] [Accepted: 02/28/2024] [Indexed: 04/04/2024]
Abstract
Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engagement of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessitating novel approaches to enhance performance. Here, we report the development of antibody fusion proteins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The complementary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell activation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic antibodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes.
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Affiliation(s)
- Seth D Ludwig
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Bunyarit Meksiriporn
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biology, School of Science, King Mongkut's Institute of Technology Ladkrabang, Bangkok 10520, Thailand
| | - Jiacheng Tan
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Rakeeb Kureshi
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Akhilesh Mishra
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kyle J Kaeo
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Angela Zhu
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Georgia Stavrakis
- Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, MD 21205, USA
| | - Stephen J Lee
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - David J Schodt
- Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA
| | - Michael J Wester
- Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA
| | - Dhiraj Kumar
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Keith A Lidke
- Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Helen M Dooley
- Department of Microbiology and Immunology, Institute of Marine and Environmental Technology (IMET), University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Sridhar Nimmagadda
- Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Jamie B Spangler
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
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3
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Lang-Meli J, Neumann-Haefelin C, Thimme R. Targeting virus-specific CD8+ T cells for treatment of chronic viral hepatitis: from bench to bedside. Expert Opin Biol Ther 2024; 24:77-89. [PMID: 38290716 DOI: 10.1080/14712598.2024.2313112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/29/2024] [Indexed: 02/01/2024]
Abstract
INTRODUCTION More than 350 million people worldwide live with chronic viral hepatitis and are thus at risk for severe complications like liver cirrhosis and hepatocellular carcinoma (HCC). To meet the goals of the World Health Organization (WHO) global hepatitis strategy, there is an urgent need for new immunotherapeutic approaches. These are particularly required for chronic hepatitis B virus infection and - B/D coinfection. AREAS COVERED This review summarizes data on mechanisms of CD8+ T cells failure in chronic hepatitis B, D, C and E virus infection. The relative contribution of the different concepts (viral escape, CD8+ T cell exhaustion, defective priming) will be discussed. On this basis, examples for future therapeutic approaches targeting virus-specific CD8+ T cells for the individual hepatitis viruses will be discussed. EXPERT OPINION Immunotherapeutic approaches targeting virus-specific CD8+ T cells have the potential to change clinical practice, especially in chronic hepatitis B virus infection. Further clinical development, however, requires a more detailed understanding of T cell immunology in chronic viral hepatitis. Some important conceptual questions remain to be addressed, e.g. regarding heterogeneity of exhausted virus-specific CD8+ T cells.
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Affiliation(s)
- Julia Lang-Meli
- Department 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
- Department of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, Medical Center - University of Freiburg and Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany
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4
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Taha TY, Chen IP, Hayashi JM, Tabata T, Walcott K, Kimmerly GR, Syed AM, Ciling A, Suryawanshi RK, Martin HS, Bach BH, Tsou CL, Montano M, Khalid MM, Sreekumar BK, Renuka Kumar G, Wyman S, Doudna JA, Ott M. Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6. Nat Commun 2023; 14:2308. [PMID: 37085489 PMCID: PMC10120482 DOI: 10.1038/s41467-023-37787-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/31/2023] [Indexed: 04/23/2023] Open
Abstract
Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (~30 kb). Here, we present a plasmid-based viral genome assembly and rescue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.
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Affiliation(s)
- Taha Y Taha
- Gladstone Institutes, San Francisco, CA, USA.
| | - Irene P Chen
- Gladstone Institutes, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, CA, USA
| | | | | | | | | | - Abdullah M Syed
- Gladstone Institutes, San Francisco, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Alison Ciling
- Gladstone Institutes, San Francisco, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | | | - Hannah S Martin
- Gladstone Institutes, San Francisco, CA, USA
- Department of Chemistry, University of California, Berkeley, CA, USA
| | - Bryan H Bach
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | | | | | | | | | | | - Stacia Wyman
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
| | - Jennifer A Doudna
- Gladstone Institutes, San Francisco, CA, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, USA
- Department of Chemistry, University of California, Berkeley, CA, USA
- Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
- Howard Hughes Medical Institute, University of California, Berkeley, CA, USA
- Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
- California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, CA, USA
| | - Melanie Ott
- Gladstone Institutes, San Francisco, CA, USA.
- Department of Medicine, University of California, San Francisco, CA, USA.
- Chan Zuckerberg Biohub - San Francisco, San Francisco, CA, USA.
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5
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Taha TY, Chen IP, Hayashi JM, Tabata T, Walcott K, Kimmerly GR, Syed AM, Ciling A, Suryawanshi RK, Martin HS, Bach BH, Tsou CL, Montano M, Khalid MM, Sreekumar BK, Kumar GR, Wyman S, Doudna JA, Ott M. Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.31.525914. [PMID: 36798416 PMCID: PMC9934579 DOI: 10.1101/2023.01.31.525914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (30kb). Here, we designed a plasmid-based viral genome assembly and resc ue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.
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6
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Warger J, Gaudieri S. On the Evolutionary Trajectory of SARS-CoV-2: Host Immunity as a Driver of Adaptation in RNA Viruses. Viruses 2022; 15:70. [PMID: 36680110 PMCID: PMC9866609 DOI: 10.3390/v15010070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 12/21/2022] [Accepted: 12/24/2022] [Indexed: 12/28/2022] Open
Abstract
Host immunity can exert a complex array of selective pressures on a pathogen, which can drive highly mutable RNA viruses towards viral escape. The plasticity of a virus depends on its rate of mutation, as well as the balance of fitness cost and benefit of mutations, including viral adaptations to the host's immune response. Since its emergence, SARS-CoV-2 has diversified into genetically distinct variants, which are characterised often by clusters of mutations that bolster its capacity to escape human innate and adaptive immunity. Such viral escape is well documented in the context of other pandemic RNA viruses such as the human immunodeficiency virus (HIV) and influenza virus. This review describes the selection pressures the host's antiviral immunity exerts on SARS-CoV-2 and other RNA viruses, resulting in divergence of viral strains into more adapted forms. As RNA viruses obscure themselves from host immunity, they uncover weak points in their own armoury that can inform more comprehensive, long-lasting, and potentially cross-protective vaccine coverage.
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Affiliation(s)
- Jacob Warger
- School of Medicine and Pharmacology, University of Western Australia, Crawley, WA 6009, Australia
| | - Silvana Gaudieri
- School of Human Sciences, University of Western Australia, Crawley, WA 6009, Australia
- Institute for Immunology and Infectious Diseases, Murdoch University, Mandurah, WA 6150, Australia
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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7
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Identification of human progenitors of exhausted CD8 + T cells associated with elevated IFN-γ response in early phase of viral infection. Nat Commun 2022; 13:7543. [PMID: 36477661 PMCID: PMC9729230 DOI: 10.1038/s41467-022-35281-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
T cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of individuals with primary infection using single-cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-γ response against the transmitted virus is associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome, we find heterogeneous subsets of progenitors of exhaustion, based on the level of PD-1 expression and loss of AP-1 transcription factors. Intra-clonal analysis shows distinct trajectories with multiple fates and evolutionary plasticity of precursor cells. These findings challenge the current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T cell differentiation in human infections.
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8
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Kombe Kombe AJ, Biteghe FAN, Ndoutoume ZN, Jin T. CD8 + T-cell immune escape by SARS-CoV-2 variants of concern. Front Immunol 2022; 13:962079. [PMID: 36389664 PMCID: PMC9647062 DOI: 10.3389/fimmu.2022.962079] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 10/03/2022] [Indexed: 07/30/2023] Open
Abstract
Despite the efficacy of antiviral drug repositioning, convalescent plasma (CP), and the currently available vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the worldwide coronavirus disease 2019 (COVID-19) pandemic is still challenging because of the ongoing emergence of certain new SARS-CoV-2 strains known as variants of concern (VOCs). Mutations occurring within the viral genome, characterized by these new emerging VOCs, confer on them the ability to efficiently resist and escape natural and vaccine-induced humoral and cellular immune responses. Consequently, these VOCs have enhanced infectivity, increasing their stable spread in a given population with an important fatality rate. While the humoral immune escape process is well documented, the evasion mechanisms of VOCs from cellular immunity are not well elaborated. In this review, we discussed how SARS-CoV-2 VOCs adapt inside host cells and escape anti-COVID-19 cellular immunity, focusing on the effect of specific SARS-CoV-2 mutations in hampering the activation of CD8+ T-cell immunity.
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Affiliation(s)
- Arnaud John Kombe Kombe
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | | | - Zélia Nelly Ndoutoume
- The Second Clinical School, Medical Imaging, Chongqing Medical University, Chongqing, China
| | - Tengchuan Jin
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Laboratory of Structural Immunology, Chinese Academic of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Chinese Academic of Sciences (CAS) Center for Excellence in Molecular Cell Science, Chinese Academy of Science, Shanghai, China
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9
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Khatamzas E, Antwerpen MH, Rehn A, Graf A, Hellmuth JC, Hollaus A, Mohr AW, Gaitzsch E, Weiglein T, Georgi E, Scherer C, Stecher SS, Gruetzner S, Blum H, Krebs S, Reischer A, Leutbecher A, Subklewe M, Dick A, Zange S, Girl P, Müller K, Weigert O, Hopfner KP, Stemmler HJ, von Bergwelt-Baildon M, Keppler OT, Wölfel R, Muenchhoff M, Moosmann A. Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection. Nat Commun 2022; 13:5586. [PMID: 36151076 PMCID: PMC9508331 DOI: 10.1038/s41467-022-32772-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 08/15/2022] [Indexed: 11/29/2022] Open
Abstract
Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.
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Affiliation(s)
- Elham Khatamzas
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.
- Division of Infectious Diseases and Tropical Medicine, Center for Infectious Diseases, Heidelberg Hospital, Heidelberg, Germany.
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, Ludwig-Maximilians University Munich, Munich, Germany.
| | - Markus H Antwerpen
- Bundeswehr, Institute of Microbiology Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Alexandra Rehn
- Bundeswehr, Institute of Microbiology Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Alexander Graf
- Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians University Munich, Munich, Germany
| | - Johannes Christian Hellmuth
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Alexandra Hollaus
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Anne-Wiebe Mohr
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Erik Gaitzsch
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Tobias Weiglein
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Enrico Georgi
- Bundeswehr, Institute of Microbiology Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Clemens Scherer
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- Department of Medicine I, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Stephanie-Susanne Stecher
- Department of Medicine II, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Stefanie Gruetzner
- Institute for Transfusion Medicine and Haemostasis, Medical Faculty, University of Augsburg, Augsburg, Germany
| | - Helmut Blum
- Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians University Munich, Munich, Germany
| | - Stefan Krebs
- Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians University Munich, Munich, Germany
| | - Anna Reischer
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Alexandra Leutbecher
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Marion Subklewe
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Andrea Dick
- Laboratory for Immunogenetics, University of Munich, LMU, Munich, Germany
| | - Sabine Zange
- Bundeswehr, Institute of Microbiology Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Philipp Girl
- Bundeswehr, Institute of Microbiology Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Katharina Müller
- Bundeswehr, Institute of Microbiology Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Oliver Weigert
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Munich, Germany
| | - Karl-Peter Hopfner
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Hans-Joachim Stemmler
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
| | - Michael von Bergwelt-Baildon
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- German Cancer Consortium (DKTK), Munich, Germany
| | - Oliver T Keppler
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
- Max von Pettenkofer Institute & Gene Center, Virology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
| | - Roman Wölfel
- Bundeswehr, Institute of Microbiology Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
| | - Maximilian Muenchhoff
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
- Max von Pettenkofer Institute & Gene Center, Virology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
| | - Andreas Moosmann
- Department of Medicine III, University Hospital, Ludwig-Maximilians University Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Munich, Germany
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10
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Barnes E, Cooke GS, Lauer GM, Chung RT. Implementation of a controlled human infection model for evaluation of HCV vaccine candidates. Hepatology 2022; 77:1757-1772. [PMID: 35736236 DOI: 10.1002/hep.32632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 06/08/2022] [Accepted: 06/10/2022] [Indexed: 12/08/2022]
Abstract
Hepatitis C virus (HCV) remains a major global health concern. Directly acting antiviral (DAA) drugs have transformed the treatment of HCV. However, it has become clear that, without an effective HCV vaccine, it will not be possible to meet the World Health Organization targets of HCV viral elimination. Promising new vaccine technologies that generate high magnitude antiviral T and B cell immune responses and significant new funding have recently become available, stimulating the HCV vaccine pipeline. In the absence of an immune competent animal model for HCV, the major block in evaluating new HCV vaccine candidates will be the assessment of vaccine efficacy in humans. The development of a controlled human infection model (CHIM) for HCV could overcome this block, enabling the head-to-head assessment of vaccine candidates. The availability of highly effective DAA means that a CHIM for HCV is possible for the first time. In this review, we highlight the challenges and issues with currently available strategies to assess HCV vaccine efficacy including HCV "at-risk" cohorts and animal models. We describe the development of CHIM in other infections that are increasingly utilized by trialists and explore the ethical and safety concerns specific for an HCV CHIM. Finally, we propose an HCV CHIM study design including the selection of volunteers, the development of an infectious inoculum, the evaluation of host immune and viral parameters, and the definition of study end points for use in an HCV CHIM. Importantly, the study design (including number of volunteers required, cost, duration of study, and risk to volunteers) varies significantly depending on the proposed mechanism of action (sterilizing/rapid viral clearance vs. delayed viral clearance) of the vaccine under evaluation. We conclude that an HCV CHIM is now realistic, that safety and ethical concerns can be addressed with the right study design, and that, without an HCV CHIM, it is difficult to envisage how the development of an HCV vaccine will be possible.
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Affiliation(s)
- Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, Oxford, UK
| | - Graham S Cooke
- Department of Infectious Disease, Imperial College London, Oxford, UK
| | - Georg M Lauer
- Liver Center, GI Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Raymond T Chung
- Liver Center, GI Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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11
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Osuch S, Laskus T, Perlejewski K, Berak H, Bukowska-Ośko I, Pollak A, Zielenkiewicz M, Radkowski M, Caraballo Cortés K. CD8 + T-Cell Exhaustion Phenotype in Chronic Hepatitis C Virus Infection Is Associated With Epitope Sequence Variation. Front Immunol 2022; 13:832206. [PMID: 35386708 PMCID: PMC8977521 DOI: 10.3389/fimmu.2022.832206] [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: 12/09/2021] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Background and Aims During chronic hepatitis C virus (HCV) infection, CD8+ T-cells become functionally exhausted, undergoing progressive phenotypic changes, i.e., overexpression of “inhibitory” molecules such as PD-1 (programmed cell death protein 1) and/or Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3). The extreme intrahost genetic diversity of HCV is a major mechanism of immune system evasion, facilitating epitope escape. The aim of the present study was to determine whether T-cell exhaustion phenotype in chronic HCV infection is related to the sequence repertoire of NS3 viral immunodominant epitopes. Methods The study population was ninety prospective patients with chronic HCV genotype 1b infection. Populations of peripheral blood CD8+ T-cells expressing PD-1/Tim-3 were assessed by multiparametric flow cytometry, including HCV-specific T-cells after magnetic-based enrichment using MHC-pentamer. Autologous epitope sequences were inferred from next-generation sequencing. The correction of sequencing errors and genetic variants reconstruction was performed using Quasirecomb. Results There was an interplay between the analyzed epitopes sequences and exhaustion phenotype of CD8+ T-cells. A predominance of NS31406 epitope sequence, representing neither prototype KLSGLGLNAV nor cross-reactive variants (KLSSLGLNAV, KLSGLGINAV or KLSALGLNAV), was associated with higher percentage of HCV-specific CD8+PD-1+Tim-3+ T-cells, P=0.0102. Variability (at least two variants) of NS31406 epitope sequence was associated with increased frequencies of global CD8+PD-1+Tim-3+ T-cells (P=0.0197) and lower frequencies of CD8+PD-1−Tim-3− T-cells (P=0.0079). In contrast, infection with NS31073 dominant variant epitope (other than prototype CVNGVCWTV) was associated with lower frequency of global CD8+PD-1+Tim-3+ T-cells (P=0.0054). Conclusions Our results indicate that PD-1/Tim-3 receptor expression is largely determined by viral epitope sequence and is evident for both HCV-specific and global CD8+ T-cells, pointing to the importance of evaluating autologous viral epitope sequences in the investigation of CD8+ T-cell exhaustion in HCV infection.
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Affiliation(s)
- Sylwia Osuch
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Hanna Berak
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, Warsaw, Poland
| | - Iwona Bukowska-Ośko
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Pollak
- Department of Human Genetics, Medical University of Warsaw, Warsaw, Poland
| | | | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Kamila Caraballo Cortés
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
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12
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Adaptive Immune Responses, Immune Escape and Immune-Mediated Pathogenesis during HDV Infection. Viruses 2022; 14:v14020198. [PMID: 35215790 PMCID: PMC8880046 DOI: 10.3390/v14020198] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/14/2022] [Accepted: 01/16/2022] [Indexed: 12/13/2022] Open
Abstract
The hepatitis delta virus (HDV) is the smallest known human virus, yet it causes great harm to patients co-infected with hepatitis B virus (HBV). As a satellite virus of HBV, HDV requires the surface antigen of HBV (HBsAg) for sufficient viral packaging and spread. The special circumstance of co-infection, albeit only one partner depends on the other, raises many virological, immunological, and pathophysiological questions. In the last years, breakthroughs were made in understanding the adaptive immune response, in particular, virus-specific CD4+ and CD8+ T cells, in self-limited versus persistent HBV/HDV co-infection. Indeed, the mechanisms of CD8+ T cell failure in persistent HBV/HDV co-infection include viral escape and T cell exhaustion, and mimic those in other persistent human viral infections, such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), and HBV mono-infection. However, compared to these larger viruses, the small HDV has perfectly adapted to evade recognition by CD8+ T cells restricted by common human leukocyte antigen (HLA) class I alleles. Furthermore, accelerated progression towards liver cirrhosis in persistent HBV/HDV co-infection was attributed to an increased immune-mediated pathology, either caused by innate pathways initiated by the interferon (IFN) system or triggered by misguided and dysfunctional T cells. These new insights into HDV-specific adaptive immunity will be discussed in this review and put into context with known well-described aspects in HBV, HCV, and HIV infections.
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13
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Frumento N, Flyak AI, Bailey JR. Mechanisms of HCV resistance to broadly neutralizing antibodies. Curr Opin Virol 2021; 50:23-29. [PMID: 34329953 PMCID: PMC8500940 DOI: 10.1016/j.coviro.2021.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/12/2022]
Abstract
Broadly neutralizing antibodies (bNAbs) block infection by genetically diverse hepatitis C virus (HCV) isolates by targeting relatively conserved epitopes on the HCV envelope glycoproteins, E1 and E2. Many amino acid substitutions conferring resistance to these bNAbs have been characterized, identifying multiple mechanisms of bNAb escape. Some resistance substitutions follow the expected mechanism of directly disrupting targeted epitopes. Interestingly, other resistance substitutions fall in E2 domains distant from bNAb-targeted epitopes. These substitutions, which can confer broad resistance to multiple bNAbs, act by less clearly defined mechanisms. Some modulate binding of HCV to cell surface receptors, while others may induce conformational changes in the E2 protein. In this review, we discuss mechanisms of HCV bNAb resistance and implications for HCV vaccine development.
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Affiliation(s)
- Nicole Frumento
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Andrew I Flyak
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Justin R Bailey
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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14
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Mutational escape from cellular immunity in viral hepatitis: variations on a theme. Curr Opin Virol 2021; 50:110-118. [PMID: 34454351 DOI: 10.1016/j.coviro.2021.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/05/2021] [Indexed: 12/19/2022]
Abstract
Approx. 320 million individuals worldwide are chronically infected with hepatitis viruses, contributing to viral hepatitis being one of the 10 leading causes of death. Cellular adaptive immunity, namely CD4+ and CD8+ T cells, plays an important role in viral clearance and control. Two main mechanisms, however, may lead to failure of the virus-specific T-cell response: T-cell exhaustion and mutational viral escape. Viral escape has been studied in detail in hepatitis C virus (HCV) infection, where it is thought to affect approx. 50% of virus-specific CD8+ T-cell responses in persistent infection, to influence natural infection outcome and to contribute to failure of preventive vaccination strategies. In hepatitis B virus (HBV) as well as HBV/hepatitis D virus (HDV) co-infection, the impact of viral escape has been studied in detail only recently.
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15
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Yates KB, Tonnerre P, Martin GE, Gerdemann U, Al Abosy R, Comstock DE, Weiss SA, Wolski D, Tully DC, Chung RT, Allen TM, Kim AY, Fidler S, Fox J, Frater J, Lauer GM, Haining WN, Sen DR. Epigenetic scars of CD8 + T cell exhaustion persist after cure of chronic infection in humans. Nat Immunol 2021; 22:1020-1029. [PMID: 34312547 DOI: 10.1038/s41590-021-00979-1] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 06/17/2021] [Indexed: 12/12/2022]
Abstract
T cell exhaustion is an induced state of dysfunction that arises in response to chronic infection and cancer. Exhausted CD8+ T cells acquire a distinct epigenetic state, but it is not known whether that chromatin landscape is fixed or plastic following the resolution of a chronic infection. Here we show that the epigenetic state of exhaustion is largely irreversible, even after curative therapy. Analysis of chromatin accessibility in HCV- and HIV-specific responses identifies a core epigenetic program of exhaustion in CD8+ T cells, which undergoes only limited remodeling before and after resolution of infection. Moreover, canonical features of exhaustion, including super-enhancers near the genes TOX and HIF1A, remain 'epigenetically scarred.' T cell exhaustion is therefore a conserved epigenetic state that becomes fixed and persists independent of chronic antigen stimulation and inflammation. Therapeutic efforts to reverse T cell exhaustion may require new approaches that increase the epigenetic plasticity of exhausted T cells.
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Affiliation(s)
- Kathleen B Yates
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Pierre Tonnerre
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA.,Inserm U976, Institut de Recherche Saint-Louis, Paris, France
| | - Genevieve E Martin
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Australia
| | - Ulrike Gerdemann
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Rose Al Abosy
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Dawn E Comstock
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
| | - Sarah A Weiss
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
| | - David Wolski
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA
| | - Damien C Tully
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.,Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Raymond T Chung
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA
| | - Todd M Allen
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Arthur Y Kim
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA
| | - Sarah Fidler
- Division of Medicine, Wright Fleming Institute, Imperial College, London, UK.,Imperial College National Institute for Health Research Biomedical Research Centre, London, UK
| | - Julie Fox
- Department of Genitourinary Medicine and Infectious Disease, Guy's and St Thomas' NHS Foundation Trust, London, UK.,King's College National Institute for Health Research Biomedical Research Centre, London, UK
| | - John Frater
- Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK
| | - Georg M Lauer
- Division of Gastroenterology, Liver Center, Massachusetts General Hospital, Boston, MA, USA
| | - W Nicholas Haining
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .,Merck Research Laboratories, Boston, MA, USA.
| | - Debattama R Sen
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .,Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
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16
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Tonnerre P, Wolski D, Subudhi S, Aljabban J, Hoogeveen RC, Damasio M, Drescher HK, Bartsch LM, Tully DC, Sen DR, Bean DJ, Brown J, Torres-Cornejo A, Robidoux M, Kvistad D, Alatrakchi N, Cui A, Lieb D, Cheney JA, Gustafson J, Lewis-Ximenez LL, Massenet-Regad L, Eisenhaure T, Aneja J, Haining WN, Chung RT, Hacohen N, Allen TM, Kim AY, Lauer GM. Differentiation of exhausted CD8 + T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nat Immunol 2021; 22:1030-1041. [PMID: 34312544 PMCID: PMC8323980 DOI: 10.1038/s41590-021-00982-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 06/22/2021] [Indexed: 12/13/2022]
Abstract
T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional, and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation towards a memory-like profile. However, functionally, the cells showed little improvement and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, T cell stimulation duration impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for development of functional T cell memory.
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Affiliation(s)
- Pierre Tonnerre
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. .,Inserm U976, Université de Paris, Institut de Recherche Saint-Louis, Paris, France.
| | - David Wolski
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Sonu Subudhi
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jihad Aljabban
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ruben C Hoogeveen
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marcos Damasio
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Hannah K Drescher
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lea M Bartsch
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Damien C Tully
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Debattama R Sen
- Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.,Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - David J Bean
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Joelle Brown
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Almudena Torres-Cornejo
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Maxwell Robidoux
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Daniel Kvistad
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Nadia Alatrakchi
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ang Cui
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA
| | - David Lieb
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - James A Cheney
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jenna Gustafson
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | | | | | | | - Jasneet Aneja
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - W Nicholas Haining
- Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.,Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Raymond T Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Nir Hacohen
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
| | - Todd M Allen
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Arthur Y Kim
- Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Georg M Lauer
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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17
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Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial. Viruses 2021; 13:v13071351. [PMID: 34372558 PMCID: PMC8310243 DOI: 10.3390/v13071351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/03/2021] [Accepted: 07/08/2021] [Indexed: 11/17/2022] Open
Abstract
Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.
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18
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Saraceni C, Birk J. A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis. J Clin Transl Hepatol 2021; 9:409-418. [PMID: 34221927 PMCID: PMC8237136 DOI: 10.14218/jcth.2020.00095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/21/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell's hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host's innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85-99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.
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Affiliation(s)
- Corey Saraceni
- Correspondence to: Corey Saraceni, University of Connecticut School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-8074, USA. Tel: +1-203-733-7408, Fax: +1-860-679-3159, E-mail:
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19
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Hartlage AS, Dravid P, Walker CM, Kapoor A. Adenovirus-vectored T cell vaccine for hepacivirus shows reduced effectiveness against a CD8 T cell escape variant in rats. PLoS Pathog 2021; 17:e1009391. [PMID: 33735321 PMCID: PMC8009437 DOI: 10.1371/journal.ppat.1009391] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 03/30/2021] [Accepted: 02/16/2021] [Indexed: 12/13/2022] Open
Abstract
There is an urgent need for a vaccine to prevent chronic infection by hepatitis C virus (HCV) and its many genetic variants. The first human vaccine trial, using recombinant viral vectors that stimulate pan-genotypic T cell responses against HCV non-structural proteins, failed to demonstrate efficacy despite significant preclinical promise. Understanding the factors that govern HCV T cell vaccine success is necessary for design of improved immunization strategies. Using a rat model of chronic rodent hepacivirus (RHV) infection, we assessed the impact of antigenic variation and immune escape upon success of a conceptually analogous RHV T cell vaccine. Naïve Lewis rats were vaccinated with a recombinant human adenovirus expressing RHV non-structural proteins (NS)3-5B and later challenged with a viral variant containing immune escape mutations within major histocompatibility complex (MHC) class I-restricted epitopes (escape virus). Whereas 7 of 11 (64%) rats cleared infection caused by wild-type RHV, only 3 of 12 (25%) were protected against heterologous challenge with escape virus. Uncontrolled replication of escape virus was associated with durable CD8 T cell responses targeting escaped epitopes alone. In contrast, clearance of escape virus correlated with CD4 T cell helper immunity and maintenance of CD8 T cell responses against intact viral epitopes. Interestingly, clearance of wild-type RHV infection after vaccination conferred enhanced protection against secondary challenge with escape virus. These results demonstrate that the efficacy of an RHV T cell vaccine is reduced when challenge virus contains escape mutations within MHC class I-restricted epitopes and that failure to sustain CD8 T cell responses against intact epitopes likely underlies immune failure in this setting. Further investigation of the immune responses that yield protection against diverse RHV challenges in this model may facilitate design of broadly effective HCV vaccines. The hepatitis C virus is one of the leading causes of chronic liver disease and cancer worldwide. A vaccine is not yet available and the first phase II clinical trial in humans using a T cell-based immunization strategy recently failed to prevent chronic infection in high risk individuals for unclear reasons. In this study we evaluated how immune escape mutations at major histocompatibility complex (MHC) class I-restricted viral epitopes influence the effectiveness of an adenoviral-vectored T cell vaccine in a rat model of chronic HCV-related rodent hepacivirus infection, currently the only animal model available for evaluation of HCV vaccine strategies. We show that vaccine efficacy is markedly diminished when challenge virus contains naturally-acquired escape mutations at dominant MHC class I-restricted viral epitopes that render a subset of vaccine-generated CD8 T cell responses ineffective. We also identify CD4 T cell help as a critical correlate of vaccine success against heterologous virus challenge. Our results have important implications for human vaccination programs that aim to induce broad protective immunity against heterogeneous HCV strains.
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Affiliation(s)
- Alex S. Hartlage
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Medical Scientist Training Program, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Piyush Dravid
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Christopher M. Walker
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
| | - Amit Kapoor
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail:
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20
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Agerer B, Koblischke M, Gudipati V, Montaño-Gutierrez LF, Smyth M, Popa A, Genger JW, Endler L, Florian DM, Mühlgrabner V, Graninger M, Aberle SW, Husa AM, Shaw LE, Lercher A, Gattinger P, Torralba-Gombau R, Trapin D, Penz T, Barreca D, Fae I, Wenda S, Traugott M, Walder G, Pickl WF, Thiel V, Allerberger F, Stockinger H, Puchhammer-Stöckl E, Weninger W, Fischer G, Hoepler W, Pawelka E, Zoufaly A, Valenta R, Bock C, Paster W, Geyeregger R, Farlik M, Halbritter F, Huppa JB, Aberle JH, Bergthaler A. SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 + T cell responses. Sci Immunol 2021; 6:6/57/eabg6461. [PMID: 33664060 PMCID: PMC8224398 DOI: 10.1126/sciimmunol.abg6461] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/27/2021] [Indexed: 12/26/2022]
Abstract
CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.
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Affiliation(s)
- Benedikt Agerer
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | | | - Venugopal Gudipati
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | | | - Mark Smyth
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Alexandra Popa
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Jakob-Wendelin Genger
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Lukas Endler
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - David M Florian
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Vanessa Mühlgrabner
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | | | - Stephan W Aberle
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Anna-Maria Husa
- St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria
| | - Lisa Ellen Shaw
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Alexander Lercher
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Pia Gattinger
- Department of Pathophysiology and Allergy Research, Division of Immunopathology, Medical University of Vienna, Vienna, Austria
| | - Ricard Torralba-Gombau
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Doris Trapin
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Thomas Penz
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Daniele Barreca
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Ingrid Fae
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Sabine Wenda
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | | | - Gernot Walder
- Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Winfried F Pickl
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.,Karl Landsteiner University of Health Sciences, Krems, Austria
| | - Volker Thiel
- Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland.,Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | | | - Hannes Stockinger
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | | | - Wolfgang Weninger
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Gottfried Fischer
- Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | | | - Erich Pawelka
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Alexander Zoufaly
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Rudolf Valenta
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.,Department of Pathophysiology and Allergy Research, Division of Immunopathology, Medical University of Vienna, Vienna, Austria.,Karl Landsteiner University of Health Sciences, Krems, Austria.,Laboratory for Immunopathology, Department of Clinical Immunology and Allergy, First Moscow State Medical University Sechenov, Moscow, Russia.,NRC Institute of Immunology FMBA of Russia, Moscow, Russia
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.,Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Paster
- St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria
| | - René Geyeregger
- St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria
| | - Matthias Farlik
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | | | - Johannes B Huppa
- Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Judith H Aberle
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Andreas Bergthaler
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
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21
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Peña-Asensio J, Calvo H, Torralba M, Miquel J, Sanz-de-Villalobos E, Larrubia JR. Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8 + T Cell Response during Chronic Hepatitis C. Cells 2021; 10:cells10030538. [PMID: 33802622 PMCID: PMC8001543 DOI: 10.3390/cells10030538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/23/2021] [Accepted: 02/26/2021] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2/IL-7/IL-15/IL-21 treatment.
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MESH Headings
- Antibodies, Monoclonal/therapeutic use
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/genetics
- B7-H1 Antigen/immunology
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/virology
- Gene Expression Regulation
- Hepacivirus/immunology
- Hepacivirus/pathogenicity
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions/drug effects
- Host-Pathogen Interactions/genetics
- Host-Pathogen Interactions/immunology
- Humans
- Immune Checkpoint Inhibitors/therapeutic use
- Immunity, Cellular/drug effects
- Immunotherapy/methods
- Interleukins/genetics
- Interleukins/immunology
- Interleukins/therapeutic use
- Lymphocyte Activation/drug effects
- Precursor Cells, T-Lymphoid/drug effects
- Precursor Cells, T-Lymphoid/immunology
- Precursor Cells, T-Lymphoid/virology
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/genetics
- Programmed Cell Death 1 Receptor/immunology
- Receptors, Antigen, T-Cell, gamma-delta/agonists
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Signal Transduction
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Affiliation(s)
- Julia Peña-Asensio
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Department of Biology of Systems, University of Alcalá, E-28805 Alcalá de Henares, Spain
| | - Henar Calvo
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
| | - Miguel Torralba
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Service of Internal Medicine, Guadalajara University Hospital, E-19002 Guadalajara, Spain
- Department of Medicine & Medical Specialties, University of Alcalá, E-28805 Alcalá de Henares, Spain
| | - Joaquín Miquel
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
| | - Eduardo Sanz-de-Villalobos
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
| | - Juan-Ramón Larrubia
- Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain; (J.P.-A.); (H.C.); (M.T.); (J.M.); (E.S.-d.-V.)
- Section of Gastroenterology & Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain
- Department of Medicine & Medical Specialties, University of Alcalá, E-28805 Alcalá de Henares, Spain
- Correspondence: ; Tel.: +34-949-20-9200
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22
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CD8 + T Cell Responses during HCV Infection and HCC. J Clin Med 2021; 10:jcm10050991. [PMID: 33801203 PMCID: PMC7957882 DOI: 10.3390/jcm10050991] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/12/2021] [Accepted: 02/22/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic hepatitis C virus (cHCV) infection is a major global health burden and the leading cause of hepatocellular carcinoma (HCC) in the Western world. The course and outcome of HCV infection is centrally influenced by CD8+ T cell responses. Indeed, strong virus-specific CD8+ T cell responses are associated with spontaneous viral clearance while failure of these responses, e.g., caused by viral escape and T cell exhaustion, is associated with the development of chronic infection. Recently, heterogeneity within the exhausted HCV-specific CD8+ T cells has been observed with implications for immunotherapeutic approaches also for other diseases. In HCC, the presence of tumor-infiltrating and peripheral CD8+ T cell responses correlates with a favorable prognosis. Thus, tumor-associated and tumor-specific CD8+ T cells are considered suitable targets for immunotherapeutic strategies. Here, we review the current knowledge of CD8+ T cell responses in chronic HCV infection and HCC and their respective failure with the potential consequences for T cell-associated immunotherapeutic approaches.
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23
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Page K, Melia MT, Veenhuis RT, Winter M, Rousseau KE, Massaccesi G, Osburn WO, Forman M, Thomas E, Thornton K, Wagner K, Vassilev V, Lin L, Lum PJ, Giudice LC, Stein E, Asher A, Chang S, Gorman R, Ghany MG, Liang TJ, Wierzbicki MR, Scarselli E, Nicosia A, Folgori A, Capone S, Cox AL. Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection. N Engl J Med 2021; 384:541-549. [PMID: 33567193 PMCID: PMC8367093 DOI: 10.1056/nejmoa2023345] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease. METHODS In this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months. RESULTS A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups. CONCLUSIONS In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).
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Affiliation(s)
- Kimberly Page
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Michael T Melia
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Rebecca T Veenhuis
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Matthew Winter
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Kimberly E Rousseau
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Guido Massaccesi
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - William O Osburn
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Michael Forman
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Elaine Thomas
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Karla Thornton
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Katherine Wagner
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Ventzislav Vassilev
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Lan Lin
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Paula J Lum
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Linda C Giudice
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Ellen Stein
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Alice Asher
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Soju Chang
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Richard Gorman
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Marc G Ghany
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - T Jake Liang
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Michael R Wierzbicki
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Elisa Scarselli
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Alfredo Nicosia
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Antonella Folgori
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Stefania Capone
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
| | - Andrea L Cox
- From the University of New Mexico, Albuquerque (K.P., E.T., K.T., K.W.); Johns Hopkins University, Baltimore (M.T.M., R.T.V., M.W., K.E.R., G.M., W.O.O., M.F., A.L.C.), the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (S. Chang, R.G.), and the Emmes Company (M.R.W.), Rockville, and the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (M.G.G., T.J.L.) - all in Maryland; GSK Vaccines, Rixensart, Belgium (V.V., L.L.); the University of California, San Francisco, San Francisco (P.J.L., L.C.G., E. Stein, A.A.); the Centers for Disease Control and Prevention, Office of Policy, Planning, and Partnerships, Atlanta (A.A.); and ReiThera, Rome (E. Scarselli, A.F., S. Capone), and CEINGE, Naples (A.N.) - both in Italy
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Memory-like HCV-specific CD8 + T cells retain a molecular scar after cure of chronic HCV infection. Nat Immunol 2021; 22:229-239. [PMID: 33398179 DOI: 10.1038/s41590-020-00817-w] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/06/2020] [Indexed: 01/05/2023]
Abstract
In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8+ T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor-progeny relationship between memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8+ T cell response. However, an exhausted core signature of memory-like CD8+ T cells was still detectable, including, to a smaller extent, in HCV-specific CD8+ T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8+ T cells even after the cessation of chronic antigen stimulation.
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Smith S, Honegger JR, Walker C. T-Cell Immunity against the Hepatitis C Virus: A Persistent Research Priority in an Era of Highly Effective Therapy. Cold Spring Harb Perspect Med 2021; 11:cshperspect.a036954. [PMID: 32205413 PMCID: PMC7778213 DOI: 10.1101/cshperspect.a036954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Approximately 70% of acute hepatitis C virus (HCV) infections become chronic, indicating that the virus is exceptionally well adapted to persist in humans with otherwise normal immune function. Robust, lifelong replication of this small RNA virus does not require a generalized failure of immunity. HCV effectively subverts innate and adaptive host defenses while leaving immunity against other viruses intact. Here, the role of CD4+ and CD8+ T-cell responses in control of HCV infection and their failure to prevent virus persistence in most individuals are reviewed. Two issues of practical importance remain priorities in an era of highly effective antiviral therapy for chronic hepatitis C. First, the characteristics of successful T-cell responses that promote resolution of HCV infection are considered, as they will underpin development of vaccines that prevent HCV persistence. Second, defects in T-cell immunity that facilitate HCV persistence and whether they are reversed after antiviral cure to provide protection from reinfection are also addressed.
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Affiliation(s)
- Stephanie Smith
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Jonathan R. Honegger
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Christopher Walker
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
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Kemming J, Thimme R, Neumann-Haefelin C. Adaptive Immune Response against Hepatitis C Virus. Int J Mol Sci 2020; 21:ijms21165644. [PMID: 32781731 PMCID: PMC7460648 DOI: 10.3390/ijms21165644] [Citation(s) in RCA: 15] [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: 07/15/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 12/18/2022] Open
Abstract
A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.
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Affiliation(s)
- Janine Kemming
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
- Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104 Freiburg im Breisgau, Germany
| | - Robert Thimme
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
- Correspondence: ; Tel.: +49-761-270-32800
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Osuch S, Metzner KJ, Caraballo Cortés K. Reversal of T Cell Exhaustion in Chronic HCV Infection. Viruses 2020; 12:v12080799. [PMID: 32722372 PMCID: PMC7472290 DOI: 10.3390/v12080799] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022] Open
Abstract
The long-term consequences of T cell responses’ impairment in chronic HCV infection are not entirely characterized, although they may be essential in the context of the clinical course of infection, re-infection, treatment-mediated viral clearance and vaccine design. Furthermore, it is unclear whether a complete reinvigoration of HCV-specific T cell response may be feasible. In most studies, attempting to reverse the effects of compromised immune response quality by specific blockades of negative immune regulators, a restoration of functional competence of HCV-specific T cells was shown. This implies that HCV-induced immune dysfunction may be reversible. The advent of highly successful, direct-acting antiviral treatment (DAA) for chronic HCV infection instigated investigation whether the treatment-driven elimination of viral antigens restores T cell function. Most of studies demonstrated that DAA treatment may result in at least partial restoration of T cell immune function. They also suggest that a complete restoration comparable to that seen after spontaneous viral clearance may not be attained, pointing out that long-term antigenic stimulation imprints an irreversible change on the T cell compartment. Understanding the mechanisms of HCV-induced immune dysfunction and barriers to immune restoration following viral clearance is of utmost importance to diminish the possible long-term consequences of chronic HCV infection.
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Affiliation(s)
- Sylwia Osuch
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-091 Warsaw, Poland;
| | - Karin J. Metzner
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland;
- Institute of Medical Virology, University of Zurich, CH-8057 Zurich, Switzerland
| | - Kamila Caraballo Cortés
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Correspondence: ; Tel.: +48-22-572-07-09; Fax: +48-22-883-10-60
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Cox AL. Challenges and Promise of a Hepatitis C Virus Vaccine. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036947. [PMID: 31548228 DOI: 10.1101/cshperspect.a036947] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
An estimated 1.5-2 million new hepatitis C virus (HCV) infections occur globally each year. Critical to the World Health Organization's (WHO) HCV elimination strategy is an 80% reduction in incidence of HCV infections by 2030. However, even among high-income countries, few are on target to achieve the WHO's incident infection-reduction goal. A preventative vaccine could have a major impact in achieving incidence-reduction targets globally. However, barriers to HCV vaccine development are significant and include at-risk populations that are often marginalized: viral diversity, limited options for testing HCV vaccines, and an incomplete understanding of protective immune responses. In part because of those factors, testing of only one vaccine strategy has been completed in at-risk individuals as of 2019. Despite challenges, immunity against HCV protects against chronic infection in some repeated HCV exposures and an effective HCV vaccine could prevent transmission regardless of risk factors. Ultimately, prophylactic vaccines will likely be necessary to achieve global HCV elimination.
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Affiliation(s)
- Andrea L Cox
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland 21205, USA
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Lérias JR, Paraschoudi G, de Sousa E, Martins J, Condeço C, Figueiredo N, Carvalho C, Dodoo E, Castillo-Martin M, Beltrán A, Ligeiro D, Rao M, Zumla A, Maeurer M. Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies. Front Cell Dev Biol 2020; 7:362. [PMID: 32039196 PMCID: PMC6989410 DOI: 10.3389/fcell.2019.00362] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
The intricate interplay between the immune system and microbes is an essential part of the physiological homeostasis in health and disease. Immunological recognition of commensal microbes, such as bacterial species resident in the gut or lung as well as dormant viral species, i.e., cytomegalovirus (CMV) or Epstein-Barr virus (EBV), in combination with a balanced immune regulation, is central to achieve immune-protection. Emerging evidence suggests that immune responses primed to guard against commensal microbes may cause unexpected pathological outcomes, e.g., chronic inflammation and/or malignant transformation. Furthermore, translocation of immune cells from one anatomical compartment to another, i.e., the gut-lung axis via the lymphatics or blood has been identified as an important factor in perpetrating systemic inflammation, tissue destruction, as well as modulating host-protective immune responses. We present in this review immune response patterns to pathogenic as well as non-pathogenic microbes and how these immune-recognition profiles affect local immune responses or malignant transformation. We discuss personalized immunological therapies which, directly or indirectly, target host biological pathways modulated by antimicrobial immune responses.
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Affiliation(s)
- Joana R. Lérias
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | - Eric de Sousa
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - João Martins
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Carolina Condeço
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Nuno Figueiredo
- Digestive Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Carlos Carvalho
- Digestive Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | | | - Antonio Beltrán
- Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Dário Ligeiro
- Lisbon Centre for Blood and Transplantation, Instituto Português do Sangue e Transplantação, Lisbon, Portugal
| | - Martin Rao
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Alimuddin Zumla
- Division of Infection and Immunity, NIHR Biomedical Research Centre, University College London Hospitals NHS Foundation Trust, University College London, London, United Kingdom
| | - Markus Maeurer
- ImmunoSurgery Unit, Champalimaud Centre for the Unknown, Lisbon, Portugal
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Wolski D, Lauer GM. Hepatitis C Virus as a Unique Human Model Disease to Define Differences in the Transcriptional Landscape of T Cells in Acute versus Chronic Infection. Viruses 2019; 11:v11080683. [PMID: 31357397 PMCID: PMC6723887 DOI: 10.3390/v11080683] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 07/21/2019] [Accepted: 07/23/2019] [Indexed: 12/12/2022] Open
Abstract
The hepatitis C virus is unique among chronic viral infections in that an acute outcome with complete viral elimination is observed in a minority of infected patients. This unique feature allows direct comparison of successful immune responses with those that fail in the setting of the same human infection. Here we review how this scenario can be used to achieve better understanding of transcriptional regulation of T-cell differentiation. Specifically, we discuss results from a study comparing transcriptional profiles of hepatitis C virus (HCV)-specific CD8 T-cells during early HCV infection between patients that do and do not control and eliminate HCV. Identification of early gene expression differences in key T-cell differentiation molecules as well as clearly distinct transcriptional networks related to cell metabolism and nucleosomal regulation reveal novel insights into the development of exhausted and memory T-cells. With additional transcriptional studies of HCV-specific CD4 and CD8 T-cells in different stages of infection currently underway, we expect HCV infection to become a valuable model disease to study human immunity to viruses.
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Affiliation(s)
- David Wolski
- Liver Center at the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Georg M Lauer
- Liver Center at the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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31
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Hepatitis C Virus Genetic Variability, Human Immune Response, and Genome Polymorphisms: Which Is the Interplay? Cells 2019; 8:cells8040305. [PMID: 30987134 PMCID: PMC6523096 DOI: 10.3390/cells8040305] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection is the main cause of chronic hepatitis, affecting an estimated 150 million people worldwide. Initial exposure to HCV is most often followed by chronic hepatitis, with only a minority of individuals spontaneously clearing the virus. The induction of sustained and broadly directed HCV-specific CD4+ and CD8+ T cell responses, together with neutralizing antibodies (nAb), and specific genetic polymorphism have been associated with spontaneous resolution of the infection. However, due to its high variability, HCV is able to overwhelm the host immune response through the rapid acquisition of mutations in the epitopes targeted by T cells and neutralizing antibodies. In this context, immune-mediated pressure represents the main force in driving HCV evolution. This review summarizes the data on HCV diversity and the current state of knowledge about the contributions of antibodies, T cells, and host genetic polymorphism in driving HCV evolution in vivo.
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Rodrigo C, Leung P, Lloyd AR, Bull RA, Luciani F, Grebely J, Dore GJ, Applegate T, Page K, Bruneau J, Cox AL, Osburn W, Kim AY, Shoukry NH, Lauer GM, Maher L, Schinkel J, Prins M, Hellard M, Eltahla AA. Genomic variability of within-host hepatitis C variants in acute infection. J Viral Hepat 2019; 26:476-484. [PMID: 30578702 PMCID: PMC6417964 DOI: 10.1111/jvh.13051] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 11/26/2018] [Indexed: 01/04/2023]
Abstract
Interactions between the host immune system and the viral variants determine persistence of hepatitis C virus (HCV) infection after the acute phase of infection. This study describes the genetic variability of within-host HCV viral variants in acute infection and correlates it with host- and virus-related traits and infection outcome. Next generation sequence data (Illumina, MiSeq platform) of viral genomes from 116 incident acute infections (within 180 days of infection) were analysed to determine all the single nucleotide polymorphism (SNP) frequencies above a threshold of 0.1%. The variability of the SNPs for the full open reading frame of the genome as well as for each protein coding region were compared using mean standardized Shannon entropy (SE) values calculated separately for synonymous and nonsynonymous mutations. The envelope glycoproteins regions (E1 and E2) had the highest SE values (indicating greater variability) followed by the NS5B region. Nonsynonymous mutations rather than synonymous mutations were the main contributors to genomic variability in acute infection. The mean difference of Shannon entropy was also compared between subjects after categorizing the samples according to host and virus-related traits. Host IFNL3 allele CC polymorphism at rs12979860 (vs others) and viral genotype 1a (vs 3a) were associated with higher genomic variability across the viral open reading frame. Time since infection, host gender or continent of origin was not associated with the viral genomic variability. Viral genomic variability did not predict spontaneous clearance.
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Affiliation(s)
| | | | | | - Rowena A. Bull
- School of Medical Sciences, UNSW, NSW, Australia
- The Kirby Institute, UNSW Sydney, NSW, Australia
| | - Fabio Luciani
- School of Medical Sciences, UNSW, NSW, Australia
- The Kirby Institute, UNSW Sydney, NSW, Australia
| | | | | | | | - Kimberly Page
- University of New Mexico, Albuquerque, New Mexico, USA
| | - Julie Bruneau
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Andrea L. Cox
- Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | | | | | - Naglaa H. Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | | | - Lisa Maher
- The Kirby Institute, UNSW Sydney, NSW, Australia
| | - Janke Schinkel
- Academic Medical Center, Amsterdam, The Netherlands
- GGD Public Health Service of Amsterdam
| | - Maria Prins
- Academic Medical Center, Amsterdam, The Netherlands
- GGD Public Health Service of Amsterdam
| | - Margaret Hellard
- Burnet Institute, Melbourne, VIC, Australia
- Monash University, Australia
- Alfred Hospital, Melbourne, Australia
- Doherty Institute and Melbourne School of Population and Global Health, University of Melbourne
| | - Auda A. Eltahla
- School of Medical Sciences, UNSW, NSW, Australia
- University of New Mexico, Albuquerque, New Mexico, USA
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33
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Rose R, Rodriguez C, Dollar JJ, Lamers SL, Massaccesi G, Osburn W, Ray SC, Thomas DL, Cox AL, Laeyendecker O. Inconsistent temporal patterns of genetic variation of HCV among high-risk subjects may impact inference of transmission networks. INFECTION GENETICS AND EVOLUTION 2019; 71:1-6. [PMID: 30802530 DOI: 10.1016/j.meegid.2019.02.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/19/2019] [Accepted: 02/21/2019] [Indexed: 01/03/2023]
Abstract
Hepatitis-C Virus (HCV) sequences are often used to establish networks of people who inject drugs (PWID). However, the degree to which within-host evolutionary dynamics affect those inferences has not been carefully studied. Here, we analyzed 702 longitudinally-sampled HCV E1 sequences from 88 HCV+ people who inject drugs (PWID) in the Baltimore Before and After Acute Study of Hepatitis (BBAASH) cohort. Individuals were tested for HCV RNA over multiple visits to the clinic, and the HCV E1 gene was sequenced for HCV+ samples. Genetic clustering was performed on the full set of sequences using a 3% genetic distance threshold to define epidemiological linkage. Maximum-likelihood (ML) phylogenies were inferred to assess evolutionary relationships. We found 22 clusters containing sequences sampled over five or more years (long-term clusters, LTC), of which 17 had >1 subject. In six of the multi-subject LTC, one subject had a sequence sampled >3 years earlier or later than the next-closest subject in the cluster (time-gap LTC). ML trees showed that, in three of the time-gap LTC, two subjects had identical sequences despite 7-10 years separating the sampling times. In four of the time-gap LTC for whom additional data were available, the subject with the later detected shared variant had both different variants and visits with no detectable HCV RNA (RNA-) prior to the appearance of the shared variant. In the subject with the earlier detection of the shared variant, different variants and RNA- visits were also detected in multiple cases subsequent to appearance of the shared variant. Complex patterns of shared viral variation among PWID reflect on-going re-infection, multiple transmission partners, and/or inconsistent detection of viral variants. Our results suggest that transmission events are currently underestimated by analysis of sequences at a single point in time.
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Affiliation(s)
- Rebecca Rose
- BioInfoExperts LLC, Thibodaux, LA, United States.
| | | | | | | | - Guido Massaccesi
- Department of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - William Osburn
- Department of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Stuart C Ray
- Department of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - David L Thomas
- Department of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Oliver Laeyendecker
- Department of Medicine, Johns Hopkins University, Baltimore, MD, United States; NIAID, NIH, Baltimore, MD, United States
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34
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Sette LHBC, Lopes EPDA, Guedes dos Anjos NC, Valente LM, Vieira de Oliveira SA, Lucena-Silva N. High prevalence of occult hepatitis C infection in predialysis patients. World J Hepatol 2019; 11:109-118. [PMID: 30705723 PMCID: PMC6354127 DOI: 10.4254/wjh.v11.i1.109] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 12/20/2018] [Accepted: 01/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Occult hepatitis C virus (HCV) infection (OCI) may be associated with extrahepatic diseases and it is known that the patients with chronic kidney disease (CKD) who are on hemodialysis (HD) present a higher prevalence of this type of infection than the general population, with a worse clinical outcome. However, there are no data in the literature to assess the presence of OCI in patients prior to the initiation of renal replacement therapy (RRT). Therefore, this study aimed to evaluate the occurrence and epidemiological aspects of OCI in patients with Predialysis CKD. We hypothesize that this infection could occur before RRT initiation.
AIM To research the status in predialysis patients when HD patients have high prevalence of OCI.
METHODS A cross-sectional study was conducted between 2015 and 2017. Adults with creatinine clearance < 60 mL/min·1.73 m2 (predialysis patients) were recruited to the study. Pregnant and postpartum women, patients with glomerulopathies, and patients showing positivity for serological markers of hepatitis B virus (HBV), HCV or human immunodeficiency virus infection were excluded. Patients were diagnosed with OCI according to test results of anti-HCV antibody negativity and HCV RNA positivity in either ultracentrifuged serum or, if serum-negative, in peripheral blood mononuclear cells.
RESULTS Among the 91 total patients included in the study, the prevalence of OCI was 16.5%. Among these 15 total OCI patients, 1 was diagnosed by 14 ultracentrifuged serum results and 14 were diagnosed by peripheral blood mononuclear cell results. Compared to the non-OCI group, the OCI patients presented higher frequency of older age (P = 0.002), patients with CKD of mixed etiology (P = 0.019), and patients with markers of previous HBV infection (i.e., combined positivity for anti-hepatitis B core protein antibody and anti-hepatitis B surface protein antibody) (P = 0.001).
CONCLUSION Among predialysis patients, OCI involved the elderly, patients with CKD of mixed etiology, and patients with previous HBV infection.
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Affiliation(s)
| | | | | | - Lucila Maria Valente
- Nephrology-Department of Clinical Medicine, Federal University of Pernambuco, Pernambuco 50670-901, Brazil
| | | | - Norma Lucena-Silva
- Laboratory of Immunogenetics of the Aggeu Magalhães Institute - Fiocruz Pernambuco, Pernambuco 50670-420, Brazil
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35
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Abdel-Hakeem MS. Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries. Viruses 2019; 11:E106. [PMID: 30691215 PMCID: PMC6410308 DOI: 10.3390/v11020106] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/16/2022] Open
Abstract
Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.
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Affiliation(s)
- Mohamed S Abdel-Hakeem
- Penn Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt.
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36
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Bailey JR, Barnes E, Cox AL. Approaches, Progress, and Challenges to Hepatitis C Vaccine Development. Gastroenterology 2019; 156:418-430. [PMID: 30268785 PMCID: PMC6340767 DOI: 10.1053/j.gastro.2018.08.060] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 08/12/2018] [Accepted: 08/14/2018] [Indexed: 12/16/2022]
Abstract
Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV.
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Affiliation(s)
- Justin R. Bailey
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, Oxford University, UK
| | - Andrea L. Cox
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland,Reprint requests Address requests for reprints to: Andrea L. Cox, MD, PhD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 551 Rangos Building, 855 N Wolfe Street, Baltimore, Maryland 21205. fax: (443)769-1221.
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37
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Xia Y, Pan W, Ke X, Skibbe K, Walker A, Hoffmann D, Lu Y, Yang X, Feng X, Tong Q, Timm J, Yang D. Differential escape of HCV from CD8 + T cell selection pressure between China and Germany depends on the presenting HLA class I molecule. J Viral Hepat 2019; 26:73-82. [PMID: 30260541 PMCID: PMC7379502 DOI: 10.1111/jvh.13011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 09/07/2018] [Indexed: 12/16/2022]
Abstract
Adaptation of hepatitis C virus (HCV) to CD8+ T cell selection pressure is well described; however, it is unclear if HCV differentially adapts in different populations. Here, we studied HLA class I-associated viral sequence polymorphisms in HCV 1b isolates in a Chinese population and compared viral substitution patterns between Chinese and German populations. We identified three HLA class I-restricted epitopes in HCV NS3 with statistical support for selection pressure and found evidence for differential escape pathways between isolates from China and Germany depending on the HLA class I molecule. The substitution patterns particularly differed in the epitope VTLTHPITK1635-1643 , which was presented by HLA-A*03 as well as HLA-A*11, two alleles with highly different frequencies in the two populations. In Germany, a substitution in position seven of the epitope was the most frequent substitution in the presence of HLA-A*03, functionally associated with immune escape and nearly absent in Chinese isolates. In contrast, the most frequent substitution in China was located at position two of the epitope and became the predominant consensus residue. Moreover, substitutions in position one of the epitope were significantly enriched in HLA-A*11-positive individuals in China and associated with different patterns of CD8+ T cell reactivity. Our study confirms the differential escape pathways selected by HCV that depended on different HLA class I alleles in Chinese and German populations, indicating that HCV differentially adapts to distinct HLA class I alleles in these populations. This result has important implications for vaccine design against highly variable and globally distributed pathogens, which may require matching antigen sequences to geographic regions for T cell-based vaccine strategies.
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Affiliation(s)
- Youchen Xia
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Department of Gastroenterology and HepatologyShanghai General HospitalShanghai Jiao Tong University School of Medicine (originally named “Shanghai First People's Hospital”)ShanghaiChina
| | - Wen Pan
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoyu Ke
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Department of EmergencyTongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Kathrin Skibbe
- Institute of VirologyUniversity Hospital DüsseldorfHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Andreas Walker
- Institute of VirologyUniversity Hospital DüsseldorfHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Daniel Hoffmann
- Bioinformatics and Computational BiophysicsFaculty of BiologyUniversity of Duisburg‐EssenEssenGermany
| | - Yinping Lu
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xuecheng Yang
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xuemei Feng
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Qiaoxia Tong
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Jörg Timm
- Institute of VirologyUniversity Hospital DüsseldorfHeinrich‐Heine‐UniversityDüsseldorfGermany
| | - Dongliang Yang
- Department of Infectious DiseasesUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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38
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Luxenburger H, Neumann-Haefelin C, Thimme R, Boettler T. HCV-Specific T Cell Responses During and After Chronic HCV Infection. Viruses 2018; 10:v10110645. [PMID: 30453612 PMCID: PMC6265781 DOI: 10.3390/v10110645] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/14/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV)-specific T cell responses are closely linked to the clinical course of infection. While T cell responses in self-limiting infection are typically broad and multi-specific, they display several distinct features of functional impairment in the chronic phase. Moreover, HCV readily adapts to immune pressure by developing escape mutations within epitopes targeted by T cells. Much of our current knowledge on HCV-specific T cell responses has been gathered under the assumption that this might eventually pave the way for a therapeutic vaccine. However, with the development of highly efficient direct acting antivirals (DAAs), there is less interest in the development of a therapeutic vaccine for HCV and the scope of T cell research has shifted. Indeed, the possibility to rapidly eradicate an antigen that has persisted over years or decades, and has led to T cell exhaustion and dysfunction, provides the unique opportunity to study potential T cell recovery after antigen cessation in a human in vivo setting. Findings from such studies not only improve our basic understanding of T cell immunity but may also advance immunotherapeutic approaches in cancer or chronic hepatitis B and D infection. Moreover, in order to edge closer to the WHO goal of HCV elimination by 2030, a prophylactic vaccine is clearly required. Thus, in this review, we will summarize our current knowledge on HCV-specific T cell responses and also provide an outlook on the open questions that require answers in this field.
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Affiliation(s)
- Hendrik Luxenburger
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Robert Thimme
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Tobias Boettler
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
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39
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Kinchen VJ, Zahid MN, Flyak AI, Soliman MG, Learn GH, Wang S, Davidson E, Doranz BJ, Ray SC, Cox AL, Crowe JE, Bjorkman PJ, Shaw GM, Bailey JR. Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection. Cell Host Microbe 2018; 24:717-730.e5. [PMID: 30439341 PMCID: PMC6250073 DOI: 10.1016/j.chom.2018.10.012] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/17/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022]
Abstract
The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.
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Affiliation(s)
- Valerie J Kinchen
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Muhammad N Zahid
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Andrew I Flyak
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Mary G Soliman
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Gerald H Learn
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shuyi Wang
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | | - Stuart C Ray
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - James E Crowe
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Pamela J Bjorkman
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - George M Shaw
- Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Justin R Bailey
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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40
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Dustin LB. Innate and Adaptive Immune Responses in Chronic HCV Infection. Curr Drug Targets 2018; 18:826-843. [PMID: 26302811 DOI: 10.2174/1389450116666150825110532] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) remains a public health problem of global importance, even in the era of potent directly-acting antiviral drugs. In this chapter, I discuss immune responses to acute and chronic HCV infection. The outcome of HCV infection is influenced by viral strategies that limit or delay the initiation of innate antiviral responses. This delay may enable HCV to establish widespread infection long before the host mounts effective T and B cell responses. HCV's genetic agility, resulting from its high rate of replication and its error prone replication mechanism, enables it to evade immune recognition. Adaptive immune responses fail to keep up with changing viral epitopes. Neutralizing antibody epitopes may be hidden by decoy structures, glycans, and lipoproteins. T cell responses fail due to changing epitope sequences and due to exhaustion, a phenomenon that may have evolved to limit immune-mediated pathology. Despite these difficulties, innate and adaptive immune mechanisms do impact HCV replication. Immune-mediated clearance of infection is possible, occurring in 20-50% of people who contract the disease. New developments raise hopes for effective immunological interventions to prevent or treat HCV infection.
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Affiliation(s)
- Lynn B Dustin
- University of Oxford, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom
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41
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Hofmann M, Wieland D, Pircher H, Thimme R. Memory vs memory-like: The different facets of CD8+T-cell memory in HCV infection. Immunol Rev 2018; 283:232-237. [DOI: 10.1111/imr.12642] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- Maike Hofmann
- Department of Medicine II; University Hospital Freiburg; Faculty of Medicine; University of Freiburg; Freiburg Germany
| | - Dominik Wieland
- Department of Medicine II; University Hospital Freiburg; Faculty of Medicine; University of Freiburg; Freiburg Germany
| | - Hanspeter Pircher
- Institute for Immunology; Medical Center; Faculty of Medicine; University of Freiburg; Freiburg Germany
| | - Robert Thimme
- Department of Medicine II; University Hospital Freiburg; Faculty of Medicine; University of Freiburg; Freiburg Germany
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42
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According to Hepatitis C Virus (HCV) Infection Stage, Interleukin-7 Plus 4-1BB Triggering Alone or Combined with PD-1 Blockade Increases TRAF1 low HCV-Specific CD8 + Cell Reactivity. J Virol 2018; 92:JVI.01443-17. [PMID: 29093082 DOI: 10.1128/jvi.01443-17] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 10/23/2017] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV)-specific CD8+ T cells suffer a progressive exhaustion during persistent infection (PI) with HCV. This process could involve the positive immune checkpoint 4-1BB/4-1BBL through the loss of its signal transducer, TRAF1. To address this issue, peripheral HCV-specific CD8+ T cells (pentamer-positive [pentamer+]/CD8+ T cells) from patients with PI and resolved infection (RI) after treatment were studied. The duration of HCV infection and the liver fibrosis progression rate inversely correlated with the likelihood of detection of peripheral pentamer+/CD8+ cells. In PI, pentamer+/CD8+ cells had impaired antigen-specific reactivity that worsened when these cells were not detectable ex vivo Short/midduration PI was characterized by detectable peripheral PD-1+ CD127low TRAF1low cells. After triggering of T cell receptors (TCR), the TRAF1 level positively correlated with the levels of CD127, Mcl-1, and CD107a expression and proliferation intensity but negatively with PD-1 expression, linking TRAF1low to exhaustion. In vitro treatment with interleukin-7 (IL-7) upregulated TRAF1 expression, while treatment with transforming growth factor-β1 (TGF-β1) did the opposite, suggesting that the IL-7/TGF-β1 balance, besides TCR stimulation, could be involved in TRAF1 regulation. In fact, the serum TGF-β1 concentration was higher in patients with PI than in patients with RI, and it negatively correlated with TRAF1 expression. In line with IL-7 increasing the level of TRAF1 expression, IL-7 plus 4-1BBL treatment in vitro enhanced T cell reactivity in patients with short/midduration infection. However, in patients with long-lasting PI, anti-PD-L1, in addition to the combination of IL-7 and 4-1BBL, was necessary to reestablish T cell proliferation in individuals with slowly progressing liver fibrosis (slow fibrosers) but had no effect in rapid fibrosers. In conclusion, a peripheral hyporeactive TRAF1low HCV-specific CD8+ T cell response, restorable by IL-7 plus 4-1BBL treatment, characterizes short/midduration PI. In long-lasting disease, HCV-specific CD8+ T cells are rarely detectable ex vivo, but treatment with IL-7, 4-1BBL, and anti-PD-L1 recovers their reactivity in vitro in slow fibrosers.IMPORTANCE Hepatitis C virus (HCV) infects 71 million people worldwide. Two-thirds develop a chronic disease that can lead to cirrhosis and hepatocellular carcinoma. Direct-acting antivirals clear the infection, but there are still patients who relapse. In these cases, additional immunotherapy could play a vital role. A successful anti-HCV immune response depends on virus-specific CD8+ T cells. During chronic infection, these cells are functionally impaired, which could be due to the failure of costimulation. This study describes exhausted specific T cells, characterized by low levels of expression of the signal transducer TRAF1 of the positive costimulatory pathway 4-1BB/4-1BBL. IL-7 upregulated TRAF1 expression and improved T cell reactivity in patients with short/midduration disease, while in patients with long-lasting infection, it was also necessary to block the negative PD-1/PD-L1 checkpoint. When the results are taken together, this work supports novel ways of restoring the specific CD8+ T cell response, shedding light on the importance of TRAF1 signaling. This could be a promising target for future immunotherapy.
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Karkhane M, Mohebbi SR, Azimzadeh P, Avarandeh H, Kazemian S, Sharifian A, Hatami B, Asadzadeh Aghdaei H. Genetic association between a single nucleotide polymorphism in Interleukin-16 (rs4072111) and susceptibility to chronic HCV infection in an Iranian population. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2018; 11:42-47. [PMID: 29564064 PMCID: PMC5849117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
AIM Our goal was to identify the putative association of rs4072111 variant in IL-16 gene and HCV susceptibility in an Iranian population. BACKGROUND Interleukin 16 (IL-16), a multifunctional cytokine, plays a vital role in modulation of immune system. METHODS In present case control and cross sectional study, IL-16 gene variant in 300 patients with hepatitis C (HCV) infection and 300 healthy individuals were analyzed. To evaluate this possible association, genomic DNA from venous blood was extracted and genotypes of IL-16 rs4072111 variant were determined by polymerase chain reaction- Fragments Length Polymorphism Technique (PCR-RFLP). Then, rs4072111 C/T genotypes frequency and allelic distribution were evaluated in each group. RESULTS The results of genotyping showed 82% CC, 17.3% CT, 0.7% TT in the control group and 78% CC, 20% CT and 2% TT in the case group. The distribution of rs4072111 C allele was 90.7% in controls and 88% in case group respectively.However, no correlation between IL-16 rs4072111 C/T variants and susceptibility to chronic HCV infection was found in the present study. CONCLUSION We concluded the rs4072111 C/T cannot be considered as a proper biomarker to identify susceptibility to chronic hepatitis C virus infection.
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Affiliation(s)
- Maryam Karkhane
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pedram Azimzadeh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hasti Avarandeh
- Foodborne and waterborne diseases research center, Research institute for gastroenterology and liver diseases, Shahid Beheshti University of Medical Sciences
| | - Shabnam Kazemian
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afsaneh Sharifian
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Complex patterns of Hepatitis-C virus longitudinal clustering in a high-risk population. INFECTION GENETICS AND EVOLUTION 2017; 58:77-82. [PMID: 29253674 DOI: 10.1016/j.meegid.2017.12.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 11/10/2017] [Accepted: 12/14/2017] [Indexed: 12/12/2022]
Abstract
We investigated longitudinal viral clustering among and within subjects in a highly networked cohort of people who inject drugs (PWID). All subjects had estimated dates of infection and two or more E1 sequences (bp 943-1288 relative to H77) with 1 to 14years of follow up. Two methods (HIV-TRACE and PhyloPart) were used to determine clusters. Genetic distance thresholds were determined by comparing intra-and inter-host distances. Additional phylogenetic analysis was performed on subjects with complicated viral histories. At the optimal threshold of 3.9%, HIV-TRACE found 77 clusters and PhyloPart found 63 clusters, of which 27 and 32 contained multiple subjects, respectively. Furthermore, 1/3 of the subjects had sequences in different clusters over the course of the study, including some cases in which a later-sampled sequence matched a cluster detected much earlier in the infection, despite being separated by RNA-negative lab visit and detection of sequences in different clusters. A detailed phylogenetic analysis of four subjects with such patterns showed that in all four cases, the earlier and later variants grouped closely on the tree, and did not group with concurrent sequences from any other subject. These observations suggest that subjects are either experiencing rapid and recurring infection-clearance-reinfection cycles from the same source, or a single transmission event produces a chronic infection that may go undetected and/or co-circulate with different viruses from separate transmission events. Furthermore, our results show the utility of using longitudinal sampling to obtain a more comprehensive view of the viral linkages in high-risk populations.
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Wolski D, Foote PK, Chen DY, Lewis-Ximenez LL, Fauvelle C, Aneja J, Walker A, Tonnerre P, Torres-Cornejo A, Kvistad D, Imam S, Waring MT, Tully DC, Allen TM, Chung RT, Timm J, Haining WN, Kim AY, Baumert TF, Lauer GM. Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8 + T Cells in Chronic versus Acute Infection. Immunity 2017; 47:648-663.e8. [PMID: 29045899 PMCID: PMC5708133 DOI: 10.1016/j.immuni.2017.09.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 06/13/2017] [Accepted: 09/13/2017] [Indexed: 01/11/2023]
Abstract
Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.
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Affiliation(s)
- David Wolski
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg 67000, France; Université de Strasbourg, Strasbourg 67081, France
| | - Peter K Foote
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Diana Y Chen
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Lia L Lewis-Ximenez
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040, Brazil
| | - Catherine Fauvelle
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg 67000, France; Université de Strasbourg, Strasbourg 67081, France
| | - Jasneet Aneja
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Andreas Walker
- Institute for Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf 40225, Germany
| | - Pierre Tonnerre
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Almudena Torres-Cornejo
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Daniel Kvistad
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Sabrina Imam
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Michael T Waring
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Damien C Tully
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Todd M Allen
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
| | - Raymond T Chung
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Jörg Timm
- Institute for Virology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf 40225, Germany
| | - W Nicholas Haining
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Arthur Y Kim
- Division of Infectious Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg 67000, France; Université de Strasbourg, Strasbourg 67081, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg 67000, France
| | - Georg M Lauer
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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Merani S, Lucas M, Deshpande P, Pfafferott K, Chopra A, Cooper D, Leary S, Luciani F, Gaudieri S. Influence of Transmitted Virus on the Host's Immune Response: A Case Study. Viral Immunol 2017; 30:533-541. [PMID: 28530508 DOI: 10.1089/vim.2017.0001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Host hepatitis C virus (HCV)-specific T cell responses and the ability of the virus to escape this response are important correlates of infection outcome. Understanding this host-viral interplay has been difficult given the often asymptomatic nature of acute HCV infection. We studied a recent transmission case to determine whether adapted viral strains can be transmitted and influence the recipient's anti-HCV T cell response. The diversity of viral populations was examined using next-generation sequencing, and HCV-specific T cell interferon (IFN)-γ responses were assessed using a peptide panel representing the autologous viruses. HCV-specific T cell responses in the source were directed against peptides that did not match the dominant autologous virus but rather low-frequency variants, implying existing viral adaptation in the source strain. Most HCV T cell epitopes that elicited an IFN-γ response in the source did not in the recipient, despite the pair sharing human leukocyte antigen alleles that govern antigen presentation and similar autologous viruses. Intrahost HCV variation in the recipient fell within predicted T cell epitopes, suggesting alternative targets of the immune response. These data suggest that transmission of adapted viral species can direct the host's HCV-specific immune response profile during acute infection.
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Affiliation(s)
- Shahzma Merani
- 1 School of Human Sciences, University of Western Australia , Crawley, Australia
| | - Michaela Lucas
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia .,3 School of Medicine and Pharmacology, Harry Perkins Institute, University of Western Australia , Crawley, Australia .,4 School of Pathology and Laboratory Medicine, University of Western Australia , Crawley, Australia
| | - Pooja Deshpande
- 1 School of Human Sciences, University of Western Australia , Crawley, Australia
| | - Katja Pfafferott
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Abha Chopra
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Don Cooper
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Shay Leary
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Fabio Luciani
- 5 Systems Immunology, School of Medical Sciences, University of New South Wales , Sydney, Australia
| | - Silvana Gaudieri
- 1 School of Human Sciences, University of Western Australia , Crawley, Australia .,2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia .,6 Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Centre , Nashville, Tennessee
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47
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Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hofmann M, Thimme R. TCF1 + hepatitis C virus-specific CD8 + T cells are maintained after cessation of chronic antigen stimulation. Nat Commun 2017; 8:15050. [PMID: 28466857 PMCID: PMC5418623 DOI: 10.1038/ncomms15050] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 02/23/2017] [Indexed: 12/22/2022] Open
Abstract
Differentiation and fate of virus-specific CD8+ T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1+CD127+PD1+ hepatitis C virus (HCV)-specific CD8+ T-cell subset exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1+CD127+PD1+ population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1hi HCV-specific CD8+ T cells. These results suggest the TCF1+CD127+PD1+ HCV-specific CD8+ T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8+ T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.
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Affiliation(s)
- Dominik Wieland
- Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.,Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg 79104, Germany.,Faculty of Biology, University of Freiburg, Freiburg 79104, Germany
| | - Janine Kemming
- Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.,Faculty of Biology, University of Freiburg, Freiburg 79104, Germany
| | - Anita Schuch
- Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany.,Faculty of Biology, University of Freiburg, Freiburg 79104, Germany
| | - Florian Emmerich
- Institute for Cell and Gene Therapy, University Hospital Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany
| | - Percy Knolle
- Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, Klinikum rechts der Isar, Ismaningerstr. 22, München 81675, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
| | - Werner Held
- Ludwig Center for Cancer Research, Department of Fundamental Oncology, University of Lausanne, 155, Ch. Des Boveresses, Epalinges 1066, Switzerland
| | - Dietmar Zehn
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University Munich, Freising, Weihenstephaner Berg 3, Freising 85354, Germany
| | - Maike Hofmann
- Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany
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Yang CM, Yoon JC, Park JH, Lee JM. Hepatitis C virus impairs natural killer cell activity via viral serine protease NS3. PLoS One 2017; 12:e0175793. [PMID: 28410411 PMCID: PMC5391949 DOI: 10.1371/journal.pone.0175793] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 03/31/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection is characterized by a high frequency of chronic cases owing to the impairment of innate and adaptive immune responses. The modulation of natural killer (NK) cell functions by HCV leads to an impaired innate immune response. However, the underling mechanisms and roles of HCV proteins in this immune evasion are controversial, especially in the early phase of HCV infection. To investigate the role of HCV nonstructural proteins especially NS3 in the impairment of NK functions, NK cells were isolated from the PBMCs by negative selection. To assess the direct cytotoxicity and IFN-γ production capability of NK cells, co-cultured with uninfected, HCV-infected, HCV-NS3 DNA-transfected Huh-7.5, or HCV-NS replicon cells. To determine the effect of an NS3 serine protease inhibitor, HCV-infected Huh-7.5 cells were treated with BILN-2061. Then, NK cells were harvested and further co-cultured with K-562 target cells. NK cell functions were analyzed by flow cytometry and enzyme-linked immunosorbent assay. When co-cultured with HCV-infected Huh-7.5 cells, the natural cytotoxicity and IFN-γ production capability of NK cells were significantly reduced. NK cell functions were inhibited to similar levels upon co-culture with HCV-NS replicon cells, NS3-transfected cells, and HCV-infected Huh-7.5 cells. These reductions were restored by BILN-2061-treatment. Furthermore, BILN-2061-treatment significantly increased degranulation against K-562 target cells and IFN-γ productivity in NK cells. Consistent with these findings, the expression levels of activating NK cell receptors, such as NKp46 and NKp30, were also increased. In HCV-infected cells, the serine protease NS3 may play a role in the abrogation of NK cell functions in the early phase of infection through downregulation of NKp46 and NKp30 receptors on NK cells. Together, these results suggest that NS3 represents a novel drug target for the treatment of HCV infections.
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Affiliation(s)
- Chang Mo Yang
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases and Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joo Chun Yoon
- Department of Microbiology and Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Republic of Korea
| | - Jeon Han Park
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases and Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Myun Lee
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases and Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- * E-mail:
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Torres-Cornejo A, Lauer GM. Hurdles to the Development of Effective HBV Immunotherapies and HCV Vaccines. Pathog Immun 2017; 2:102-125. [PMID: 28664194 PMCID: PMC5486412 DOI: 10.20411/pai.v2i1.201] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chronic infections with HBV and HCV continue to be major public health problems, with hundreds of millions of people infected worldwide; this is despite the availability of both an effective prophylactic HBV vaccine for more than 3 decades and potent direct antivirals for HBV and, more recently, HCV infection. Consequently, development of HBV immunotherapies and prophylactic HCV vaccines remains extremely urgent, but limited funding and significant gaps in our understanding of the correlates of immune protection pose serious hurdles for the development of novel immune-based interventions. Here we discuss immunological questions related to HBV and HCV, some shared and some pertinent to only 1 of the viruses, that should be addressed for the rational design of HBV immunotherapies and HCV vaccines.
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Affiliation(s)
- Almudena Torres-Cornejo
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Georg M. Lauer
- Gastrointestinal Unit and Liver Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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50
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Zhang H, Zhang J, Chen L, Weng Z, Tian Y, Zhao H, Li Y, Chen L, Liang Z, Zheng H, Zhao W, Zhong S, Li Y. Targeting naturally occurring epitope variants of hepatitis C virus with high-affinity T-cell receptors. J Gen Virol 2017; 98:374-384. [PMID: 27902325 PMCID: PMC5797947 DOI: 10.1099/jgv.0.000656] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) readily establishes chronic infection, which is characterized by failure of virus-specific CD8+ T cells. HCV uses epitope mutation and T-cell exhaustion to escape from the host immune response. Previously, we engineered high-affinity T-cell receptors (HATs) targeting human immunodeficiency virus escape mutants. In this study, the affinity of a T-cell receptor specific for the HLA-A2-restricted HCV immunodominant epitope NS3 1406–1415 (KLVALGINAV) was improved from a KD of 6.6 µM to 40 pM. These HATs could also target HCV NS3 naturally occurring variants, including an escape variant vrt1 (KLVVLGINAV), with high affinities. The HATs can be used as high-affinity targeting molecules at the centre of the immune synapse for the HLA-restricted NS3 antigen. By fusing the HAT with a T-cell activation molecule, an anti-CD3 single-chain variable fragment, we constructed a molecule called high-affinity T-cell activation core (HATac), which can redirect functional CTLs possessing any specificity to recognize and kill cells presenting HCV NS3 antigens. This capability was verified with T2 cells loaded with prototype or variant peptides and HepG2 cells expressing the truncated NS3 prototype or variant proteins. The results indicate that HATac targeting the HLA-restricted NS3 antigen may provide a useful tool for circumventing immune escape mutants and T-cell exhaustion caused by HCV infection.
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Affiliation(s)
- Huajun Zhang
- State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.,Present address: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, PR China
| | - Jianbing Zhang
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
| | - Lei Chen
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
| | - Zhiming Weng
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
| | - Ye Tian
- State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China
| | - Haifeng Zhao
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
| | - Youjia Li
- State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China
| | - Lin Chen
- State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China
| | - Zhaoduan Liang
- State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China
| | - Hongjun Zheng
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
| | - Wenzhuo Zhao
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
| | - Shi Zhong
- XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
| | - Yi Li
- State Key Lab of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.,XiangXue Life Sciences Research Center, XiangXue Pharmaceutical Co. Ltd, Guangzhou, PR China
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