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Costa GL, Sautto GA. Towards an HCV vaccine: an overview of the immunization strategies for eliciting an effective B-cell response. Expert Rev Vaccines 2025; 24:96-120. [PMID: 39825640 DOI: 10.1080/14760584.2025.2452955] [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: 03/08/2024] [Revised: 10/26/2024] [Accepted: 01/09/2025] [Indexed: 01/20/2025]
Abstract
INTRODUCTION Fifty-eight million people worldwide are chronically infected with hepatitis C virus (HCV) and are at risk of developing cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antivirals are highly effective; however, they are burdened by high costs and the unchanged risk of HCC and reinfection, making prophylactic countermeasures an urgent medical need. HCV high genetic diversity is one of the main obstacles to vaccine development. The protective role of the humoral response directed against the HCV E2 glycoprotein is well established, and broadly neutralizing antibodies play a crucial role in effective viral clearance. AREAS COVERED This review explores the HCV targets and the different vaccination approaches, encompassing different expression systems, antigen selection strategies, and delivery methods, focusing on those aimed at eliciting a broad and effective humoral response. Our search criteria included the keywords 'HCV,' 'Hepatitis C,' and 'vaccine' using publicly available databases. Following the screening, 54 papers were selected. EXPERT OPINION The investigation of novel vaccine platforms beyond traditional approaches is necessary. While progress has been made in this direction, continued investigations on the HCV virology, immunology, and vaccinology are essential to surmount associated obstacles, heling in the development of an HCV vaccine that can benefit the global public health.
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Affiliation(s)
- Gabriel L Costa
- Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, USA
| | - Giuseppe A Sautto
- Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, USA
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Millian DE, Arroyave E, Wanninger TG, Krishnan S, Bao D, Zhang JR, Rao A, Spratt H, Ferguson M, Chen V, Stevenson HL, Saldarriaga OA. Alterations in the hepatic microenvironment following direct-acting antiviral therapy for chronic hepatitis C. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.02.17.25321289. [PMID: 40034770 PMCID: PMC11875275 DOI: 10.1101/2025.02.17.25321289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Background and aims. The first direct-acting antivirals (DAAs) to treat the viral hepatitis C (HCV) became available in 2011. Despite numerous clinical studies of patient outcomes after treatment, few have evaluated changes in the liver microenvironment. Despite achieving sustained virologic response (SVR), patients may still experience adverse outcomes like cirrhosis and hepatocellular carcinoma. By comparing gene and protein expression in liver biopsies collected before and after treatment, we sought to determine whether specific signatures correlated with disease progression and adverse clinical outcomes. Methods. Biopsies were collected from 22 patients before and after DAA treatment. We measured ∼770 genes and used multispectral imaging with custom machine learning algorithms to analyze phenotypes of intrahepatic macrophages (CD68, CD14, CD16, MAC387, CD163) and T cells (CD3, CD4, CD8, CD45, FoxP3). Results. Before DAA treatment, patients showed two distinct gene expression patterns: one with high pro-inflammatory and antiviral gene expression and another with weaker expression. Patients with adverse outcomes exhibited significantly (p<0.05) more inflammatory activity and had more advanced fibrosis stages in their baseline biopsies than those with liver disease resolution. Patients who achieved SVR had significantly decreased liver enzymes, reduced inflammatory scores, and restored type 1 interferon pathways similar to controls. However, after DAA treatment, patients with persistently high gene expression (67%, pre-hot) still had significantly worse outcomes (p<0.049) despite achieving SVR. A persistent lymphocytic infiltrate was observed in a subset of these patients (76.5%). After therapy, anti-inflammatory macrophages (CD16+, CD16+CD163+, CD16+CD68+) increased, and T cell heterogeneity was more pronounced, showing a predominance of helper and memory T cells (CD3+CD45RO+, CD4+CD45RO+, CD3+CD4+CD45RO+). Conclusions. Patients who have more inflamed livers and more advanced fibrosis before DAA treatment should be closely followed for the development of adverse outcomes, even after achieving SVR. We can enhance patient risk stratification by integrating gene and protein expression profiles with clinical data. This could identify those who may benefit from more intensive monitoring or alternative therapeutic approaches, inspiring a new era of personalized patient care. Lay Summary Direct-acting antiviral (DAA) therapy has dramatically improved the treatment of chronic HCV, making it curable for most people. This study determined gene and protein expression differences in the liver before and after treatment of HCV. These results will lead to a deeper understanding of the changes in the hepatic immune microenvironment with and without the virus present in the liver in hopes of improving patient surveillance, prognosis, and outcome in the future.
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Niepmann M. Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion-Revisiting the Warburg Effect. Cancers (Basel) 2024; 16:2290. [PMID: 39001354 PMCID: PMC11240417 DOI: 10.3390/cancers16132290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024] Open
Abstract
Cancer cells metabolize a large fraction of glucose to lactate, even under a sufficient oxygen supply. This phenomenon-the "Warburg Effect"-is often regarded as not yet understood. Cancer cells change gene expression to increase the uptake and utilization of glucose for biosynthesis pathways and glycolysis, but they do not adequately up-regulate the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, an increased glycolytic flux causes an increased production of cytosolic NADH. However, since the corresponding gene expression changes are not neatly fine-tuned in the cancer cells, cytosolic NAD+ must often be regenerated by loading excess electrons onto pyruvate and secreting the resulting lactate, even under sufficient oxygen supply. Interestingly, the Michaelis constants (KM values) of the enzymes at the pyruvate junction are sufficient to explain the priorities for pyruvate utilization in cancer cells: 1. mitochondrial OXPHOS for efficient ATP production, 2. electrons that exceed OXPHOS capacity need to be disposed of and secreted as lactate, and 3. biosynthesis reactions for cancer cell growth. In other words, a number of cytosolic electrons need to take the "emergency exit" from the cell by lactate secretion to maintain the cytosolic redox balance.
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Affiliation(s)
- Michael Niepmann
- Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, 35392 Giessen, Germany
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Woo J, Choi Y. Biomarkers in Detection of Hepatitis C Virus Infection. Pathogens 2024; 13:331. [PMID: 38668286 PMCID: PMC11054098 DOI: 10.3390/pathogens13040331] [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: 04/01/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/29/2024] Open
Abstract
The hepatitis C virus (HCV) infection affects 58 million people worldwide. In the United States, the incidence rate of acute hepatitis C has doubled since 2014; during 2021, this increased to 5% from 2020. Acute hepatitis C is defined by any symptom of acute viral hepatitis plus either jaundice or elevated serum alanine aminotransferase (ALT) activity with the detection of HCV RNA, the anti-HCV antibody, or hepatitis C virus antigen(s). However, most patients with acute infection are asymptomatic. In addition, ALT activity and HCV RNA levels can fluctuate, and a delayed detection of the anti-HCV antibody can occur among some immunocompromised persons with HCV infection. The detection of specific biomarkers can be of great value in the early detection of HCV infection at an asymptomatic stage. The high rate of HCV replication (which is approximately 1010 to 1012 virions per day) and the lack of proofreading by the viral RNA polymerase leads to enormous genetic diversity, creating a major challenge for the host immune response. This broad genetic diversity contributes to the likelihood of developing chronic infection, thus leading to the development of cirrhosis and liver cancer. Direct-acting antiviral (DAA) therapies for HCV infection are highly effective with a cure rate of up to 99%. At the same time, many patients with HCV infection are unaware of their infection status because of the mostly asymptomatic nature of hepatitis C, so they remain undiagnosed until the liver damage has advanced. Molecular mechanisms induced by HCV have been intensely investigated to find biomarkers for diagnosing the acute and chronic phases of the infection. However, there are no clinically verified biomarkers for patients with hepatitis C. In this review, we discuss the biomarkers that can differentiate acute from chronic hepatitis C, and we summarize the current state of the literature on the useful biomarkers that are detectable during acute and chronic HCV infection, liver fibrosis/cirrhosis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
| | - Youkyung Choi
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, US Centers for Disease Control and Prevention (CDC), Atlanta, GA 30329-4018, USA;
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Mondelli MU, Ottolini S, Oliviero B, Mantovani S, Cerino A, Mele D, Varchetta S. Hepatitis C Virus and the Host: A Mutual Endurance Leaving Indelible Scars in the Host's Immunity. Int J Mol Sci 2023; 25:268. [PMID: 38203436 PMCID: PMC10779088 DOI: 10.3390/ijms25010268] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatitis C virus (HCV) has spread worldwide, and it is responsible for potentially severe chronic liver disease and primary liver cancer. Chronic infection remains for life if not spontaneously eliminated and viral persistence profoundly impairs the efficiency of the host's immunity. Attempts have been made to develop an effective vaccine, but efficacy trials have met with failure. The availability of highly efficacious direct-acting antivirals (DAA) has created hope for the progressive elimination of chronic HCV infections; however, this approach requires a monumental global effort. HCV elicits a prompt innate immune response in the host, characterized by a robust production of interferon-α (IFN-α), although interference in IFN-α signaling by HCV proteins may curb this effect. The late appearance of largely ineffective neutralizing antibodies and the progressive exhaustion of T cells, particularly CD8 T cells, result in the inability to eradicate the virus in most infected patients. Moreover, an HCV cure resulting from DAA treatment does not completely restore the normal immunologic homeostasis. Here, we discuss the main immunological features of immune responses to HCV and the epigenetic scars that chronic viral persistence leaves behind.
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Affiliation(s)
- Mario U. Mondelli
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Sabrina Ottolini
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Barbara Oliviero
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Stefania Mantovani
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Antonella Cerino
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Dalila Mele
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
| | - Stefania Varchetta
- Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (B.O.); (S.M.); (A.C.); (D.M.); (S.V.)
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Dravid P, Murthy S, Attia Z, Cassady C, Chandra R, Trivedi S, Vyas A, Gridley J, Holland B, Kumari A, Grakoui A, Cullen JM, Walker CM, Sharma H, Kapoor A. Phenotype and fate of liver-resident CD8 T cells during acute and chronic hepacivirus infection. PLoS Pathog 2023; 19:e1011697. [PMID: 37812637 PMCID: PMC10602381 DOI: 10.1371/journal.ppat.1011697] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/26/2023] [Accepted: 09/19/2023] [Indexed: 10/11/2023] Open
Abstract
Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and memory CD8 and CD4 T cells primarily produced Th1 cytokines, IFN-γ, TNF-α, and IL-2, upon ex vivo antigen stimulation, and their phenotype and transcriptome differed significantly between the liver and spleen. Rapid clearance of RHV reinfection coincided with the proliferation of virus-specific CD8 TRM cells in the liver. Chronic RHV infection was associated with the exhaustion of CD8 T cells (Tex) and the development of severe liver diseases. Interestingly, the virus-specific CD8 Tex cells continued proliferation in the liver despite the persistent high-titer viremia and retained partial antiviral functions, as evident from their ability to degranulate and produce IFN-γ upon ex vivo antigen stimulation. Thus, RHV infection in mice provides a unique model to study the function and fate of liver-resident T cells during acute and chronic hepatotropic infection.
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Affiliation(s)
- Piyush Dravid
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Satyapramod Murthy
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Zayed Attia
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Cole Cassady
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Rahul Chandra
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Sheetal Trivedi
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Ashish Vyas
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - John Gridley
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - Brantley Holland
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - Anuradha Kumari
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - Arash Grakoui
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Division of Infectious Diseases, Atlanta, Georgia, United States of America
| | - John M. Cullen
- North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, 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
| | - Himanshu Sharma
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, 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
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7
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Winkler F, Hipp AV, Ramirez C, Martin B, Villa M, Neuwirt E, Gorka O, Aerssens J, Johansson SE, Rana N, Llewellyn-Lacey S, Price DA, Panning M, Groß O, Pearce EL, Hermann CM, Schumann K, Hannibal L, Neumann-Haefelin C, Boettler T, Knolle P, Hofmann M, Wohlleber D, Thimme R, Bengsch B. Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8 + T cells. Gut 2023; 72:1971-1984. [PMID: 37541771 PMCID: PMC10511960 DOI: 10.1136/gutjnl-2022-328734] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 06/20/2023] [Indexed: 08/06/2023]
Abstract
OBJECTIVE Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction. DESIGN Metabolic state, exhaustion and transcriptome of virus-specific CD8+ T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52) were determined ex vivo and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested in vitro. Intrahepatic virus-specific CD8+ T cells were analysed by scRNA-Seq in a HBV-replicating murine in vivo model of acute and chronic infection. RESULTS HBV-specific (core18-27, polymerase455-463) and HCV-specific (NS31073-1081, NS31406-1415, NS5B2594-2602) CD8+ T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase455-463 -specific CD8+ T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core18-27-specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8+ T cells in a murine model of chronic infection. CONCLUSION Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.
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Affiliation(s)
- Frances Winkler
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Faculty of Biology, University of Freiburg, Freiburg im Breisgau, Germany
| | - Anna V Hipp
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Carlos Ramirez
- Health Data Science Unit, Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Bianca Martin
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Matteo Villa
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau, Germany
| | - Emilia Neuwirt
- Institute of Neuropathology, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany
| | - Oliver Gorka
- Institute of Neuropathology, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Jeroen Aerssens
- Translational Biomarkers, Infectious Diseases Therapeuic Area, Janssen Pharmaceutica, Beerse, Belgium
| | - Susanne E Johansson
- Translational Biomarkers, Infectious Diseases Therapeuic Area, Janssen Pharmaceutica, Beerse, Belgium
| | - Nisha Rana
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Sian Llewellyn-Lacey
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
| | - David A Price
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
- Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK
| | - Marcus Panning
- Institute of Virology, Freiburg University Medical Center, Faculty of Medicine, University Hospital Freiburg, Freiburg im Breisgau, Germany
| | - Olaf Groß
- Institute of Neuropathology, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany
| | - Erika L Pearce
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Carl M Hermann
- Health Data Science Unit, Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Kathrin Schumann
- Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich (TUM), Munich, Germany
| | - Luciana Hannibal
- Department of General Pediatrics, Laboratory of Clinical Biochemistry and Metabolism, Medical Center-University of Freiburg, Adolescent Medicine and Neonatology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christoph Neumann-Haefelin
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Tobias Boettler
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Percy Knolle
- German Center for Infection Research (DZIF), Munich Partner Site, Munich, Germany
- Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Maike Hofmann
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Dirk Wohlleber
- Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Robert Thimme
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Bertram Bengsch
- Clinic for Internal Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg im Breisgau, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, Heidelberg, Germany
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8
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Ambikan AT, Elaldi N, Svensson-Akusjärvi S, Bagci B, Pektas AN, Hewson R, Bagci G, Arasli M, Appelberg S, Mardinoglu A, Sood V, Végvári Á, Benfeitas R, Gupta S, Cetin I, Mirazimi A, Neogi U. Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection. Proc Natl Acad Sci U S A 2023; 120:e2304722120. [PMID: 37669378 PMCID: PMC10500270 DOI: 10.1073/pnas.2304722120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/21/2023] [Indexed: 09/07/2023] Open
Abstract
Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.
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Affiliation(s)
- Anoop T. Ambikan
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Stockholm-14152, Sweden
| | - Nazif Elaldi
- Department of Infectious Diseases and Clinical Microbiology, Medical Faculty, Sivas Cumhuriyet University, Sivas58140, Turkey
| | - Sara Svensson-Akusjärvi
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Stockholm-14152, Sweden
| | - Binnur Bagci
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Sivas Cumhuriyet University, Sivas, Turkey
| | - Ayse Nur Pektas
- Cumhuriyet University Advanced Technology Application and Research Center, Sivas Cumhuriyet University, Sivas58140, Turkey
| | - Roger Hewson
- United Kingdom Health Security Agency, Porton Down, Salisbury, WiltshireSP4 0JG, United Kingdom
- Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, LondonWC1E 7HT, United Kingdom
| | - Gokhan Bagci
- Department of Biochemistry, Faculty of Medicine, Altinbas University, Istanbul34147, Turkey
| | - Mehmet Arasli
- Department of Immunology, Medical Faculty, Bulent Ecevit University, Zonguldak67600, Turkey
| | - Sofia Appelberg
- Public Health Agency of Sweden, Solna, Stockholm-17165, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, Kungliga Tekniska Högskolan–Royal Institute of Technology, Stockholm-17121, Sweden
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, LondonWC2R 2LS, United Kingdom
| | - Vikas Sood
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Stockholm-14152, Sweden
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard University, Delhi110062, India
| | - Ákos Végvári
- Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm-17177, Sweden
| | - Rui Benfeitas
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Stockholm-14152, Sweden
| | - Soham Gupta
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Stockholm-14152, Sweden
| | - Ilhan Cetin
- Department of Public Health, Medical Faculty, Sivas Cumhuriyet University, Sivas 58140, Turkey
| | - Ali Mirazimi
- Public Health Agency of Sweden, Solna, Stockholm-17165, Sweden
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm-14152, Sweden
- National Veterinary Institute, Uppsala-75189, Sweden
| | - Ujjwal Neogi
- The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Stockholm-14152, Sweden
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Zhang C, Sheng Q, Zhang X, Xu K, Jin X, Zhou W, Zhang M, Lv D, Yang C, Li Y, Xu J, Li X. Prioritizing exhausted T cell marker genes highlights immune subtypes in pan-cancer. iScience 2023; 26:106484. [PMID: 37091230 PMCID: PMC10119613 DOI: 10.1016/j.isci.2023.106484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 11/29/2022] [Accepted: 03/18/2023] [Indexed: 04/08/2023] Open
Abstract
Exhausted T (TEX) cells are main immunotherapy targets in cancer, but it lacks a general identification method to characterize TEX cell in disease. To assess the characterization of TEX cell, we extract signature of TEX cell from large cancer and chronic infection cohorts. Based on single-cell transcriptomes, a systematic T cell exhaustion prediction (TEXP) model is designed to define TEX cell in cancer and chronic infection. We then prioritize 42 marker genes, including HAVCR2, PDCD1, TOX, TIGIT and LAG3, which are associated with T cell exhaustion. TEXP could identify high TEX and low TEX subtypes in pan-cancer of TCGA. The high TEX subtypes are characterized by high immune score, immune cell infiltration, high expression of TEX marker genes and poor prognosis. In summary, TEXP and marker genes provide a resource for understanding the function of TEX cell, with implications for immune prediction and immunotherapy in chronic infection and cancer.
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Affiliation(s)
- Chunlong Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
- College of Information and Computer Engineering, Northeast Forestry University, Harbin 150040, China
| | - Qi Sheng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Xue Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Kang Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Xiaoyan Jin
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Weiwei Zhou
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Mengying Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Dezhong Lv
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Changbo Yang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Yongsheng Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Women and Children’s Medical Center, Hainan Medical University, Haikou, Hainan 571199, China
- Corresponding author
| | - Juan Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
- Corresponding author
| | - Xia Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Women and Children’s Medical Center, Hainan Medical University, Haikou, Hainan 571199, China
- Corresponding author
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10
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Lopez-Scarim J, Nambiar SM, Billerbeck E. Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment. Vaccines (Basel) 2023; 11:681. [PMID: 36992265 PMCID: PMC10056334 DOI: 10.3390/vaccines11030681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.
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Affiliation(s)
| | | | - Eva Billerbeck
- Division of Hepatology, Department of Medicine and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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11
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Nishio A, Hasan S, Park H, Park N, Salas JH, Salinas E, Kardava L, Juneau P, Frumento N, Massaccesi G, Moir S, Bailey JR, Grakoui A, Ghany MG, Rehermann B. Serum neutralization activity declines but memory B cells persist after cure of chronic hepatitis C. Nat Commun 2022; 13:5446. [PMID: 36114169 PMCID: PMC9481596 DOI: 10.1038/s41467-022-33035-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/30/2022] [Indexed: 11/09/2022] Open
Abstract
The increasing incidence of hepatitis C virus (HCV) infections underscores the need for an effective vaccine. Successful vaccines to other viruses generally depend on a long-lasting humoral response. However, data on the half-life of HCV-specific responses are lacking. Here we study archived sera and mononuclear cells that were prospectively collected up to 18 years after cure of chronic HCV infection to determine the role of HCV antigen in maintaining neutralizing antibody and B cell responses. We show that HCV-neutralizing activity decreases rapidly in potency and breadth after curative treatment. In contrast, HCV-specific memory B cells persist, and display a restored resting phenotype, normalized chemokine receptor expression and preserved ability to differentiate into antibody-secreting cells. The short half-life of HCV-neutralizing activity is consistent with a lack of long-lived plasma cells. The persistence of HCV-specific memory B cells and the reduced inflammation after cure provide an opportunity for vaccination to induce protective immunity against re-infection.
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Affiliation(s)
- Akira Nishio
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Sharika Hasan
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Heiyoung Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Nana Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Jordan H Salas
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Eduardo Salinas
- Division of Infectious Diseases, Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory National Primate Research Center, Emory Vaccine Center, Atlanta, GA, 30329, USA
| | - Lela Kardava
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Paul Juneau
- Division of Data Services, NIH Library, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
- Contractor- Zimmerman Associates, Inc, Fairfax, VA, USA
| | - Nicole Frumento
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Guido Massaccesi
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Susan Moir
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Justin R Bailey
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Arash Grakoui
- Division of Infectious Diseases, Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory National Primate Research Center, Emory Vaccine Center, Atlanta, GA, 30329, USA
| | - Marc G Ghany
- Clinical Research Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA
| | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, 20892, USA.
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12
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Chakraborty S, Khamaru P, Bhattacharyya A. Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets. Cell Biol Int 2022; 46:1729-1746. [PMID: 35900141 DOI: 10.1002/cbin.11867] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 04/03/2022] [Accepted: 07/05/2022] [Indexed: 12/15/2022]
Abstract
Metabolism is a dynamic process and keeps changing from time to time according to the demand of a particular cell to meet its bio-energetic requirement. Different immune cells rely on distinct metabolic programs which allow the cell to balance its requirements for energy, molecular biosynthesis, and effector activity. In the aspect of infection and cancer immunology, effector T and B cells get exhausted and help tumor cells to evade immunosurveillance. On the other hand, T cells become hyperresponsive in the scenario of autoimmune diseases. In this article, we have explored the uniqueness and distinct metabolic features of key CD4+ T and B helper cell subsets, CD4+ T, B regulatory cell subsets and CD8+ T cells regarding health and disease. Th1 cells rely on glycolysis and glutaminolysis; inhibition of these metabolic pathways promotes Th1 cells in Treg population. However, Th2 cells are also dependent on glycolysis but an abundance of lactate within TME shifts their metabolic dependency to fatty acid metabolism. Th17 cells depend on HIF-1α mediated glycolysis, ablation of HIF-1α reduces Th17 cells but enhance Treg population. In contrast to effector T cells which are largely dependent on glycolysis for their differentiation and function, Treg cells mainly rely on FAO for their function. Therefore, it is of utmost importance to understand the metabolic fates of immune cells and how it facilitates their differentiation and function for different disease models. Targeting metabolic pathways to restore the functionality of immune cells in diseased conditions can lead to potent therapeutic measures.
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Affiliation(s)
- Sayan Chakraborty
- Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
| | - Poulomi Khamaru
- Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
| | - Arindam Bhattacharyya
- Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
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13
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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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14
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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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15
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Reina-Campos M, Scharping NE, Goldrath AW. CD8 + T cell metabolism in infection and cancer. Nat Rev Immunol 2021; 21:718-738. [PMID: 33981085 PMCID: PMC8806153 DOI: 10.1038/s41577-021-00537-8] [Citation(s) in RCA: 345] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2021] [Indexed: 02/03/2023]
Abstract
Cytotoxic CD8+ T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8+ T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8+ T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8+ T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8+ T cell-mediated immunity. Defining the metabolic adaptations of CD8+ T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8+ T cell programmes and discuss how metabolism is integrated with CD8+ T cell differentiation and function and determined by environmental cues.
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Affiliation(s)
- Miguel Reina-Campos
- Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, CA, USA
| | - Nicole E. Scharping
- Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, CA, USA
| | - Ananda W. Goldrath
- Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, CA, USA.,
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16
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Echeverría N, Comas V, Aldunate F, Perbolianachis P, Moreno P, Cristina J. In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet? World J Hepatol 2021; 13:1234-1268. [PMID: 34786164 PMCID: PMC8568586 DOI: 10.4254/wjh.v13.i10.1234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/14/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is responsible for no less than 71 million people chronically infected and is one of the most frequent indications for liver transplantation worldwide. Despite direct-acting antiviral therapies fuel optimism in controlling HCV infections, there are several obstacles regarding treatment accessibility and reinfection continues to remain a possibility. Indeed, the majority of new HCV infections in developed countries occur in people who inject drugs and are more plausible to get reinfected. To achieve global epidemic control of this virus the development of an effective prophylactic or therapeutic vaccine becomes a must. The coronavirus disease 19 (COVID-19) pandemic led to auspicious vaccine development against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which has renewed interest on fighting HCV epidemic with vaccination. The aim of this review is to highlight the current situation of HCV vaccine candidates designed to prevent and/or to reduce HCV infectious cases and their complications. We will emphasize on some of the crossroads encountered during vaccine development against this insidious virus, together with some key aspects of HCV immunology which have, so far, hampered the progress in this area. The main focus will be on nucleic acid-based as well as recombinant viral vector-based vaccine candidates as the most novel vaccine approaches, some of which have been recently and successfully employed for SARS-CoV-2 vaccines. Finally, some ideas will be presented on which methods to explore for the design of live-attenuated vaccines against HCV.
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Affiliation(s)
- Natalia Echeverría
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Victoria Comas
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Fabián Aldunate
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Paula Perbolianachis
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Pilar Moreno
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Juan Cristina
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
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17
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Shoukry NH, Walker CM. T cell responses during HBV and HCV infections: similar but not quite the same? Curr Opin Virol 2021; 51:80-86. [PMID: 34619514 DOI: 10.1016/j.coviro.2021.08.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/25/2021] [Accepted: 08/31/2021] [Indexed: 12/30/2022]
Abstract
The hepatitis B and C viruses persist by evasion of T cell immunity. Persistence depends upon premature failure of CD4+ T cell help and loss of CD8+ T cell control because of epitope mutational escape and/or functional exhaustion. Powerful new immunological and transcriptomic tools provide insight into the mechanisms of T cell silencing by HBV and HCV. Similarities are apparent, including dysregulated expression of common inhibitory/immune checkpoint receptors and transcription factors. There are also differences. T cell exhaustion is uniform in HCV infection, but varies in HBV infection depending on disease stage and/or protein target. Here, we review recent advances defining similarities and differences in T cell evasion by HBV and HCV, and the potential for reversal following antiviral therapy.
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Affiliation(s)
- Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Christopher M Walker
- Center for Vaccines and Immunity, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA.
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18
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Barili V, Vecchi A, Rossi M, Montali I, Tiezzi C, Penna A, Laccabue D, Missale G, Fisicaro P, Boni C. Unraveling the Multifaceted Nature of CD8 T Cell Exhaustion Provides the Molecular Basis for Therapeutic T Cell Reconstitution in Chronic Hepatitis B and C. Cells 2021; 10:2563. [PMID: 34685543 PMCID: PMC8533840 DOI: 10.3390/cells10102563] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
In chronic hepatitis B and C virus infections persistently elevated antigen levels drive CD8+ T cells toward a peculiar differentiation state known as T cell exhaustion, which poses crucial constraints to antiviral immunity. Available evidence indicates that T cell exhaustion is associated with a series of metabolic and signaling deregulations and with a very peculiar epigenetic status which all together lead to reduced effector functions. A clear mechanistic network explaining how intracellular metabolic derangements, transcriptional and signaling alterations so far described are interconnected in a comprehensive and unified view of the T cell exhaustion differentiation profile is still lacking. Addressing this issue is of key importance for the development of innovative strategies to boost host immunity in order to achieve viral clearance. This review will discuss the current knowledge in HBV and HCV infections, addressing how innate immunity, metabolic derangements, extensive stress responses and altered epigenetic programs may be targeted to restore functionality and responsiveness of virus-specific CD8 T cells in the context of chronic virus infections.
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Affiliation(s)
- Valeria Barili
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
| | - Marzia Rossi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Ilaria Montali
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Camilla Tiezzi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
| | - Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
| | - Diletta Laccabue
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Gabriele Missale
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Paola Fisicaro
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy; (V.B.); (A.V.); (M.R.); (I.M.); (C.T.); (A.P.); (D.L.); (G.M.)
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19
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Rahman ANU, Liu J, Mujib S, Kidane S, Ali A, Szep S, Han C, Bonner P, Parsons M, Benko E, Kovacs C, Yue FY, Ostrowski M. Elevated glycolysis imparts functional ability to CD8 + T cells in HIV infection. Life Sci Alliance 2021; 4:4/11/e202101081. [PMID: 34548381 PMCID: PMC8473722 DOI: 10.26508/lsa.202101081] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 09/03/2021] [Accepted: 09/07/2021] [Indexed: 12/23/2022] Open
Abstract
The mechanisms inducing exhaustion of HIV-specific CD8+ T cells are not fully understood. Metabolic programming directly influences T-cell differentiation, effector function, and memory. We evaluated metabolic profiles of ex vivo CD8+ T cells in HIV-infected individuals. The baseline oxygen consumption rate of CD8+ T cells was elevated in all infected individuals and CD8+ T cells were working at maximal respiratory capacity. The baseline glycolysis rate was enhanced only during early untreated HIV and in viral controllers, but glycolytic capacity was conserved at all stages of infection. CD8+ T-cell mTOR activity was found to be reduced. Enhanced glycolysis was crucial for HIV-specific killing of CD8+ T cells. CD8+ T-cell cytoplasmic GAPDH content was reduced in HIV, but less in early infection and viral controllers. Thus, CD8+ T-cell exhaustion in HIV is characterized by reduced glycolytic activity, enhanced OXPHOS demands, dysregulated mTOR, and reduced cytoplasmic GAPDH. These data provide potential metabolic strategies to reverse CD8+ T-cell dysfunction in HIV.
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Affiliation(s)
| | - Jun Liu
- Deparment of Medicine, University of Toronto, Toronto, Canada
| | - Shariq Mujib
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
| | - Segen Kidane
- Institute of Medical Sciences, University of Toronto, Toronto, Canada
| | - Arman Ali
- Deparment of Medicine, University of Toronto, Toronto, Canada
| | - Steven Szep
- Deparment of Medicine, University of Toronto, Toronto, Canada
| | - Carrie Han
- Deparment of Medicine, University of Toronto, Toronto, Canada
| | - Phil Bonner
- Deparment of Medicine, University of Toronto, Toronto, Canada
| | - Michael Parsons
- Flow Cytometry Facility, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
| | | | | | - Feng Yun Yue
- Deparment of Medicine, University of Toronto, Toronto, Canada
| | - Mario Ostrowski
- Deparment of Medicine, University of Toronto, Toronto, Canada .,Institute of Medical Sciences, University of Toronto, Toronto, Canada.,Deparment of Immunology, University of Toronto, Toronto, Canada.,Keenan Research Centre for Biomedical Sciences of St. Michael's Hospital Toronto, Toronto, Canada
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20
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Shoukry NH. Towards a Systems Immunology Approach to Understanding Correlates of Protective Immunity against HCV. Viruses 2021; 13:1871. [PMID: 34578451 PMCID: PMC8473057 DOI: 10.3390/v13091871] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 12/23/2022] Open
Abstract
Over the past decade, tremendous progress has been made in systems biology-based approaches to studying immunity to viral infections and responses to vaccines. These approaches that integrate multiple facets of the immune response, including transcriptomics, serology and immune functions, are now being applied to understand correlates of protective immunity against hepatitis C virus (HCV) infection and to inform vaccine development. This review focuses on recent progress in understanding immunity to HCV using systems biology, specifically transcriptomic and epigenetic studies. It also examines proposed strategies moving forward towards an integrated systems immunology approach for predicting and evaluating the efficacy of the next generation of HCV vaccines.
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Affiliation(s)
- Naglaa H. Shoukry
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Tour Viger, Local R09.414, 900 Rue St-Denis, Montréal, QC H2X 0A9, Canada;
- Département de Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC H2X 0A9, Canada
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21
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Gobran ST, Ancuta P, Shoukry NH. A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection. Front Immunol 2021; 12:726419. [PMID: 34456931 PMCID: PMC8387722 DOI: 10.3389/fimmu.2021.726419] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 07/26/2021] [Indexed: 12/13/2022] Open
Abstract
Nearly 2.3 million individuals worldwide are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Odds of HCV infection are six times higher in people living with HIV (PLWH) compared to their HIV-negative counterparts, with the highest prevalence among people who inject drugs (PWID) and men who have sex with men (MSM). HIV coinfection has a detrimental impact on the natural history of HCV, including higher rates of HCV persistence following acute infection, higher viral loads, and accelerated progression of liver fibrosis and development of end-stage liver disease compared to HCV monoinfection. Similarly, it has been reported that HCV coinfection impacts HIV disease progression in PLWH receiving anti-retroviral therapies (ART) where HCV coinfection negatively affects the homeostasis of CD4+ T cell counts and facilitates HIV replication and viral reservoir persistence. While ART does not cure HIV, direct acting antivirals (DAA) can now achieve HCV cure in nearly 95% of coinfected individuals. However, little is known about how HCV cure and the subsequent resolution of liver inflammation influence systemic immune activation, immune reconstitution and the latent HIV reservoir. In this review, we will summarize the current knowledge regarding the pathogenesis of HIV/HCV coinfection, the effects of HCV coinfection on HIV disease progression in the context of ART, the impact of HIV on HCV-associated liver morbidity, and the consequences of DAA-mediated HCV cure on immune reconstitution and HIV reservoir persistence in coinfected patients.
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Affiliation(s)
- Samaa T Gobran
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.,Department of Medical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Petronela Ancuta
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.,Département de médecine, Faculté de médecine, Université de Montréal, Montréal, QC, Canada
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22
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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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23
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Hartlage AS, Kapoor A. Hepatitis C Virus Vaccine Research: Time to Put Up or Shut Up. Viruses 2021; 13:1596. [PMID: 34452460 PMCID: PMC8402855 DOI: 10.3390/v13081596] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/27/2021] [Accepted: 07/31/2021] [Indexed: 12/16/2022] Open
Abstract
Unless urgently needed to prevent a pandemic, the development of a viral vaccine should follow a rigorous scientific approach. Each vaccine candidate should be designed considering the in-depth knowledge of protective immunity, followed by preclinical studies to assess immunogenicity and safety, and lastly, the evaluation of selected vaccines in human clinical trials. The recently concluded first phase II clinical trial of a human hepatitis C virus (HCV) vaccine followed this approach. Still, despite promising preclinical results, it failed to protect against chronic infection, raising grave concerns about our understanding of protective immunity. This setback, combined with the lack of HCV animal models and availability of new highly effective antivirals, has fueled ongoing discussions of using a controlled human infection model (CHIM) to test new HCV vaccine candidates. Before taking on such an approach, however, we must carefully weigh all the ethical and health consequences of human infection in the absence of a complete understanding of HCV immunity and pathogenesis. We know that there are significant gaps in our knowledge of adaptive immunity necessary to prevent chronic HCV infection. This review discusses our current understanding of HCV immunity and the critical gaps that should be filled before embarking upon new HCV vaccine trials. We discuss the importance of T cells, neutralizing antibodies, and HCV genetic diversity. We address if and how the animal HCV-like viruses can be used for conceptualizing effective HCV vaccines and what we have learned so far from these HCV surrogates. Finally, we propose a logical but narrow path forward for HCV vaccine development.
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Affiliation(s)
- Alex S. Hartlage
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Medical Scientist Training Program, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43205, USA
| | - Amit Kapoor
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43205, USA
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24
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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: 151] [Impact Index Per Article: 37.8] [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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25
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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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26
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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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27
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Viral Infection Modulates Mitochondrial Function. Int J Mol Sci 2021; 22:ijms22084260. [PMID: 33923929 PMCID: PMC8073244 DOI: 10.3390/ijms22084260] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 02/08/2023] Open
Abstract
Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the innate immunity of host cells against viruses. The abnormality of mitochondrial morphology and function might lead to a variety of diseases. A large number of studies have found that a variety of viral infections could change mitochondrial dynamics, mediate mitochondria-induced cell death, and alter the mitochondrial metabolic status and cellular innate immune response to maintain intracellular survival. Meanwhile, mitochondria can also play an antiviral role during viral infection, thereby protecting the host. Therefore, mitochondria play an important role in the interaction between the host and the virus. Herein, we summarize how viral infections affect microbial pathogenesis by altering mitochondrial morphology and function and how viruses escape the host immune response.
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28
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Zhang Y, Lu W, Chen X, Cao Y, Yang Z. A Bioinformatic Analysis of Correlations between Polymeric Immunoglobulin Receptor (PIGR) and Liver Fibrosis Progression. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5541780. [PMID: 33937393 PMCID: PMC8055406 DOI: 10.1155/2021/5541780] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/20/2021] [Accepted: 03/31/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This study is aimed at investigating the enriched functions of polymeric immunoglobulin receptor (PIGR) and its correlations with liver fibrosis stage. METHODS PIGR mRNA expression in normal liver, liver fibrosis, hepatic stellate cells (HSCs), and hepatitis virus infection samples was calculated in Gene Expression Omnibus (GEO) and Oncomine databases. Enrichment analysis of PIGR-related genes was conducted in Metascape and Gene Set Enrichment Analysis (GSEA). Logistic model and ROC curve were performed to evaluate the correlations between pIgR and liver fibrosis. RESULTS PIGR mRNA was upregulated in advanced liver fibrosis, cirrhosis compared to normal liver (all p < 0.05). PIGR mRNA was also overexpressed in activated HSCs compared to senescent HSCs, liver stem/progenitor cells, and reverted HSCs (all p < 0.05). Enrichment analysis revealed that PIGR-related genes involved in the defense response to virus and interferon (IFN) signaling. In GEO series, PIGR mRNA was also upregulated by hepatitis virus B, C, D, and E infection (all p < 0.05). After adjusting age and gender, multivariate logistic regression models revealed that high PIGR in the liver was a risk factor for liver fibrosis (OR = 82.2, p < 0.001). The area under curve (AUC), positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of PIGR for liver fibrosis stage >2 were 0.84, 0.86, 0.7, 0.61, and 0.90. CONCLUSION PIGR was correlated with liver fibrosis and might involve in hepatitis virus infection and HSC transdifferentiation.
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Affiliation(s)
- Yuan Zhang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Wenjun Lu
- Department of Rheumatology and Immunology, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Jiangsu 212300, China
| | - Xiaorong Chen
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
| | - Yajuan Cao
- Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University School of Medicine, Shanghai 200433, China
- Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China
| | - Zongguo Yang
- Department of Integrative Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
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29
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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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30
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Kusnadi A, Ramírez-Suástegui C, Fajardo V, Chee SJ, Meckiff BJ, Simon H, Pelosi E, Seumois G, Ay F, Vijayanand P, Ottensmeier CH. Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8 + T cells. Sci Immunol 2021; 6:eabe4782. [PMID: 33478949 PMCID: PMC8101257 DOI: 10.1126/sciimmunol.abe4782] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/15/2021] [Indexed: 12/11/2022]
Abstract
The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2.
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Affiliation(s)
| | | | | | - Serena J Chee
- NIHR and CRUK Southampton Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Hayley Simon
- La Jolla Institute for Immunology, La Jolla, CA 92037
| | - Emanuela Pelosi
- Southampton Specialist Virology Centre, Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | | | - Ferhat Ay
- La Jolla Institute for Immunology, La Jolla, CA 92037
| | - Pandurangan Vijayanand
- La Jolla Institute for Immunology, La Jolla, CA 92037.
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, UK
- Department of Medicine, University of California San Diego, La Jolla, CA 92037
| | - Christian H Ottensmeier
- La Jolla Institute for Immunology, La Jolla, CA 92037.
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, UK
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31
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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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32
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Thimme R. T cell immunity to hepatitis C virus: Lessons for a prophylactic vaccine. J Hepatol 2021; 74:220-229. [PMID: 33002569 DOI: 10.1016/j.jhep.2020.09.022] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
There is consensus that HCV-specific T cells play a central role in the outcome (clearance vs. persistence) of acute infection and that they contribute to protection against the establishment of persistence after reinfection. However, these T cells often fail and the virus can persist, largely as a result of T cell exhaustion and the emergence of viral escape mutations. Importantly, HCV cure by direct-acting antivirals does not lead to a complete reversion of T cell exhaustion and thus HCV reinfections can occur. The current lack of detailed knowledge about the immunological determinants of viral clearance, persistence and protective immunity is a major roadblock to the development of a prophylactic T cell vaccine. This minireview highlights the basic concepts of successful T cell immunity, major mechanisms of T cell failure and how our understanding of these concepts can be translated into a prophylactic vaccine.
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Affiliation(s)
- Robert Thimme
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Medical Center - University of Freiburg, Faculty of Medicine, Germany.
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33
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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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34
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Immune system control of hepatitis C virus infection. Curr Opin Virol 2020; 46:36-44. [PMID: 33137689 DOI: 10.1016/j.coviro.2020.10.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/11/2020] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) remains a global public health problem even though more than 95% of infections can be cured by treatment with direct-acting antiviral agents. Resolution of viremia post antiviral therapy does not lead to protective immunity and therefore reinfections can occur. Immune cell detection of HCV activates signaling pathways that produce interferons and trigger the innate immune response against the virus, preventing HCV replication and spread. Cells in the innate immune system, including natural killer, dendritic, and Kupffer cells, interact with infected hepatocytes and present viral antigens to T and B cells where their effector responses contribute to infection outcome. Despite the immune activation, HCV can evade the host response and establish persistent infection. Plans to understand the correlates of protection and strategies to activate proper innate and adaptive immune responses are needed for development of an effective prophylactic vaccine that stimulates protective immunity and limits HCV transmission.
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35
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Simmonds P. Pervasive RNA Secondary Structure in the Genomes of SARS-CoV-2 and Other Coronaviruses. mBio 2020; 11:e01661-20. [PMID: 33127861 PMCID: PMC7642675 DOI: 10.1128/mbio.01661-20] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 10/12/2020] [Indexed: 12/25/2022] Open
Abstract
The ultimate outcome of the coronavirus disease 2019 (COVID-19) pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility, and population immunity. In the current study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was investigated for the presence of large-scale internal RNA base pairing in its genome. This property, termed genome-scale ordered RNA structure (GORS) has been previously associated with host persistence in other positive-strand RNA viruses, potentially through its shielding effect on viral RNA recognition in the cell. Genomes of SARS-CoV-2 were remarkably structured, with minimum folding energy differences (MFEDs) of 15%, substantially greater than previously examined viruses such as hepatitis C virus (HCV) (MFED of 7 to 9%). High MFED values were shared with all coronavirus genomes analyzed and created by several hundred consecutive energetically favored stem-loops throughout the genome. In contrast to replication-associated RNA structure, GORS was poorly conserved in the positions and identities of base pairing with other sarbecoviruses-even similarly positioned stem-loops in SARS-CoV-2 and SARS-CoV rarely shared homologous pairings, indicative of more rapid evolutionary change in RNA structure than in the underlying coding sequences. Sites predicted to be base paired in SARS-CoV-2 showed less sequence diversity than unpaired sites, suggesting that disruption of RNA structure by mutation imposes a fitness cost on the virus that is potentially restrictive to its longer evolution. Although functionally uncharacterized, GORS in SARS-CoV-2 and other coronaviruses represents important elements in their cellular interactions that may contribute to their persistence and transmissibility.IMPORTANCE The detection and characterization of large-scale RNA secondary structure in the genome of SARS-CoV-2 indicate an extraordinary and unsuspected degree of genome structural organization; this could be effectively visualized through a newly developed contour plotting method that displays positions, structural features, and conservation of RNA secondary structure between related viruses. Such RNA structure imposes a substantial evolutionary cost; paired sites showed greater restriction in diversity and represent a substantial additional constraint in reconstructing its molecular epidemiology. Its biological relevance arises from previously documented associations between possession of structured genomes and persistence, as documented for HCV and several other RNA viruses infecting humans and mammals. Shared properties potentially conferred by large-scale structure in SARS-CoV-2 include increasing evidence for prolonged infections and induced immune dysfunction that prevents development of protective immunity. The findings provide an additional element to cellular interactions that potentially influences the natural history of SARS-CoV-2, its pathogenicity, and its transmission.
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Affiliation(s)
- P Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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36
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Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal. Int J Mol Sci 2020; 21:ijms21207473. [PMID: 33050486 PMCID: PMC7589490 DOI: 10.3390/ijms21207473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 12/17/2022] Open
Abstract
Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.
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37
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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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38
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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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39
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Kusnadi A, Ramírez-Suástegui C, Fajardo V, Chee SJ, Meckiff BJ, Simon H, Pelosi E, Seumois G, Ay F, Vijayanand P, Ottensmeier CH. Severely ill COVID-19 patients display augmented functional properties in SARS-CoV-2-reactive CD8 + T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2020:2020.07.09.194027. [PMID: 32676602 PMCID: PMC7359524 DOI: 10.1101/2020.07.09.194027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
The molecular properties of CD8 + T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8 + T cells from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8 + T cell response to SARS-CoV-2 was 'exhausted' or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the non-exhausted subsets from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8 + T cell memory responses in patients with severe COVID-19 illness. CD8 + T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features. Cells with such features were mostly absent in SARS-CoV-2 responsive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8 + T cells responding to SARS-CoV-2.
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Affiliation(s)
- Anthony Kusnadi
- La Jolla Institute for Immunology, La Jolla, CA, USA
- These authors jointly contributed to the work
| | - Ciro Ramírez-Suástegui
- La Jolla Institute for Immunology, La Jolla, CA, USA
- These authors jointly contributed to the work
| | - Vicente Fajardo
- La Jolla Institute for Immunology, La Jolla, CA, USA
- These authors jointly contributed to the work
| | - Serena J Chee
- NIHR and CRUK Southampton Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK
- These authors jointly contributed to the work
| | | | - Hayley Simon
- La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Emanuela Pelosi
- Southampton Specialist Virology Centre, Department of Infection, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | | | - Ferhat Ay
- La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Pandurangan Vijayanand
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, United Kingdom
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- These authors jointly directed the work
| | - Christian H Ottensmeier
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Liverpool Head and Neck Center, Institute of Translational Medicine, University of Liverpool & Clatterbridge Cancer Center NHS Foundation Trust, Liverpool, United Kingdom
- These authors jointly directed the work
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40
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Ferrari C, Barili V, Varchetta S, Mondelli MU. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2020:821-850. [DOI: 10.1002/9781119436812.ch63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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41
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Barili V, Fisicaro P, Montanini B, Acerbi G, Filippi A, Forleo G, Romualdi C, Ferracin M, Guerrieri F, Pedrazzi G, Boni C, Rossi M, Vecchi A, Penna A, Zecca A, Mori C, Orlandini A, Negri E, Pesci M, Massari M, Missale G, Levrero M, Ottonello S, Ferrari C. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nat Commun 2020; 11:604. [PMID: 32001678 PMCID: PMC6992697 DOI: 10.1038/s41467-019-14137-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 12/11/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus infection (HCV) represents a unique model to characterize, from early to late stages of infection, the T cell differentiation process leading to exhaustion of human CD8+ T cells. Here we show that in early HCV infection, exhaustion-committed virus-specific CD8+ T cells display a marked upregulation of transcription associated with impaired glycolytic and mitochondrial functions, that are linked to enhanced ataxia-telangiectasia mutated (ATM) and p53 signaling. After evolution to chronic infection, exhaustion of HCV-specific T cell responses is instead characterized by a broad gene downregulation associated with a wide metabolic and anti-viral function impairment, which can be rescued by histone methyltransferase inhibitors. These results have implications not only for treatment of HCV-positive patients not responding to last-generation antivirals, but also for other chronic pathologies associated with T cell dysfunction, including cancer.
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Affiliation(s)
- Valeria Barili
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Paola Fisicaro
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Barbara Montanini
- Biomolecular, Genomic and Biocomputational Sciences Unit, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.,Biopharmanet-Tec, University of Parma, Parma, Italy
| | - Greta Acerbi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Anita Filippi
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Giovanna Forleo
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | | | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy
| | | | - Giuseppe Pedrazzi
- Unit of Neuroscience, Department of Medicine and Surgery, Robust Statistics Academy (Ro.S.A.), University of Parma, Parma, Italy
| | - Carolina Boni
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Marzia Rossi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Andrea Vecchi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Amalia Penna
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Alessandra Zecca
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Cristina Mori
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Alessandra Orlandini
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Elisa Negri
- Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Marco Pesci
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Marco Massari
- Unit of Infectious Diseases, IRCCS-Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, Italy
| | - Gabriele Missale
- Department of Medicine and Surgery, University of Parma, Parma, Italy.,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL)-INSERM U1052, Lyon, France.,Université Claude Bernard Lyon 1, Service d'Hepatologie et Gastroenterologie Hopital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.,Center for Life Nano Science, Istituto Italiano di Tecnologia, Rome, Italy
| | - Simone Ottonello
- Biomolecular, Genomic and Biocomputational Sciences Unit, Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.,Biopharmanet-Tec, University of Parma, Parma, Italy
| | - Carlo Ferrari
- Department of Medicine and Surgery, University of Parma, Parma, Italy. .,Unit of Infectious Diseases and Hepatology, Laboratory of Viral Immunopathology, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
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42
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Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells. Cells 2019; 8:cells8111410. [PMID: 31717433 PMCID: PMC6912740 DOI: 10.3390/cells8111410] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the “Warburg Effect” and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.
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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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Naggie S, Fierer DS, Hughes MD, Kim AY, Luetkemeyer A, Vu V, Roa J, Rwema S, Brainard DM, McHutchison JG, Peters MG, Kiser JJ, Marks KM, Chung RT. Ledipasvir/Sofosbuvir for 8 Weeks to Treat Acute Hepatitis C Virus Infections in Men With Human Immunodeficiency Virus Infections: Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals. Clin Infect Dis 2019; 69:514-522. [PMID: 31220220 PMCID: PMC6637278 DOI: 10.1093/cid/ciy913] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 11/12/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Current guidelines for the management of hepatitis C virus (HCV) infections provide varying recommendations for the optimal treatment of acute HCV infections. There are limited data from small cohort studies to provide guidance on the best approach to treatment of this important patient population. METHODS Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals is an open-label, 2-cohort, Phase 1 clinical trial in which the second cohort assessed the safety and efficacy of 8 weeks of ledipasvir/sofosbuvir for the treatment of acute HCV infections in participants with chronic human immunodeficiency virus (HIV)-1 infections. This final analysis of the second cohort had a planned accrual of 27 participants, based on non-inferiority criteria, compared to the study-defined, historical, sustained virologic response (SVR) of 60% with pegylated-interferon/ribavirin. RESULTS We enrolled 27 men (9 Hispanic; 11 White, non-Hispanic; 5 Black, non-Hispanic; 2 Asian or Pacific Islander; median age 46 years). Most (96%) had HCV genotype-1 infection and 59% had the favorable interleukin 28B CC genotype. The median baseline HCV RNA load was 6.17 log10 IU/mL (interquartile range 4.51 - 6.55). All participants (100%) achieved the primary outcome of a sustained virologic response 12 weeks after the date of the last dose of study treatment (90% confidence interval 90-100%), achieving non-inferiority versus the 60% historic benchmark. No treatment discontinuations occurred. CONCLUSIONS This multicenter clinical trial, investigating 8 weeks of ledipasvir/sofosbuvir for acute HCV infections in men with HIV infections, reports a 100% SVR. This study provides the rationale for larger studies of shortened courses of direct-acting antiviral therapies in persons with HIV infections, including those with high baseline HCV RNA loads. CLINICAL TRIALS REGISTRATION NCT02128217.
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Affiliation(s)
| | | | | | | | | | - Vincent Vu
- Harvard T.H. Chan School of Public Health, Boston
| | - Jhoanna Roa
- Harvard T.H. Chan School of Public Health, Boston
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Casey JL, Feld JJ, MacParland SA. Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection. Cells 2019; 8:cells8040317. [PMID: 30959825 PMCID: PMC6523849 DOI: 10.3390/cells8040317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022] Open
Abstract
Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.
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Affiliation(s)
- Julia L Casey
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Jordan J Feld
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
| | - Sonya A MacParland
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
- Departments of Laboratory Medicine & Pathobiology and Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada.
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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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Cheng ML, Abdel-Hakeem MS, Cousineau SE, Grebely J, Marshall AD, Saeed S, Sagan SM, Shoukry NH, Feld JJ, MacParland SA. The 7th Canadian Symposium on Hepatitis C Virus: “Toward Elimination of HCV: How to Get There”. CANADIAN LIVER JOURNAL 2018; 1:139-152. [DOI: 10.3138/canlivj.2018-0018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 06/06/2018] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) affects more than 268,000 people in Canada. Both the Canadian Institutes of Health Research and the Public Health Agency of Canada recognize the significant impact of HCV-related liver diseases and supported the establishment of a national hepatitis C research network, the Canadian Network on Hepatitis C (CanHepC). Interferon-free direct-acting antiviral regimens lead to more than 95% cure rates in almost all patients with well-tolerated short-course therapy. However, the goal of eliminating HCV in Canada cannot be fully realized until we overcome the financial, geographical, cultural, and social barriers that affect the entire continuum of care from diagnosis and linkage to care through treatment and prevention of new and reinfections. Current practices face difficulties in reversing HCV-induced immunological defects, expanding treatment to neglected communities, combating reinfections and co-infections, and expediting and simplifying the processes of diagnosis and treatment. As part of its knowledge translation mandate, CanHepC has organized the annual Canadian symposium on hepatitis C since 2012. The theme of this year’s symposium, “Toward Elimination of HCV: How to Get There?” focused on identifying the requirements of our therapeutic strategies and health policies for the elimination of HCV in Canada.
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Affiliation(s)
- Michael L Cheng
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario
| | - Mohamed S Abdel-Hakeem
- Penn Institute for Immunology, Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sophie E Cousineau
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec
| | - Jason Grebely
- Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Alison D Marshall
- Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Sahar Saeed
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec
| | - Selena M Sagan
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec
- Department of Biochemistry, McGill University, Montreal, Quebec
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal, Montreal, Quebec
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario
| | - Sonya A MacParland
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario
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48
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Rosenberg BR, Depla M, Freije CA, Gaucher D, Mazouz S, Boisvert M, Bédard N, Bruneau J, Rice CM, Shoukry NH. Longitudinal transcriptomic characterization of the immune response to acute hepatitis C virus infection in patients with spontaneous viral clearance. PLoS Pathog 2018; 14:e1007290. [PMID: 30222771 PMCID: PMC6160227 DOI: 10.1371/journal.ppat.1007290] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/27/2018] [Accepted: 08/22/2018] [Indexed: 02/08/2023] Open
Abstract
Most individuals exposed to hepatitis C virus (HCV) become persistently infected while a minority spontaneously eliminate the virus. Although early immune events influence infection outcome, the cellular composition, molecular effectors, and timeframe of the host response active shortly after viral exposure remain incompletely understood. Employing specimens collected from people who inject drugs (PWID) with high risk of HCV exposure, we utilized RNA-Seq and blood transcriptome module (BTM) analysis to characterize immune function in peripheral blood mononuclear cells (PBMC) before, during, and after acute HCV infection resulting in spontaneous resolution. Our results provide a detailed description of innate immune programs active in peripheral blood during acute HCV infection, which include prominent type I interferon and inflammatory signatures. Innate immune gene expression rapidly returns to pre-infection levels upon viral clearance. Comparative analyses using peripheral blood gene expression profiles from other viral and vaccine studies demonstrate similarities in the immune responses to acute HCV and flaviviruses. Of note, both acute dengue virus (DENV) infection and acute HCV infection elicit similar innate antiviral signatures. However, while transient in DENV infection, this signature was sustained for many weeks in the response to HCV. These results represent the first longitudinal transcriptomic characterization of human immune function in PBMC during acute HCV infection and identify several dynamically regulated features of the complex response to natural HCV exposure.
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Affiliation(s)
- Brad R. Rosenberg
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Program in Immunogenomics, The Rockefeller University, New York, NY, United States of America
| | - Marion Depla
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Catherine A. Freije
- Program in Immunogenomics, The Rockefeller University, New York, NY, United States of America
| | - Denis Gaucher
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Sabrina Mazouz
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Departement de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
| | - Maude Boisvert
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Nathalie Bédard
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine familiale et de médecine d’urgence, Université de Montréal, Montréal, QC, Canada
| | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, United States of America
- Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, United States of America
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de médecine, Université de Montréal, Montréal, QC, Canada
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