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1
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de Almeida Pondé RA. Detection of hepatitis B virus surface antigen, IgM and IgG antibodies to hepatitis B virus core antigen in the clinical classification and epidemiological surveillance of HBV infection. Mol Biol Rep 2025; 52:195. [PMID: 39903324 DOI: 10.1007/s11033-025-10278-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
Hepatitis B virus surface antigen (HBsAg), IgM and IgG antibodies to hepatitis B virus core antigen (anti-HBcIgM and anti-HBcIgG) comprise serological markers of hepatitis B virus (HBV) infection of great importance in the epidemiological surveillance of hepatitis B, since they have been routinely considered for classifying the acute and chronic clinical forms of HBV infection. This classification is established according to the expression and dynamics of these markers in the infected person's bloodstream, which serves as the basis for the differential diagnosis between the two clinical entities. However, in certain circumstances, both acute and chronic infection, the detection of these markers may not occur in the bloodstream, favoring the occurrence of atypical serological profiles of infection, and compromising the correct infection clinical classification. In addition, the complex and varied nature of hepatitis B serological profiles may compromise the health professional's ability to analyze the case and, thus, correctly classify the infection's clinical form. Since the expression of these markers in the bloodstream occurs dynamically, with consequent changes in the patient's serological profile as he progresses towards recovery or chronicity, the diagnosis of acute or chronic infection may also be compromised, if it is established based on the collection of a single sample and without knowing the patient's clinical history and their epidemiological antecedents. This manuscript addresses the sensitivity and specificity of HBsAg, anti-HBcIgM, and anti-HBcIgG serological markers detection in the clinical classification of HBV infection and in the epidemiological surveillance of hepatitis B. This review is covering the clinical and epidemiological interpretations of the markers in and of themselves, not in reference to any specific assays.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde -SES/Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil.
- , Rua 136 Qd F44 Lt 22/24 Ed. César Sebba- Setor Sul, Goiânia, Goiás, 74-093-250, Brazil.
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Fasano M, Ieva F, Ciarallo M, Caccianotti B, Santantonio TA. Acute Hepatitis C: Current Status and Future Perspectives. Viruses 2024; 16:1739. [PMID: 39599853 PMCID: PMC11599108 DOI: 10.3390/v16111739] [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: 09/20/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
The hepatitis C virus (HCV) infection continues to represent a significant public health threat and is a leading cause of liver cirrhosis, liver cancer, and liver-related mortality. The World Health Organization (WHO) has set a goal for 2030: to eliminate HCV infection as a public health threat by reducing new HCV infections by 90% and mortality by 65%. The early phase of HCV infection represents a pivotal point in the evolution of hepatitis C. Despite a favourable course in the majority of patients, approximately 50-70% of individuals with recently acquired hepatitis C will develop a chronic infection, defined as the persistence of viremia for a period exceeding six months. The diagnosis and treatment of a recent HCV infection should facilitate engagement in multidisciplinary care, prevent the development and complications of chronic liver disease, and reduce ongoing transmission in key populations. Therefore, early treatment in the early phase of infection compared with deferring treatment until the chronic infection remains a valid approach in the era of direct antiviral agents (DAAs). This approach is supported by a cost-effectiveness analysis. The aim of this review is to synthesise the existing knowledge on the early phase of hepatitis C virus infection, with a particular focus on the current risk factors, natural history, therapeutic management, and future perspectives.
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Affiliation(s)
- Massimo Fasano
- Infectious Diseases Unit, PO Della Murgia “F. Perinei”, 70022 Altamura, Italy
| | - Francesco Ieva
- Department of Medical and Surgical Sciences, Section of Infectious Diseases, University of Foggia, 71122 Foggia, Italy; (F.I.); (M.C.); (B.C.); (T.A.S.)
| | - Marianna Ciarallo
- Department of Medical and Surgical Sciences, Section of Infectious Diseases, University of Foggia, 71122 Foggia, Italy; (F.I.); (M.C.); (B.C.); (T.A.S.)
| | - Bruno Caccianotti
- Department of Medical and Surgical Sciences, Section of Infectious Diseases, University of Foggia, 71122 Foggia, Italy; (F.I.); (M.C.); (B.C.); (T.A.S.)
| | - Teresa Antonia Santantonio
- Department of Medical and Surgical Sciences, Section of Infectious Diseases, University of Foggia, 71122 Foggia, Italy; (F.I.); (M.C.); (B.C.); (T.A.S.)
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Eisa M, Gomez-Escobar E, Bédard N, Abdeltawab NF, Flores N, Mazouz S, Fieffé-Bédard A, Sakayan P, Gridley J, Abdel-Hakeem MS, Bruneau J, Grakoui A, Shoukry NH. Coordinated expansion of memory T follicular helper and B cells mediates spontaneous clearance of HCV reinfection. Front Immunol 2024; 15:1403769. [PMID: 38947319 PMCID: PMC11211980 DOI: 10.3389/fimmu.2024.1403769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/15/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction Follicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections. However, their role during recall responses is unclear. Here, we used hepatitis C virus (HCV) reinfection in humans as a model to study the recall collaborative interaction between circulating CD4 T follicular helper cells (cTfh) and memory B cells (MBCs) leading to the generation of NAbs. Methods We evaluated this interaction longitudinally in subjects who have spontaneously resolved primary HCV infection during a subsequent reinfection episode that resulted in either another spontaneous resolution (SR/SR, n = 14) or chronic infection (SR/CI, n = 8). Results Both groups exhibited virus-specific memory T cells that expanded upon reinfection. However, early expansion of activated cTfh (CD4+CXCR5+PD-1+ICOS+FoxP3-) occurred in SR/SR only. The frequency of activated cTfh negatively correlated with time post-infection. Concomitantly, NAbs and HCV-specific MBCs (CD19+CD27+IgM-E2-Tet+) peaked during the early acute phase in SR/SR but not in SR/CI. Finally, the frequency of the activated cTfh1 (CXCR3+CCR6-) subset correlated with the neutralization breadth and potency of NAbs. Conclusion These results underscore a key role for early activation of cTfh1 cells in helping antigen-specific B cells to produce NAbs that mediate the clearance of HCV reinfection.
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Affiliation(s)
- Mohamed Eisa
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Elsa Gomez-Escobar
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
| | - Nathalie Bédard
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Nourtan F. Abdeltawab
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- School of Pharmacy, Newgiza University, Giza, Egypt
| | - Nicol Flores
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
| | - Sabrina Mazouz
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
| | - Alizée Fieffé-Bédard
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Patrick Sakayan
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - John Gridley
- Department of Medicine, Emory University, Atlanta, GA, United States
| | - Mohamed S. Abdel-Hakeem
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada
- Département de Médecine familiale et département d’urgence, Université de Montréal, Montréal, QC, Canada
| | - Arash Grakoui
- Department of Medicine, Emory University, Atlanta, GA, United States
| | - 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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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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Ivashkin VT, Chulanov VP, Mamonova NA, Maevskaya MV, Zharkova MS, Tikhonov IN, Bogomolov PO, Volchkova EV, Dmitriev AS, Znojko OO, Klimova EA, Kozlov KV, Kravchenko IE, Malinnikova EY, Maslennikov RV, Mikhailov MI, Novak KE, Nikitin IG, Syutkin VE, Esaulenko EV, Sheptulin AA, Shirokova EN, Yushchuk ND. Clinical Practice Guidelines of the Russian Society for the Study of the Liver, the Russian Gastroenterological Association, the National Scientific Society of Infectious Disease Specialists for the Diagnosis and Treatment of Chronic Hepatitis C. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2023; 33:84-124. [DOI: 10.22416/1382-4376-2023-33-1-84-124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
Аim:diagnosis and treatment algorithms in the clinical recommendations intended for general practitioners, gastroenterologists, infectious disease specialists, hepatologists on the of chronic hepatitis C are presented.Summary.Chronic viral hepatitis C is a socially significant infection, the incidence of which in the Russian Federation remains significantly high. Over the past 10 years, great progress has been made in the treatment of hepatitis C — direct acting antiviral drugs have appeared. The spectrum of their effectiveness allows to achieve a sustained virological response in more than 90 % of cases, even in groups that were not previously considered even as candidates for therapy or were difficult to treat — patients receiving renal replacement therapy, after liver transplantation (or other organs), at the stage of decompensated liver cirrhosis, HIV co-infected, etc. Interferons are excluded from the recommendations due to their low effectiveness and a wide range of adverse events. The indications for the treatment have been expanded, namely, the fact of confirmation of viral replication. The terms of dispensary observation of patients without cirrhosis of the liver have been reduced (up to 12 weeks after the end of therapy). Also, these recommendations present approaches to active screening of hepatitis in risk groups, preventive and rehabilitation measures after the end of treatment.Conclusion.Great success has been achieved in the treatment of chronic hepatitis C. In most cases, eradication of viral HCV infection is a real task even in patients at the stage of cirrhosis of the liver, with impaired renal function, HIV co-infection, after solid organs transplantation.
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Affiliation(s)
- V. T. Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - V. P. Chulanov
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - N. A. Mamonova
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - M. V. Maevskaya
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. S. Zharkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - I. N. Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - P. O. Bogomolov
- M.F. Vladimirsky Moscow Regional Research Clinical Institute
| | - E. V. Volchkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - A. S. Dmitriev
- Sechenov First Moscow State Medical University (Sechenov University)
| | - O. O. Znojko
- Moscow State University of Medicine and Dentistry
| | | | | | | | - E. Yu. Malinnikova
- Department of Virology, Russian Medical Academy of Continuing Professional Education
| | - R. V. Maslennikov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. I. Mikhailov
- North-Western State Medical University named after I.I. Mechnikov
| | | | | | - V. E. Syutkin
- Sklifosovsky Clinical and Research Institute for Emergency Medicine; Russian State Research Center — Burnazyan Federal Medical Biophysical Center
| | | | - A. A. Sheptulin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - E. N. Shirokova
- Sechenov First Moscow State Medical University (Sechenov University)
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Liu B, Zhang E, Ma X, Luo S, Wang C, Zhang L, Wang W, Fu Y, Allain JP, Li C, Li T. Early Phase of Specific Cellular Immune Status Associates with HCV Infection Outcomes in Marmosets. Viruses 2023; 15:v15051082. [PMID: 37243168 DOI: 10.3390/v15051082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/26/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
The major mechanism for determination of HCV infection outcomes has not been fully described, particularly in the early phase of the "window-period" of infection. Based on two groups of marmosets infected with HCV-CE1E2p7/GBV-B chimeric virus (HCV chimera) or GBV-B, the immune mechanism correlating with the different outcomes of virus infections was explored in this study. HCV chimera containing the entire HCV core and envelope proteins (CE1E2p7) and GBV-B RNA were intrahepatically injected into four marmosets in each group, respectively. Blood samples were taken from individual animals in an interval of 2 weeks. Viral load and specific T cell responses were detected in two groups of HCV chimera- and GBV-B-infected marmosets. HCV chimera-infected marmosets appeared to have a virally persistent infection over 6 months post inoculation of the virus. Of these, the specific IFN-γ-secretion T cell response slowly developed over 13 to 19 weeks and was maintained at a relatively low level with 40-70 SFC/106 PBMCs, while the specific Treg cell response was rapidly activated over 3 weeks and was maintained at a high level around 5% among lymphocytes. In contrast, GBV-B-infected marmosets presented spontaneous viral clearance within 6 months; the specific IFN-γ-secretion T cell response was quickly established over 5 to 7 weeks and was maintained at a high level with 50-130 SFC/106 PBMCs, while the specific Treg cell response was inactivated and maintained at a baseline below 3% among lymphocytes. In conclusion, the HCV structural proteins inducing immune suppression in the early phase of HCV infection contributed to the viral persistence, of which the activation of Treg cells might play an important role in the inhibition of an effective T cell antiviral response.
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Affiliation(s)
- Bochao Liu
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
- Guangzhou Blood Center, Guangzhou 510095, China
| | - Enhui Zhang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Xiaorui Ma
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Shengxue Luo
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Chong Wang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Ling Zhang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Wenjing Wang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Yongshui Fu
- Guangzhou Blood Center, Guangzhou 510095, China
| | - Jean-Pierre Allain
- Division of Transfusion Medicine, University of Cambridge, Cambridge CB2 2PT, UK
| | - Chengyao Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
| | - Tingting Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
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McDonald SA, Myring G, Palmateer NE, McAuley A, Beer L, Dillon JF, Hollingworth W, Gunson R, Hickman M, Hutchinson SJ. Improved health-related quality of life after hepatitis C viraemic clearance among people who inject drugs may not be durable. Addiction 2023. [PMID: 36808787 DOI: 10.1111/add.16169] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 02/07/2023] [Indexed: 02/22/2023]
Abstract
BACKGROUND AND AIMS Chronic infection with the hepatitis C virus (HCV) has a detrimental impact on health-related quality of life (QoL). Scale-up of HCV direct-acting antiviral (DAA) therapy among people who inject drugs (PWID) is underway in several countries since the introduction of interferon-free regimens. This study aimed to assess the impact of DAA treatment success on QoL for PWID. DESIGN Cross-sectional study using two rounds of the Needle Exchange Surveillance Initiative, a national anonymous bio-behavioural survey and a longitudinal study involving PWID who underwent DAA therapy. SETTING The setting for the cross-sectional study was Scotland (2017-2018, 2019-2020). The setting for the longitudinal study was the Tayside region of Scotland (2019-2021). PARTICIPANTS In the cross-sectional study PWID were recruited from services providing injecting equipment (n = 4009). In the longitudinal study, participants were PWID on DAA therapy (n = 83). MEASUREMENTS In the cross-sectional study, the association between QoL (measured using the EQ-5D-5L quality of life instrument) and HCV diagnosis and treatment was assessed using multilevel linear regression. In the longitudinal study, QoL was compared at four timepoints using multilevel regression, from treatment commencement until 12 months following commencement. FINDINGS In the cross-sectional study, 41% (n = 1618) were ever chronically HCV infected, of whom 78% (n = 1262) were aware of their status and of whom 64% (n = 704) had undergone DAA therapy. There was no evidence for a marked QoL improvement associated with viral clearance among those treated for HCV (B = 0.03; 95% CI, -0.03 to 0.09). In the longitudinal study, improved QoL was observed at the sustained virologic response test timepoint (B = 0.18; 95% CI, 0.10-0.27), but this was not maintained at 12 months following start of treatment (B = 0.02; 95% CI, -0.05 to 0.10). CONCLUSIONS Successful direct-acting antiviral therapy for hepatitis C infection may not lead to a durable improvement in quality of life among people who inject drugs, although there may be a transient improvement around the time of sustained virologic response. Economic models of the impact of scaling-up treatment may need to include more conservative quality of life benefits over and above reductions in mortality, disease progression and transmission of infection.
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Affiliation(s)
- Scott A McDonald
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, G4 0BA, UK.,Public Health Scotland, Meridian Court, Glasgow, G2 6QE, UK
| | | | - Norah E Palmateer
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, G4 0BA, UK.,Public Health Scotland, Meridian Court, Glasgow, G2 6QE, UK
| | - Andrew McAuley
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, G4 0BA, UK.,Public Health Scotland, Meridian Court, Glasgow, G2 6QE, UK
| | | | | | | | - Rory Gunson
- West of Scotland Specialist Virology Centre, Glasgow Royal Infirmary, Glasgow, UK
| | - Matthew Hickman
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 1TL, UK
| | - Sharon J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, G4 0BA, UK.,Public Health Scotland, Meridian Court, Glasgow, G2 6QE, UK
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9
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Jay C, Ratcliff J, Turtle L, Goulder P, Klenerman P. Exposed seronegative: Cellular immune responses to SARS-CoV-2 in the absence of seroconversion. Front Immunol 2023; 14:1092910. [PMID: 36776841 PMCID: PMC9909393 DOI: 10.3389/fimmu.2023.1092910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/16/2023] [Indexed: 01/27/2023] Open
Abstract
The factors determining whether infection will occur following exposure to SARS-CoV-2 remain elusive. Certain SARS-CoV-2-exposed individuals mount a specific T-cell response but fail to seroconvert, representing a population that may provide further clarity on the nature of infection susceptibility and correlates of protection against SARS-CoV-2. Exposed seronegative individuals have been reported in patients exposed to the blood-borne pathogens Human Immunodeficiency virus and Hepatitis C virus and the sexually transmitted viruses Hepatitis B virus and Herpes Simplex virus. By comparing the quality of seronegative T-cell responses to SARS-CoV-2 with seronegative cellular immunity to these highly divergent viruses, common patterns emerge that offer insights on the role of cellular immunity against infection. For both SARS-CoV-2 and Hepatitis C, T-cell responses in exposed seronegatives are consistently higher than in unexposed individuals, but lower than in infected, seropositive patients. Durability of T-cell responses to Hepatitis C is dependent upon repeated exposure to antigen - single exposures do not generate long-lived memory T-cells. Finally, exposure to SARS-CoV-2 induces varying degrees of immune activation, suggesting that exposed seronegative individuals represent points on a spectrum rather than a discrete group. Together, these findings paint a complex landscape of the nature of infection but provide clues as to what may be protective early on in SARS-CoV-2 disease course. Further research on this phenomenon, particularly through cohort studies, is warranted.
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Affiliation(s)
- Cecilia Jay
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Jeremy Ratcliff
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Lance Turtle
- National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, United Kingdom
| | - Philip Goulder
- Peter Medawar Building for Pathogen Research, Department of Paediatrics, University of Oxford, Oxford, United Kingdom
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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10
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Gupta T. Acute Hepatitis in an Immunosuppressed Patient: A Dilemma. Euroasian J Hepatogastroenterol 2023; 13:26-27. [PMID: 37554978 PMCID: PMC10405803 DOI: 10.5005/jp-journals-10018-1368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/21/2022] [Indexed: 08/10/2023] Open
Abstract
Acute hepatitis in patients on chemotherapy has always been challenging. Demystifying the truth becomes essential to continue chemotherapy. Wepresent a case of carcinoma buccal mucosa who developed acute hepatitis following a single dose of cisplatin and radiotherapy. In the background of a history of chronic alcoholism, and alcohol abstinence of more than 3 months, acute alcoholic hepatitis was unlikely. Though he had occult hepatitis B with HBsAg negative and positive IgG anti-HBc antibody status, however, with undetectable HBV DNA PCR quantitative, hepatitis B was unlikely to be the cause of acute hepatitis. With all viral markers including atypical viruses and autoimmune work-up being negative, it was a real-time challenge to find the exact cause. How to cite this article Gupta T. Acute Hepatitis in an Immunosuppressed Patient: A Dilemma. Euroasian J Hepato-Gastroenterol 2023;13(1):26-27.
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Affiliation(s)
- Tarana Gupta
- Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
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11
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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12
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Sugrue JA, Posseme C, Tan Z, Pou C, Charbit B, Bondet V, Bourke NM, Brodin P, Duffy D, O'Farrelly C. Enhanced TLR3 responsiveness in hepatitis C virus resistant women from the Irish anti-D cohort. Cell Rep Med 2022; 3:100804. [PMID: 36334594 PMCID: PMC9729829 DOI: 10.1016/j.xcrm.2022.100804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 08/03/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022]
Abstract
Natural resistance to infection is an overlooked outcome after hepatitis C virus (HCV) exposure. Between 1977 and 1979, 1,200 Rhesus D-negative Irish women were exposed to HCV-contaminated anti-D immunoglobulin. Here, we investigate why some individuals appear to resist infection despite exposure (exposed seronegative [ESN]). We screen HCV-resistant and -susceptible donors for anti-HCV adaptive immune responses using ELISpots and VirScan to profile antibodies against all know human viruses. We perform standardized ex vivo whole blood stimulation (TruCulture) assays with antiviral ligands and assess antiviral responses using NanoString transcriptomics and Luminex proteomics. We describe an enhanced TLR3-type I interferon response in ESNs compared with seropositive women. We also identify increased inflammatory cytokine production in response to polyIC in ESNs compared with seropositive women. These enhanced responses may have contributed to innate immune protection against HCV infection in our cohort.
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Affiliation(s)
- Jamie A Sugrue
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Céline Posseme
- Translational Immunology Unit, Institut Pasteur, Paris, France
| | - Ziyang Tan
- Science for Life Laboratory, Department of Women's and Children Health, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Christian Pou
- Science for Life Laboratory, Department of Women's and Children Health, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Bruno Charbit
- Cytometry and Biomarkers UTechS, CRT, Institut Pasteur, Paris, France
| | - Vincent Bondet
- Translational Immunology Unit, Institut Pasteur, Paris, France
| | - Nollaig M Bourke
- Discipline of Medical Gerontology, School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Petter Brodin
- Science for Life Laboratory, Department of Women's and Children Health, Karolinska Institutet, 17165 Stockholm, Sweden
| | - Darragh Duffy
- Translational Immunology Unit, Institut Pasteur, Paris, France; Cytometry and Biomarkers UTechS, CRT, Institut Pasteur, Paris, France
| | - Cliona O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; School of Medicine, Trinity College Dublin, Dublin, Ireland.
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13
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Modified E2 Glycoprotein of Hepatitis C Virus Enhances Proinflammatory Cytokines and Protective Immune Response. J Virol 2022; 96:e0052322. [PMID: 35612312 DOI: 10.1128/jvi.00523-22] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatitis C virus (HCV) is characterized by a high number of chronic cases owing to an impairment of innate and adaptive immune responses. CD81 on the cell surface facilitates HCV entry by interacting with the E2 envelope glycoprotein. In addition, CD81/E2 binding on immunity-related cells may also influence host response outcome to HCV infection. Here, we performed site-specific amino acid substitution in the front layer of E2 sequence to reduce CD81 binding and evaluate the potential of the resulting immunogen as an HCV vaccine candidate. The modified sE2 protein (F442NYT), unlike unmodified sE2, exhibited a significant reduction in CD81 binding, induced higher levels of proinflammatory cytokines, repressed anti-inflammatory response in primary monocyte-derived macrophages as antigen-presenting cells, and stimulated CD4+ T cell proliferation. Immunization of BALB/c mice with an E1/sE2F442NYT nucleoside-modified mRNA-lipid nanoparticle (mRNA-LNP) vaccine resulted in improved IgG1-to-IgG2a isotype switching, an increase in neutralizing antibodies against HCV pseudotype virus, a B and T cell proliferative response to antigens, and improved protection against infection with a surrogate recombinant vaccinia virus-expressing HCV E1-E2-NS2aa134-966 challenge model compared to E1/unmodified sE2 mRNA-LNP vaccine. Further investigation of the modified E2 antigen may provide helpful information for HCV vaccine development. IMPORTANCE Hepatitis C virus (HCV) E2-CD81 binding dampens protective immune response. We have identified that an alteration of amino acids in the front layer of soluble E2 (sE2) disrupts CD81 interaction and alters the cytokine response. Immunization with modified sE2F442NYT (includes an added potential N-linked glycosylation site and reduces CD81 binding activity)-mRNA-LNP candidate vaccine generates improved proinflammatory response and protective efficacy against a surrogate HCV vaccinia challenge model in mice. The results clearly suggested that HCV E2 exhibits immunoregulatory activity that inhibits induction of robust protective immune responses. Selection of engineered E2 antigen in an mRNA-LNP platform amenable to nucleic acid sequence alterations may open a novel approach for multigenotype HCV vaccine development.
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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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Siliciano JD, Siliciano RF. In Vivo Dynamics of the Latent Reservoir for HIV-1: New Insights and Implications for Cure. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:271-294. [PMID: 34736342 DOI: 10.1146/annurev-pathol-050520-112001] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Although antiretroviral therapy (ART) can reduce viremia to below the limit of detection and allow persons living with HIV-1 (PLWH) to lead relatively normal lives, viremia rebounds when treatment is interrupted. Rebound reflects viral persistence in a stable latent reservoir in resting CD4+ T cells. This reservoir is now recognized as the major barrier to cure and is the focus of intense international research efforts. Strategies to cure HIV-1 infection include interventions to eliminate this reservoir, to prevent viral rebound from the reservoir, or to enhance immune responses such that viral replication is effectively controlled. Here we consider recent developments in understanding the composition of the reservoir and how it can be measured in clinical studies. We also discuss exciting new insights into the in vivo dynamics of the reservoir and the reasons for its remarkable stability. Finally we discuss recent discoveries on the complex processes that govern viral rebound. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Janet D Siliciano
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
| | - Robert F Siliciano
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; .,Howard Hughes Medical Institute, Baltimore, Maryland 21205, 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. 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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18
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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: 42] [Impact Index Per Article: 10.5] [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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19
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Mazouz S, Boisvert M, Abdel-Hakeem MS, Khedr O, Bruneau J, Shoukry NH. Expansion of Unique Hepatitis C Virus-Specific Public CD8 + T Cell Clonotypes during Acute Infection and Reinfection. THE JOURNAL OF IMMUNOLOGY 2021; 207:1180-1193. [PMID: 34341170 DOI: 10.4049/jimmunol.2001386] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 06/09/2021] [Indexed: 11/19/2022]
Abstract
Hepatitis C virus (HCV) infection resolves spontaneously in ∼25% of acutely infected humans where viral clearance is mediated primarily by virus-specific CD8+ T cells. Previous cross-sectional analysis of the CD8+ TCR repertoire targeting two immunodominant HCV epitopes reported widespread use of public TCRs shared by different subjects, irrespective of infection outcome. However, little is known about the evolution of the public TCR repertoire during acute HCV and whether cross-reactivity to other Ags can influence infectious outcome. In this article, we analyzed the CD8+ TCR repertoire specific to the immunodominant and cross-reactive HLA-A2-restricted nonstructural 3-1073 epitope during acute HCV in humans progressing to either spontaneous resolution or chronic infection and at ∼1 y after viral clearance. TCR repertoire diversity was comparable among all groups with preferential usage of the TCR-β V04 and V06 gene families. We identified a set of 13 public clonotypes in HCV-infected humans independent of infection outcome. Six public clonotypes used the V04 gene family. Several public clonotypes were long-lived in resolvers and expanded on reinfection. By mining publicly available data, we identified several low-frequency CDR3 sequences in the HCV-specific repertoire matching human TCRs specific for other HLA-A2-restricted epitopes from melanoma, CMV, influenza A, EBV, and yellow fever viruses, but they were of low frequency and limited cross-reactivity. In conclusion, we identified 13 new public human CD8+ TCR clonotypes unique to HCV that expanded during acute infection and reinfection. The low frequency of cross-reactive TCRs suggests that they are not major determinants of infectious outcome.
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Affiliation(s)
- Sabrina Mazouz
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec, Canada
| | - Maude Boisvert
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Mohamed S Abdel-Hakeem
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec, Canada
| | - Omar Khedr
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.,Département de Médecine Familiale et de Médecine d'Urgence, Université de Montréal, Montreal, Quebec, Canada; and
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada; .,Département de Médecine, Université de Montréal, Montreal, Quebec, Canada
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20
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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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21
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Rausch JW, Le Grice SFJ. Characterizing the Latent HIV-1 Reservoir in Patients with Viremia Suppressed on cART: Progress, Challenges, and Opportunities. Curr HIV Res 2021; 18:99-113. [PMID: 31889490 PMCID: PMC7475929 DOI: 10.2174/1570162x18666191231105438] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/05/2019] [Accepted: 12/09/2019] [Indexed: 02/07/2023]
Abstract
Modern combination antiretroviral therapy (cART) can bring HIV-1 in blood plasma to level undetectable by standard tests, prevent the onset of acquired immune deficiency syndrome (AIDS), and allow a near-normal life expectancy for HIV-infected individuals. Unfortunately, cART is not curative, as within a few weeks of treatment cessation, HIV viremia in most patients rebounds to pre-cART levels. The primary source of this rebound, and the principal barrier to a cure, is the highly stable reservoir of latent yet replication-competent HIV-1 proviruses integrated into the genomic DNA of resting memory CD4+ T cells. In this review, prevailing models for how the latent reservoir is established and maintained, residual viremia and viremic rebound upon withdrawal of cART, and the types and characteristics of cells harboring latent HIV-1 will be discussed. Selected technologies currently being used to advance our understanding of HIV latency will also be presented, as will a perspective on which areas of advancement are most essential for producing the next generation of HIV-1 therapeutics.
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Affiliation(s)
- Jason W Rausch
- Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, MD 21702, United States
| | - Stuart F J Le Grice
- Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, MD 21702, United States
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22
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Miyashita K, Hongo Y, Nakashima A, Kato S, Kusano H, Morizono S, Higashi N. Fatal Hepatitis C after Chemotherapy in a Patient with Malignant Lymphoma: Possible Reactivation of Seronegative Occult Hepatitis C Virus Infection Due to Chemotherapy. Intern Med 2021; 60:1533-1539. [PMID: 33191319 PMCID: PMC8188017 DOI: 10.2169/internalmedicine.4768-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
A 79-year-old man with lymphoma who tested negative for anti-hepatitis C virus (HCV) antibody received rituximab-containing chemotherapy. Liver dysfunction of unknown cause had persisted since the second cycle of chemotherapy. Ten months after treatment, he rapidly developed massive ascites and atrophy of the liver, and we detected HCV RNA in his serum using real time polymerase chain reaction. Furthermore, medical interviews showed that the patient had no episodes for acute HCV infection, but he did have a history of unspecified liver dysfunction. These findings support the possibility of the reactivation of seronegative occult HCV infection due to chemotherapy in a cancer patient.
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Affiliation(s)
- Kaname Miyashita
- Department of Haematology, Saiseikai Fukuoka General Hospital, Japan
- Department of Hematology, National Hospital Organization Kyushu Cancer Center, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Yui Hongo
- Department of Diabetes and Endocrinology, Saiseikai Fukuoka General Hospital, Japan
| | | | - Seiya Kato
- Division of Pathology, Saiseikai Fukuoka General Hospital, Japan
| | - Hironori Kusano
- Department of Pathology, Kurume University School of Medicine, Japan
| | - Shusuke Morizono
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
- Department of Hepatology, Saiseikai Fukuoka General Hospital, Japan
| | - Nobuhiko Higashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
- Department of Hepatology, Saiseikai Fukuoka General Hospital, Japan
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23
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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: 34] [Impact Index Per Article: 8.5] [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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24
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Coto-Llerena M, Lepore M, Spagnuolo J, Di Blasi D, Calabrese D, Suslov A, Bantug G, Duong FH, Terracciano LM, De Libero G, Heim MH. Interferon lambda 4 can directly activate human CD19 + B cells and CD8 + T cells. Life Sci Alliance 2021; 4:e201900612. [PMID: 33158978 PMCID: PMC7668538 DOI: 10.26508/lsa.201900612] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 10/26/2020] [Accepted: 10/26/2020] [Indexed: 12/12/2022] Open
Abstract
Compared with the ubiquitous expression of type I (IFNα and IFNβ) interferon receptors, type III (IFNλ) interferon receptors are mainly expressed in epithelial cells of mucosal barriers of the of the intestine and respiratory tract. Consequently, IFNλs are important for innate pathogen defense in the lung and intestine. IFNλs also determine the outcome of hepatitis C virus (HCV) infections, with IFNλ4 inhibiting spontaneous clearance of HCV. Because viral clearance is dependent on T cells, we explored if IFNλs can directly bind to and regulate human T cells. We found that human B cells and CD8+ T cells express the IFNλ receptor and respond to IFNλs, including IFNλ4. IFNλs were not inhibitors but weak stimulators of B- and T-cell responses. Furthermore, IFNλ4 showed neither synergistic nor antagonistic effects in co-stimulatory experiments with IFNλ1 or IFNα. Multidimensional flow cytometry of cells from liver biopsies of hepatitis patients from IFNλ4-producers showed accumulation of activated CD8+ T cells with a central memory-like phenotype. In contrast, CD8+ T cells with a senescent/exhausted phenotype were more abundant in IFNλ4-non-producers. It remains to be elucidated how IFNλ4 promotes CD8 T-cell responses and inhibits the host immunity to HCV infections.
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Affiliation(s)
- Mairene Coto-Llerena
- Department of Biomedicine, Hepatology, University Hospital and University of Basel, Basel, Switzerland
| | - Marco Lepore
- Department of Biomedicine, Experimental Immunology, University Hospital and University of Basel, Basel, Switzerland
| | - Julian Spagnuolo
- Department of Biomedicine, Experimental Immunology, University Hospital and University of Basel, Basel, Switzerland
| | - Daniela Di Blasi
- Department of Biomedicine, Hepatology, University Hospital and University of Basel, Basel, Switzerland
- Department of Biomedicine, Experimental Immunology, University Hospital and University of Basel, Basel, Switzerland
| | - Diego Calabrese
- Department of Biomedicine, Hepatology, University Hospital and University of Basel, Basel, Switzerland
| | - Aleksei Suslov
- Department of Biomedicine, Hepatology, University Hospital and University of Basel, Basel, Switzerland
| | - Glenn Bantug
- Department of Biomedicine, Immunobiology, University Hospital and University of Basel, Basel, Switzerland
| | - Francois Ht Duong
- Department of Biomedicine, Hepatology, University Hospital and University of Basel, Basel, Switzerland
| | - Luigi M Terracciano
- Molecular Pathology Division, Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Gennaro De Libero
- Department of Biomedicine, Experimental Immunology, University Hospital and University of Basel, Basel, Switzerland
| | - Markus H Heim
- Department of Biomedicine, Hepatology, University Hospital and University of Basel, Basel, Switzerland
- Division of Gastroenterology and Hepatology, Clarunis, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
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25
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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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26
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Abstract
Liver cancer is a global problem and hepatocellular carcinoma (HCC) accounts for about 85% of this cancer. In the USA, etiologies and risk factors for HCC include chronic hepatitis C virus (HCV) infection, diabetes, non-alcoholic steatohepatitis (NASH), obesity, excessive alcohol drinking, exposure to tobacco smoke, and genetic factors. Chronic HCV infection appears to be associated with about 30% of HCC. Chronic HCV infection induces multistep changes in liver, involving metabolic disorders, steatosis, cirrhosis and HCC. Liver carcinogenesis requires initiation of neoplastic clones, and progression to clinically diagnose malignancy. Tumor progression associates with profound exhaustion of tumor-antigen-specific CD8+T cells, and accumulation of PD-1hi CD8+T cells and Tregs. In this chapter, we provide a brief description of HCV and environmental/genetic factors, immune regulation, and highlight mechanisms of HCV associated HCC. We also underscore HCV treatment and recent paradigm of HCC progression, highlighted the current treatment and potential future therapeutic opportunities.
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27
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Pawlotsky JM, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H. EASL recommendations on treatment of hepatitis C: Final update of the series ☆. J Hepatol 2020; 73:1170-1218. [PMID: 32956768 DOI: 10.1016/j.jhep.2020.08.018] [Citation(s) in RCA: 725] [Impact Index Per Article: 145.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, as well as developments in diagnostic procedures and improvements in therapy and prevention. These therapies make it possible to eliminate hepatitis C as a major public health threat, as per the World Health Organization target, although the timeline and feasibility vary from region to region. These European Association for the Study of the Liver recommendations on treatment of hepatitis C describe the optimal management of patients with recently acquired and chronic HCV infections in 2020 and onwards.
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28
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Hartnell F, Esposito I, Swadling L, Brown A, Phetsouphanh C, de Lara C, Gentile C, Turner B, Dorrell L, Capone S, Folgori A, Barnes E, Klenerman P. Characterizing Hepatitis C Virus-Specific CD4 + T Cells Following Viral-Vectored Vaccination, Directly Acting Antivirals, and Spontaneous Viral Cure. Hepatology 2020; 72:1541-1555. [PMID: 32012325 PMCID: PMC7610807 DOI: 10.1002/hep.31160] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 01/07/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Induction of functional helper CD4+ T cells is the hallmark of a protective immune response against hepatitis C virus (HCV), associated with spontaneous viral clearance. Heterologous prime/boost viral vectored vaccination has demonstrated induction of broad and polyfunctional HCV-specific CD8+ T cells in healthy volunteers; however, much less is known about CD4+ T-cell subsets following vaccination. APPROACH AND RESULTS We analyzed HCV-specific CD4+ T-cell populations using major histocompatibility complex class II tetramers in volunteers undergoing HCV vaccination with recombinant HCV adenoviral/modified vaccinia Ankara viral vectors. Peptide-specific T-cell responses were tracked over time, and functional (proliferation and cytokine secretion) and phenotypic (cell surface and intranuclear) markers were assessed using flow cytometry. These were compared to CD4+ responses in 10 human leukocyte antigen-matched persons with HCV spontaneous resolution and 21 chronically infected patients treated with directly acting antiviral (DAA) therapy. Vaccination induced tetramer-positive CD4+ T cells that were highest 1-4 weeks after boosting (mean, 0.06%). Similar frequencies were obtained for those tracked following spontaneous resolution of disease (mean, 0.04%). In addition, the cell-surface phenotype (CD28, CD127) memory subset markers and intranuclear transcription factors, as well as functional capacity of peptide-specific CD4+ T-cell responses characterized after vaccination, are comparable to those following spontaneous viral resolution. In contrast, helper responses in chronic infection were infrequently detected and poorly functional and did not consistently recover following HCV cure. CONCLUSIONS Helper CD4+ T-cell phenotype and function following HCV viral vectored vaccination resembles "protective memory" that is observed following spontaneous clearance of HCV. DAA cure does not promote resurrection of exhausted CD4+ T-cell memory in chronic infection.
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Affiliation(s)
- Felicity Hartnell
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | - Ilaria Esposito
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | - Leo Swadling
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | - Anthony Brown
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | | | - Catherine de Lara
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom
| | | | - Bethany Turner
- Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | - Lucy Dorrell
- Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | | | | | - Eleanor Barnes
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom,Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom,NIHR Biomedical Research Centre OxfordJohn Radcliffe HospitalOxfordUnited Kingdom,Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
| | - Paul Klenerman
- Peter Medawar Building for Pathogen ResearchUniversity of OxfordOxfordUnited Kingdom,Jenner Vaccine TrialsNuffield Department of MedicineUniversity of OxfordOxfordUnited Kingdom,NIHR Biomedical Research Centre OxfordJohn Radcliffe HospitalOxfordUnited Kingdom,Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
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29
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Han JW, Sung PS, Hong SH, Lee H, Koh JY, Lee H, White S, Maslow JN, Weiner DB, Park SH, Jeong M, Heo J, Ahn SH, Shin EC. IFNL3-adjuvanted HCV DNA vaccine reduces regulatory T cell frequency and increases virus-specific T cell responses. J Hepatol 2020; 73:72-83. [PMID: 32088322 DOI: 10.1016/j.jhep.2020.02.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 02/06/2020] [Accepted: 02/10/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Although direct-acting antiviral (DAA) treatment results in a sustained virologic response (SVR) in most patients with chronic HCV infection, they are at risk of re-infection. Moreover, the immune system is not completely normalized even after SVR (e.g. increased regulatory T [Treg] cell frequency). We developed a DNA vaccine, GLS-6150, to prevent re-infection of patients with DAA-induced SVR and evaluated its safety and immunogenicity in individuals with chronic HCV infection. METHODS GLS-6150 consists of plasmids encoding HCV non-structural proteins (NS3-NS5A) and adjuvant IFNL3. The vaccine was administered 4 times at 4-weekly intervals to 3 groups (1, 3, or 6 mg/vaccination; n = 6 per group), followed by a 6 mg boost at 24 weeks (n = 14). Peripheral blood T cell responses were evaluated by interferon (IFN)-γ enzyme-linked immunospot assays, intracellular cytokine staining, and major histocompatibility complex class-I (MHC-I) dextramer staining. Treg cell frequency was assessed by flow cytometry. RESULTS Severe adverse events or vaccine discontinuation were not reported. The IFN-γ spot-forming cells specific to NS3-NS5A were increased by GLS-6150. Both CD4+ and CD8+ T cells produced multiple cytokines. However, the frequency and phenotype of HCV-specific MHC-I dextramer+CD8+ T cells were not changed. Interestingly, the frequency of Treg cells, particularly activated Treg cells, was decreased by GLS-6150, as expected from previous reports that IFNL3 adjuvants decrease Treg cell frequency. Ex vivo IFN-λ3 treatment reduced Treg frequency in pre-vaccination peripheral blood mononuclear cells. Finally, Treg cell frequency inversely correlated with HCV-specific, IFN-γ-producing T cell responses in the study participants. CONCLUSIONS We demonstrate that GLS-6150 decreases Treg cell frequency and enhances HCV-specific T cell responses without significant side effects. A phase I clinical trial of GLS-6150 is currently underway in patients with DAA-induced SVR. CLINICAL TRIAL NUMBER NCT02027116. LAY SUMMARY Although direct-acting antivirals (DAAs) are successfully used for the treatment of chronic hepatitis C virus (HCV) infection, a prophylactic HCV vaccine needs to be developed, especially for patients who achieve a sustained virologic response. In the current study, we show that a DNA vaccine (GLS-6150) was safe and increased HCV-specific T cell responses. A clinical trial is underway to test this vaccine in patients with a sustained virologic response following DAA therapy.
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Affiliation(s)
- Ji Won Han
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Pil Soo Sung
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seon-Hui Hong
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
| | - Hoyoung Lee
- Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
| | - June Young Koh
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Hyojin Lee
- GeneOne Life Science, Inc., Seoul 06060, Republic of Korea
| | - Scott White
- Inovio Pharmaceuticals, Plymouth Meeting, PA 19462, USA
| | - Joel N Maslow
- GeneOne Life Science, Inc., Seoul 06060, Republic of Korea
| | | | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea
| | - Moonsup Jeong
- GeneOne Life Science, Inc., Seoul 06060, Republic of Korea
| | - Jeong Heo
- Department of Internal Medicine, College of Medicine, Pusan National University, Busan 49241, Republic of Korea.
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea; Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon 34141, Republic of Korea.
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30
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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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31
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Chionne P, Madonna E, Villano U, Tritarelli E, Pisani G, Costantino A, Equestre M, Marcantonio C, Bruni R, Ciccaglione AR. Sensitivity of hepatitis C virus rapid tests in detecting antibodies in general population. Panminerva Med 2019; 62:125-130. [PMID: 31692308 DOI: 10.23736/s0031-0808.19.03678-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Evaluation of clinical performance of the anti-hepatitis C virus (HCV) rapid tests were carried out mostly in chronic hepatitis C patients and in individuals at high risk of HCV infection. METHODS The aim of this study was to evaluate the performance of OraQuick and Wantai rapid tests on archived serum samples from 1408 individuals (mean age 46, range 18-90; 65% female) recruited with a systematic sampling procedure during a general population survey. RESULTS The analysis of samples by Ortho HCV 3.0 ELISA and Cobas Taqman HCV RNA assays resulted in 69 anti-HCV antibody positive sera, including 42 HCV RNA positive (group 1) and 27 HCV RNA negative (group 2) samples. The performance of rapid tests was evaluated on the 69 anti-HCV positive (group 1+2) and 206 (OraQuick) and 198 (Wantai) anti-HCV negative sera, randomly selected from the 1339 anti-HCV negative samples. The OraQuick and Wantai rapid assays showed a sensitivity in group 1 of 92.9% and 90.5%, respectively. The sensitivity in group 2 was 40.7% and 51.9%, respectively. The anti-HCV antibodies signal/cutoff mean value was the only parameter that statistically differed between group 1 and group 2 individuals (P<0.0001). Further, 3 (OraQuick) and 4 samples (Wantai) from group 1, with very low HCV RNA level (<25 UI/mL), were misdiagnosed by rapid assays as false negative. CONCLUSIONS The proportion of infections with low level of viremia and the risk associated with rapid assay failure remained to be carefully estimated in general population.
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Affiliation(s)
- Paola Chionne
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Elisabetta Madonna
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Umbertina Villano
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Elena Tritarelli
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Giulio Pisani
- Center for Immunobiologicals Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Angela Costantino
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Michele Equestre
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Cinzia Marcantonio
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Roberto Bruni
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Anna R Ciccaglione
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy -
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32
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Vigón L, Vázquez-Morón S, Berenguer J, González-García J, Jiménez-Sousa MÁ, Guardiola JM, Crespo M, de Los Santos I, Von Wichmann MA, Carrero A, Yélamos MB, Gómez J, Resino S, Martínez I. Rapid decrease in titer and breadth of neutralizing anti-HCV antibodies in HIV/HCV-coinfected patients who achieved SVR. Sci Rep 2019; 9:12163. [PMID: 31434968 PMCID: PMC6704069 DOI: 10.1038/s41598-019-48592-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 08/08/2019] [Indexed: 02/06/2023] Open
Abstract
The main targets for neutralizing anti-hepatitis C virus (HCV) antibodies (HCV-nAbs) are the E1 and E2 envelope glycoproteins. We have studied the characteristics of HCV-nAbs through a retrospective study involving 29 HIV/HCV-coinfected patients who achieved sustained virological response (SVR) with peg-IFNα + ribavirin anti-HCV therapy. Plasma samples at baseline and week 24 after SVR were used to perform neutralization assays against five JFH1-based HCV recombinant viruses coding for E1 and E2 from genotypes 1a (H77), 1b (J4), 2a (JFH1), 3a (S52) and 4a (ED43). At baseline, the majority of plasma samples neutralized 1a, 1b, 2a, and 4a, but not 3a, genotypes. Twenty-four weeks following SVR, most neutralizing titers declined substantially. Furthermore, titers against 3a and 2a were not detected in many patients. Plasma samples with high HCV-nAb titers neutralized all genotypes, and the highest titers at the starting point correlated with the highest titers at week 24 after SVR. In conclusion, high titers of broad-spectrum HCV-nAbs were detected in HIV/HCV-coinfected individuals, however, those titers declined soon after SVR.
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Affiliation(s)
- Lorena Vigón
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Sonia Vázquez-Morón
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | - Juan Berenguer
- Unidad de Enfermedades Infecciosas/VIH; Hospital General Universitario "Gregorio Marañón", Madrid, Spain.,Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain
| | - Juan González-García
- Unidad de VIH, Servicio de Medicina Interna, Hospital Universitario "La Paz", Madrid, Spain
| | - Ma Ángeles Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
| | | | | | | | | | - Ana Carrero
- Unidad de Enfermedades Infecciosas/VIH; Hospital General Universitario "Gregorio Marañón", Madrid, Spain.,Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain
| | - María Belén Yélamos
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain
| | - Julián Gómez
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
| | - Isidoro Martínez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
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Dawood RM, Salum GM, Abdelhafez TH, El Shenawy R, Ibrahim NE, El Awady MK. Safety and tolerability of mice to repeated subcutaneous injections of a peptide mix as a potential vaccine against HCV infection. Hum Antibodies 2019; 27:105-110. [PMID: 30594921 DOI: 10.3233/hab-180354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS In this study, the safety and tolerability of new candidate HCV vaccine named Cenv6 were screened in mice. Cenv6 peptide is composed of 6 synthetic HCV peptides (3 structural and 3 nonstructural peptides). METHODS Forty eight mice were enrolled in this study, 12 controls and 36 mice (the thirty-six mice were categorized into 3 groups according to administered doses (3 monthly doses of 800 ng, 1600 ng, and 16 μg/25 gm mouse body weight (bw))). Hematological, biochemical and histopathological changes were appraised. RESULTS Our data indicated that the doses of 800 ng and 1600 ng of Cenv6 per 25 gm mouse body weight were safe as compared to the dose 16 μg/25 gm bw (10 times more than the potential therapeutic dose) for all examined tissues while the 16 μg Cenv6 dose provoked histopathological changes in kidneys, liver and lungs. CONCLUSIONS The extravagant histopathological changes in different organs have exiled the 16 μg dose out of acceptable range and validated that Cenv6 is safe and tolerable at the two lower doses (800 and 1600 ng/25 gm bw).
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34
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Caraballo Cortés K, Osuch S, Perlejewski K, Pawełczyk A, Kaźmierczak J, Janiak M, Jabłońska J, Nazzal K, Stelmaszczyk‐Emmel A, Berak H, Bukowska‐Ośko I, Paciorek M, Laskus T, Radkowski M. Expression of programmed cell death protein 1 and T-cell immunoglobulin- and mucin-domain-containing molecule-3 on peripheral blood CD4+CD8+ double positive T cells in patients with chronic hepatitis C virus infection and in subjects who spontaneously cleared the virus. J Viral Hepat 2019; 26:942-950. [PMID: 30972915 PMCID: PMC6850126 DOI: 10.1111/jvh.13108] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 01/21/2019] [Accepted: 03/18/2019] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis C virus (HCV) infection is characterized by increased proportion of CD4+CD8+ double positive (DP) T cells, but their role in this infection is unclear. In chronic hepatitis C, immune responses to HCV become functionally exhausted, which manifests itself by increased expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) on T cells. The aim of our study was to determine PD-1 and Tim-3 phenotype of DP T cells in subjects with naturally resolved and chronic HCV infection. Peripheral blood mononuclear cells from 16 patients with chronic infection and 14 subjects who cleared HCV in the past were stained with anti-CD3, anti-CD4, anti-CD8, anti-PD-1 and anti-Tim-3 antibodies and, in 12 HLA-A*02-positive subjects, MHC class I pentamer with HCV NS31406 epitope. In chronic and past HCV infection, proportions of total DP T cells and PD-1+ DP T cells were similar but significantly higher than in healthy controls. DP T cells were more likely to be PD-1+ than either CD4+ or CD8+ single positive (SP) T cells. HCV-specific cells were present in higher proportions among DP T cells than among CD8+ SP T cells in both patient groups. Furthermore, while the majority of HCV-specific DP T cells were PD-1+, the proportion of HCV-specific CD8+ T cells which were PD-1+ was 4.9 and 1.9 times lower (chronic and past infection, respectively). PD-1 and Tim-3 were predominantly expressed on CD4high CD8low and CD4low CD8high cells, respectively, and co-expression of both markers was uncommon.
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Affiliation(s)
- Kamila Caraballo Cortés
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Sylwia Osuch
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Agnieszka Pawełczyk
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Justyna Kaźmierczak
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Maciej Janiak
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Joanna Jabłońska
- Clinic for Infectious, Tropical Diseases and HepatologyMedical University of WarsawWarsawPoland
| | - Khalil Nazzal
- Clinic for Infectious, Tropical Diseases and HepatologyMedical University of WarsawWarsawPoland
| | - Anna Stelmaszczyk‐Emmel
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental AgeMedical University of WarsawWarsawPoland
| | - Hanna Berak
- Outpatient ClinicWarsaw Hospital for Infectious DiseasesWarsawPoland
| | - Iwona Bukowska‐Ośko
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Marcin Paciorek
- Department of Infectious DiseasesMedical University of WarsawWarsawPoland
| | - Tomasz Laskus
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic DiseasesMedical University of WarsawWarsawPoland
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Brochado-Kith Ó, Gómez Sanz A, Real LM, Crespo García J, Ryan Murúa P, Macías J, Cabezas González J, Troya J, Pineda JA, Arias Loste MT, Díez Viñas V, Jiménez-Sousa MÁ, Medrano de Dios LM, Cuesta De la Plaza I, Monzón Fernández S, Resino García S, Fernández-Rodríguez A. MicroRNA Profile of HCV Spontaneous Clarified Individuals, Denotes Previous HCV Infection. J Clin Med 2019; 8:jcm8060849. [PMID: 31207946 PMCID: PMC6617112 DOI: 10.3390/jcm8060849] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 12/12/2022] Open
Abstract
Factors involved in the spontaneous cleareance of a hepatitis C (HCV) infection are related to both HCV and the interaction with the host immune system, but little is known about the consequences after a spontaneous resolution. The main HCV extrahepatic reservoir is the peripheral blood mononuclear cells (PBMCs), and their transcriptional profile provides us information of innate and adaptive immune responses against an HCV infection. MicroRNAs regulate the innate and adaptive immune responses, and they are actively involved in the HCV cycle. High Throughput sequencing was used to analyze the miRNA profiles from PBMCs of HCV chronic naïve patients (CHC), individuals that spontaneously clarified HCV (SC), and healthy controls (HC). We did not find any differentially expressed miRNAs between SC and CHC. However, both groups showed similar expression differences (21 miRNAs) with respect to HC. This miRNA signature correctly classifies HCV-exposed (CHC and SC) vs. HC, with the has-miR-21-3p showing the best performance. The potentially targeted molecular pathways by these 21 miRNAs mainly belong to fatty acids pathways, although hippo signaling, extracellular matrix (ECM) interaction, proteoglycans-related, and steroid biosynthesis pathways were also altered. These miRNAs target host genes involved in an HCV infection. Thus, an HCV infection promotes molecular alterations in PBMCs that can be detected after an HCV spontaneous resolution, and the 21-miRNA signature is able to identify HCV-exposed patients (either CHC or SC).
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Affiliation(s)
- Óscar Brochado-Kith
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Alicia Gómez Sanz
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Luis Miguel Real
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - Javier Crespo García
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Pablo Ryan Murúa
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - Juan Macías
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - Joaquín Cabezas González
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Jesús Troya
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - Juan Antonio Pineda
- Unidad Clínica de Enfermedades Infecciosas, Hospital Universitario de Valme, 41014 Sevilla, Spain.
| | - María Teresa Arias Loste
- Gastroenterology and Hepatology Department, Hospital Universitario Marques de Valdecilla, 39008 Santander, Spain.
- Institute Valdecilla (IDIVAL), School of Medicine, University of Cantabria, 39005 Santander, Spain.
| | - Victorino Díez Viñas
- Internal Medicine Service, University Hospital Infanta Leonor, School of Medicine, Complutense University of Madrid, Gregorio Marañón Health Research Institute, 28009 Madrid, Spain.
| | - María Ángeles Jiménez-Sousa
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Luz María Medrano de Dios
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Isabel Cuesta De la Plaza
- Bioinformatics Unit, Unidades Comunes Científico Técnicas, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Sara Monzón Fernández
- Bioinformatics Unit, Unidades Comunes Científico Técnicas, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Salvador Resino García
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
| | - Amanda Fernández-Rodríguez
- Unit of Viral Infection and Immunity, National Center for Microbiology, Institute of Health Carlos III, Majadahonda, 28220 Madrid, Spain.
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Chigbu DI, Loonawat R, Sehgal M, Patel D, Jain P. Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence. Cells 2019; 8:cells8040376. [PMID: 31027278 PMCID: PMC6523734 DOI: 10.3390/cells8040376] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/25/2019] [Accepted: 04/17/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.
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Affiliation(s)
- DeGaulle I Chigbu
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
- Pennsylvania College of Optometry at Salus University, Elkins Park, PA 19027, USA.
| | - Ronak Loonawat
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Mohit Sehgal
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
| | - Dip Patel
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
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Antibody and Memory B Cell Responses in Hepatitis E Recovered Individuals, 1-30 Years Post Hepatitis E Virus Infection. Sci Rep 2019; 9:4090. [PMID: 30858463 PMCID: PMC6411774 DOI: 10.1038/s41598-019-40603-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 02/15/2019] [Indexed: 01/16/2023] Open
Abstract
Generation and persistence of anti-hepatitis E virus (HEV) antibodies are synonymous with the development of immunity and considered as correlates of protection against HEV infection. However, issues like longevity of immunological memory following recovery from hepatitis E still remains a puzzle. It is critical to understand whether anamnestic response exists for protection from HEV re-infection. The levels and persistence of anti-HEV antibodies were assessed in hepatitis E recovered individuals 1–30 years post HEV infection. The frequencies and functionality of recombinant HEV capsid protein (rORF2p)-stimulated memory B and T cells were also investigated 1–16 years post infection. Anti-HEV antibodies persisted in 91% of hepatitis E recovered individuals. HEV-specific memory B cell responses were detected in 95% of seropositive hepatitis E recovered individuals. CD4+ and CD8+ T cells displayed an effector memory cell phenotype in hepatitis E recovered individuals. In conclusion, long-lived anti-HEV antibodies and HEV-specific memory B cells are maintained for several years in hepatitis E recovered individuals. Involvement of CD4+ and CD8+ effector memory T cells is an important observation since it is inextricably linked to long-lasting protective immunity. In addition to anti-HEV antibodies, possible role of memory B cell response against HEV re-infection could also be considered.
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Monette A, Mouland AJ. T Lymphocytes as Measurable Targets of Protection and Vaccination Against Viral Disorders. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2019; 342:175-263. [PMID: 30635091 PMCID: PMC7104940 DOI: 10.1016/bs.ircmb.2018.07.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Continuous epidemiological surveillance of existing and emerging viruses and their associated disorders is gaining importance in light of their abilities to cause unpredictable outbreaks as a result of increased travel and vaccination choices by steadily growing and aging populations. Close surveillance of outbreaks and herd immunity are also at the forefront, even in industrialized countries, where previously eradicated viruses are now at risk of re-emergence due to instances of strain recombination, contractions in viral vector geographies, and from their potential use as agents of bioterrorism. There is a great need for the rational design of current and future vaccines targeting viruses, with a strong focus on vaccine targeting of adaptive immune effector memory T cells as the gold standard of immunity conferring long-lived protection against a wide variety of pathogens and malignancies. Here, we review viruses that have historically caused large outbreaks and severe lethal disorders, including respiratory, gastric, skin, hepatic, neurologic, and hemorrhagic fevers. To observe trends in vaccinology against these viral disorders, we describe viral genetic, replication, transmission, and tropism, host-immune evasion strategies, and the epidemiology and health risks of their associated syndromes. We focus on immunity generated against both natural infection and vaccination, where a steady shift in conferred vaccination immunogenicity is observed from quantifying activated and proliferating, long-lived effector memory T cell subsets, as the prominent biomarkers of long-term immunity against viruses and their associated disorders causing high morbidity and mortality rates.
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Rehermann B, Thimme R. Insights From Antiviral Therapy Into Immune Responses to Hepatitis B and C Virus Infection. Gastroenterology 2019; 156:369-383. [PMID: 30267712 PMCID: PMC6340757 DOI: 10.1053/j.gastro.2018.08.061] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/05/2018] [Accepted: 08/21/2018] [Indexed: 12/17/2022]
Abstract
There are 257 million persons worldwide with chronic hepatitis B virus (HBV) infection, a leading causes of liver cancer. Almost all adults with acute HBV infection have a rapid immune response to the virus, resulting in life-long immunity, but there is no cure for individuals with chronic HBV infection, which they acquire during early life. The mechanisms that drive the progression of HBV through distinct clinical phases to end-stage liver disease are poorly understood. Likewise, it is not clear whether and how immune responses can be modulated to allow control and/or clearance of intrahepatic HBV DNA. We review the innate and adaptive immune responses to acute and chronic HBV infections and responses to antiviral therapy. Comparisons with hepatitis C virus infection provide insights into the reversibility of innate inflammatory responses and the potential for successful therapy to recover virus-specific memory immune responses.
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Affiliation(s)
- Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
| | - Robert Thimme
- Klinik für Innere Medizin II, University Hospital Freiburg, Faculty of Medicine, Hugstetter Straße 55, 79106 Freiburg, Germany
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40
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Villani R, Vendemiale G, Serviddio G. Molecular Mechanisms Involved in HCC Recurrence after Direct-Acting Antiviral Therapy. Int J Mol Sci 2018; 20:ijms20010049. [PMID: 30583555 PMCID: PMC6337751 DOI: 10.3390/ijms20010049] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.
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MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Hepacivirus/drug effects
- Hepacivirus/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Interferons/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Macrophages/drug effects
- Monocytes/drug effects
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/virology
- Neutrophils/drug effects
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gianluigi Vendemiale
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gaetano Serviddio
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
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Pawlotsky JM, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018; 69:461-511. [PMID: 29650333 DOI: 10.1016/j.jhep.2018.03.026] [Citation(s) in RCA: 1200] [Impact Index Per Article: 171.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Ayoub HH, Chemaitelly H, Omori R, Abu-Raddad LJ. Hepatitis C virus infection spontaneous clearance: Has it been underestimated? Int J Infect Dis 2018; 75:60-66. [PMID: 30031139 DOI: 10.1016/j.ijid.2018.07.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 07/11/2018] [Accepted: 07/11/2018] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Hepatitis C virus (HCV) clearance rate (fclearance) is defined as the proportion of infected persons who will spontaneously clear their infection after acute infection. We aimed to estimate fclearance using a novel approach that avoids limitations in existing estimates, and to clarify the link between fclearance and HCV viremic rate-the latter being the proportion of RNA positivity among those antibody positive. METHODS A mathematical model was developed to describe HCV transmission. fclearance was estimated by fitting the model to probability-based and nationally representative population-based data for Egypt (Egypt 2008 and Egypt 2015) and USA (NHANES A and NHANES B). Uncertainty and sensitivity analyses were conducted. RESULTS fclearance was estimated at 39.9% (95% uncertainty interval (UI): 34.3%-46.4%) and 33.5% (95% UI: 29.2%-38.3%) for Egypt 2008 and Egypt 2015 data, respectively; and at 29.6% (23.0%-37.1%) and 39.9% (31.2%-51.0%) for NHANES A and NHANES B data, respectively. fclearance was found related to HCV viremic rate through (approximately) the formula fclearance=1.16 (1-HCV viremic rate). HCV viremic rate was higher with higher risk of HCV exposure. Robustness of results was demonstrated in uncertainty and sensitivity analyses. CONCLUSION One-third of HCV-infected persons clear their infection spontaneously, higher than earlier estimates-the immune-system capacity to clear HCV infection may have been underestimated.
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Affiliation(s)
- Houssein H Ayoub
- Infectious Disease Epidemiology Group, Weill Cornell Medicine - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar; Department of Healthcare Policy and Research, Weill Cornell Medicine, Cornell University, New York, USA; Department of Mathematics, Statistics, and Physics, Qatar University, Doha, Qatar.
| | - Hiam Chemaitelly
- Infectious Disease Epidemiology Group, Weill Cornell Medicine - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar
| | - Ryosuke Omori
- Division of Bioinformatics, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan; JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
| | - Laith J Abu-Raddad
- Infectious Disease Epidemiology Group, Weill Cornell Medicine - Qatar, Cornell University, Qatar Foundation - Education City, Doha, Qatar; Department of Healthcare Policy and Research, Weill Cornell Medicine, Cornell University, New York, USA.
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Shoukry NH. Hepatitis C Vaccines, Antibodies, and T Cells. Front Immunol 2018; 9:1480. [PMID: 30002657 PMCID: PMC6031729 DOI: 10.3389/fimmu.2018.01480] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/14/2018] [Indexed: 12/22/2022] Open
Abstract
The development of vaccines that protect against persistent hepatitis C virus (HCV) infection remain a public health priority. The broad use of highly effective direct-acting antivirals (DAAs) is unlikely to achieve HCV elimination without vaccines that can limit viral transmission. Two vaccines targeting either the antibody or the T cell response are currently in preclinical or clinical trials. Next-generation vaccines will likely involve a combination of these two strategies. This review summarizes the state of knowledge about the immune protective role of HCV-specific antibodies and T cells and the current vaccine strategies. In addition, it discusses the potential efficacy of vaccination in DAA-cured individuals. Finally, it summarizes the challenges to vaccine development and the collaborative efforts required to overcome them.
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Affiliation(s)
- 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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Sengupta S, Siliciano RF. Targeting the Latent Reservoir for HIV-1. Immunity 2018; 48:872-895. [PMID: 29768175 PMCID: PMC6196732 DOI: 10.1016/j.immuni.2018.04.030] [Citation(s) in RCA: 253] [Impact Index Per Article: 36.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 04/26/2018] [Accepted: 04/26/2018] [Indexed: 02/07/2023]
Abstract
Antiretroviral therapy can effectively block HIV-1 replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to a cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will most likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, a cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here could pave the way.
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Affiliation(s)
- Srona Sengupta
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Immunology and Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Robert F Siliciano
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
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Sacks-Davis R, Pedrana AE, Scott N, Doyle JS, Hellard ME. Eliminating HIV/HCV co-infection in gay and bisexual men: is it achievable through scaling up treatment? Expert Rev Anti Infect Ther 2018; 16:411-422. [PMID: 29722275 DOI: 10.1080/14787210.2018.1471355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Broad availability of direct-acting antiviral therapy for hepatitis C virus (HCV) raises the possibility that HCV prevalence and incidence can be reduced through scaling-up treatment, leading to the elimination of HCV. High rates of linkage to HIV care among HIV-infected gay and bisexual men may facilitate high uptake of HCV treatment, possibly making HCV elimination more achievable in this group. Areas covered: This review covers HCV elimination in HIV-infected gay and bisexual men, including epidemiology, spontaneous clearance and long term sequelae in the absence of direct-acting antiviral therapy; direct-acting antiviral therapy uptake and effectiveness in this group; HCV reinfection following successful treatment; and areas for further research. Expert commentary: Early data from the direct-acting antiviral era suggest that treatment uptake is increasing among HIV infected GBM, and SVR rates are very promising. However, in order to sustain current treatment rates, additional interventions at the behavioral, physician, and structural levels may be required to increase HCV diagnosis, including prompt detection of HCV reinfection. Timely consideration of these issues is required to maximize the population-level impact of HCV direct-acting antiviral therapy. Potential HCV transmissions from HIV-uninfected GBM, across international borders, and from those who are not GBM also warrant consideration.
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Affiliation(s)
- Rachel Sacks-Davis
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,b Department of Medicine , University of Melbourne , Parkville , Australia
| | - Alisa E Pedrana
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,c Department of Epidemiology and Preventive Medicine , Monash University , Melbourne , Australia
| | - Nick Scott
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,c Department of Epidemiology and Preventive Medicine , Monash University , Melbourne , Australia
| | - Joseph S Doyle
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,d Central Clinical School , Monash University , Melbourne , Australia
| | - Margaret E Hellard
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,c Department of Epidemiology and Preventive Medicine , Monash University , Melbourne , Australia
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46
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Dustin LB. Innate and Adaptive Immune Responses in Chronic HCV Infection. Curr Drug Targets 2018; 18:826-843. [PMID: 26302811 DOI: 10.2174/1389450116666150825110532] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) remains a public health problem of global importance, even in the era of potent directly-acting antiviral drugs. In this chapter, I discuss immune responses to acute and chronic HCV infection. The outcome of HCV infection is influenced by viral strategies that limit or delay the initiation of innate antiviral responses. This delay may enable HCV to establish widespread infection long before the host mounts effective T and B cell responses. HCV's genetic agility, resulting from its high rate of replication and its error prone replication mechanism, enables it to evade immune recognition. Adaptive immune responses fail to keep up with changing viral epitopes. Neutralizing antibody epitopes may be hidden by decoy structures, glycans, and lipoproteins. T cell responses fail due to changing epitope sequences and due to exhaustion, a phenomenon that may have evolved to limit immune-mediated pathology. Despite these difficulties, innate and adaptive immune mechanisms do impact HCV replication. Immune-mediated clearance of infection is possible, occurring in 20-50% of people who contract the disease. New developments raise hopes for effective immunological interventions to prevent or treat HCV infection.
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Affiliation(s)
- Lynn B Dustin
- University of Oxford, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom
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47
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Aebi-Popp K, Wandeler G, Salazar-Vizcaya L, Metzner K, Stöckle M, Cavassini M, Hoffmann M, Lüthi A, Suter F, Bernasconi E, Fehr J, Furrer H, Rauch A. Rapid decline of anti-hepatitis C virus (HCV) antibodies following early treatment of incident HCV infections in HIV-infected men who have sex with men. HIV Med 2018; 19:420-425. [PMID: 29573533 DOI: 10.1111/hiv.12602] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2018] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Following clearance of incident hepatitis C virus (HCV) infections, HCV antibody levels may decline, resulting in seroreversion. It is unclear to what extent HCV antibody level trajectories differ between patients with treatment-induced sustained virological response (SVR), those with spontaneous clearance and those with untreated replicating HCV infection. We investigated HCV antibody level dynamics in HIV-infected MSM with different clinical outcomes. METHODS We investigated anti-HCV antibody level dynamics following an incident HCV infection in 67 HIV-infected men who have sex with men (MSM) with different clinical outcomes: SVR (n = 33), spontaneous clearance (n = 12), and untreated replicating infection (n = 22). Antibody levels were measured at the time of HCV diagnosis, and at yearly intervals for 3 years thereafter. RESULTS At baseline, median HCV antibody levels were similar in the three groups: 13.4, 13.8 and 13.5 sample to cut-off (S/CO) for SVR, spontaneous clearance and untreated infection, respectively. Over 3 years of follow-up, SVR was associated with a more pronounced decrease in anti-HCV levels compared with spontaneous clearance and untreated infection [median decline 71% [interquartile range (IQR: 43-87%), 38% (IQR: 29-60%) and 12% (IQR: 9-22%), respectively; P < 0.001]. Seroreversions occurred in five of 33 (15%) patients with SVR and in one of 12 (8%) with spontaneous clearance. A shorter delay between time of infection and treatment start correlated with higher rates of decline in antibody levels. Seven patients experienced a reinfection. CONCLUSIONS Treatment-induced HCV clearance was associated with a more pronounced decline in anti-HCV antibody levels and with higher rates of seroreversion compared with spontaneous clearance or untreated replicating HCV infection among HIV-infected MSM with incident HCV infections. Rapid clearance of HCV RNA following early HCV treatment might impair the development of persistent antibody titres.
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Affiliation(s)
- K Aebi-Popp
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - G Wandeler
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - L Salazar-Vizcaya
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - K Metzner
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Institute of Medical Virology, University of Zurich, Zurich, Switzerland
| | - M Stöckle
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - M Cavassini
- Division of Infectious Diseases, University Hospital Lausanne, Lausanne, Switzerland
| | - M Hoffmann
- Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St Gallen, St Gallen, Switzerland
| | - A Lüthi
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - F Suter
- Institute for Infectious Diseases, University of Bern, Bern, Switzerland
| | - E Bernasconi
- Division of Infectious Diseases, Regional Hospital Lugano, Lugano, Switzerland
| | - J Fehr
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - H Furrer
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - A Rauch
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
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48
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Ow MM, Hegazy D, Warshow UM, Cramp ME. Enhanced natural killer cell activity is found in exposed uninfected recipients of hepatitis C-contaminated blood. J Viral Hepat 2018; 25:245-253. [PMID: 29063663 DOI: 10.1111/jvh.12810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/04/2017] [Indexed: 12/17/2022]
Abstract
A minority of injecting drug users, termed exposed uninfected, are resistant to hepatitis C (HCV) infection despite repeated low-dose exposures. We identify for the first time a cohort of blood recipients who remained uninfected despite large-dose exposure to HCV-contaminated blood and characterize immune factors that may confer protection. Of 1340 blood recipients from the English Look Back database who were transfused HCV-contaminated blood, we identified 8 who remained uninfected. In these 8 exposed uninfecteds, we characterized their natural killer (NK) cell populations and HCV-specific T-cell responses. Findings were compared with 10 spontaneous resolvers of HCV infection, 10 patients with chronic HCV infection and 10 healthy controls. Exposed uninfecteds had significantly greater numbers of NK cells with the activating receptor NKp30+ on CD56bright and CD56dim subsets compared with other groups (P < .05). Following interleukin-2 activation, NK cells of exposed uninfecteds had enhanced cytotoxicity that positively correlated with NKp30 expression (P = .02). Differences in NKp80 and KIR2DL3 expression were also observed. HCV-specific T-cell responses were observed in some exposed uninfecteds but of low amplitude. Exposure without infection following transfusion of HCV-contaminated blood is a very rare phenomenon and suggests a high level of resistance to infection. Enhanced NK cell activation and killing, with weak HCV-specific T-cell responses, were observed many years after exposure in uninfected recipients and may contribute to protection from HCV acquisition, although additional protective factors are being sought in this important cohort.
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Affiliation(s)
- M M Ow
- Department of Medicine, University of Auckland, Auckland, New Zealand.,Hepatology Research Group, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - D Hegazy
- Hepatology Research Group, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - U M Warshow
- Hepatology Research Group, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - M E Cramp
- Hepatology Research Group, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.,Southwest Liver Unit, Derriford Hospital, Plymouth Hospitals NHS Trust, Plymouth, UK
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49
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Pallarés C, Carvalho-Gomes Â, Hontangas V, Conde I, Di Maira T, Aguilera V, Benlloch S, Berenguer M, López-Labrador FX. Performance of the OraQuick Hepatitis C virus antibody test in oral fluid and fingerstick blood before and after treatment-induced viral clearance. J Clin Virol 2018. [PMID: 29525634 DOI: 10.1016/j.jcv.2018.02.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND A reliable population screening strategy for hepatitis C virus (HCV) infection may be based in easy-to-use point-of-care (POC) tests for HCV antibodies, but validation data is needed before their potential widespread use in primary care or outreach practice. Besides, the sensitivity of these POC tests in patients with spontaneous or treatment-induced viral clearance is unknown. OBJECTIVES To test the performance of a non-invasive POC anti-HCV test (OraQuick HCV rapid test) in oral mucosal transudate (OMT) and fingerstick blood from patients with known anti-HCV serostatus and with or without active viremia (after treatment-induced clearance). STUDY DESIGN A risk factor questionnaire was collected from 317 consecutive patients (anti-HCV positive/HCV-RNA positive n = 107; anti-HCV positive/HCV-RNA negative after antiviral treatment n = 107; anti-HCV negative with other liver diseases n = 109) before performing the OraQuick HCV rapid test in OMT (n = 317) and fingerstick blood (n = 251). We calculated the sensitivity and specificity of the test by using anti-HCV serostatus as the reference gold-standard. RESULTS Among all anti-HCV seropositive patients, the clinical sensitivity and specificity of the OraQuick HCV rapid test in OMT was 89.9% and 100%, respectively. In fingerstick blood, the sensitivity improved to 98.8%. The sensitivity was higher in OMT (97.2%) in anti-HCV seropositive patients who were viremic as compared to that in non-viremic individuals (82.2%). In contrast, there were no significant differences in sensitivity between viremic and non-viremic individuals when testing fingerstick blood. Finally, extension of the read time to 40 min enhanced the sensitivity, especially in OMT (up to 94.7%) and in the subgroup of non-viremic, anti-HCV-positive patients (up to 90.1%). CONCLUSIONS The OraQuick HCV rapid test in OMT has a high sensitivity and specificity for detecting active HCV infection that decreases substantially in anti-HCV positive/HCV-RNA negative patients with treatment-induced viral clearance. For these individuals, extension of read times and testing fingerstick blood showed improved sensitivity.
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Affiliation(s)
- Carmina Pallarés
- Liver Transplantation and Hepatology Laboratory, Instituto Investigación Sanitaria La Fe, Valencia, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Ângela Carvalho-Gomes
- Liver Transplantation and Hepatology Laboratory, Instituto Investigación Sanitaria La Fe, Valencia, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Vanessa Hontangas
- Liver Transplantation and Hepatology Laboratory, Instituto Investigación Sanitaria La Fe, Valencia, Spain
| | - Isabel Conde
- Liver Transplantation and Hepatology Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Tomasso Di Maira
- Liver Transplantation and Hepatology Laboratory, Instituto Investigación Sanitaria La Fe, Valencia, Spain
| | - Victoria Aguilera
- Liver Transplantation and Hepatology Laboratory, Instituto Investigación Sanitaria La Fe, Valencia, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Liver Transplantation and Hepatology Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Salvador Benlloch
- Liver Transplantation and Hepatology Laboratory, Instituto Investigación Sanitaria La Fe, Valencia, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Liver Transplantation and Hepatology Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Marina Berenguer
- Liver Transplantation and Hepatology Laboratory, Instituto Investigación Sanitaria La Fe, Valencia, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Liver Transplantation and Hepatology Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain; Department of Medicine, Medical School, Universitat de València, Spain
| | - F Xavier López-Labrador
- Virology Laboratory, Genomics and Health Area, Center for Public Health Research, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO-Public Health), Generalitat Valenciana, Valencia, Spain; CIBEResp, Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Spain.
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50
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Al-Ayoubi J, Behrendt P, Bremer B, Suneetha PV, Gisa A, Rinker F, Manns MP, Cornberg M, Wedemeyer H, Kraft ARM. Hepatitis E virus ORF 1 induces proliferative and functional T-cell responses in patients with ongoing and resolved hepatitis E. Liver Int 2018; 38:266-277. [PMID: 28718943 DOI: 10.1111/liv.13521] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 07/08/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Hepatitis E virus (HEV) is a major cause of acute viral hepatitis with >3 million symptomatic cases per year accounting for 70 000 HEV-related deaths. HEV-specific T-cell responses have been investigated against structural proteins expressed by open reading frames (ORF) 2 and 3. T-cell responses against non-structural HEV proteins encoded by ORF1 are hardly studied. The aim of this study was to determine HEV ORF1-specific T-cell responses in comparison to ORF2/3 in patients exposed to HEV. METHODS HEV-specific CD4+ and CD8+ T-cell responses against HEV genotype 3 were investigated in patients with acute and chronic hepatitis E as well as in HEV seropositive and seronegative individuals. HEV-specific T-cell responses were determined by proliferation and intracellular cytokine assay upon stimulation of PBMCs with HEV-specific overlapping peptide pools spanning the entire HEV genome. HEV-antigen was measured using an anti-HEV antigen-specific ELISA. RESULTS Broad HEV ORF1-specific T-cell responses were detected in patients with acute, resolved and chronic hepatitis E without distinct dominant regions. The magnitude and frequency in recognition of ORF1-specific T-cell responses were similar compared to responses against HEV ORF2/3. Longitudinal studies of HEV-specific T-cell responses displayed similar behaviour against structural and non-structural proteins. HEV-antigen levels were inversely correlated with HEV-specific T-cell responses. CONCLUSIONS HEV-specific T-cell responses are detectable against the entire HEV genome including the non-structural proteins. HEV-specific T-cell responses are associated with control of HEV infection. These findings have implications for the design of HEV vaccines.
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Affiliation(s)
- Jana Al-Ayoubi
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Anett Gisa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Franziska Rinker
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
| | - Anke R M Kraft
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Hannover, Germany
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