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Li J, Vranjkovic A, Read D, Delaney SP, Stanford WL, Cooper CL, Crawley AM. Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction. Front Immunol 2024; 15:1375485. [PMID: 38887299 PMCID: PMC11180750 DOI: 10.3389/fimmu.2024.1375485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/19/2024] [Indexed: 06/20/2024] Open
Abstract
Background The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. Methods RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry. Results In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-β response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance. Conclusions This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.
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Affiliation(s)
- Jiafeng Li
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
| | - Agatha Vranjkovic
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Daniel Read
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Sean P. Delaney
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - William L. Stanford
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
| | - Curtis L. Cooper
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Angela M. Crawley
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, ON, Canada
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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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Casey JL, Dore GJ, Grebely J, Matthews GV, Cherepanov V, Martinello M, Marks P, Janssen HLA, Hansen BE, Kaul R, MacParland SA, Gehring AJ, Feld JJ. Hepatitis C virus-specific immune responses following direct-acting antivirals administered during recent hepatitis C virus infection. J Viral Hepat 2023; 30:64-72. [PMID: 36302162 DOI: 10.1111/jvh.13761] [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: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 12/09/2022]
Abstract
Individuals who spontaneously clear hepatitis C virus (HCV) infection have demonstrated evidence of partial protective immunity, whereas treatment-induced clearance provides little or no protection against reinfection. We aimed to investigate whether treatment of acute HCV infection with direct-acting antivirals (DAA) prevents establishment of, or reverses, T-cell exhaustion, leading to a virus-specific T-cell immune profile more similar to that seen in spontaneous clearance. The magnitude and breadth of HCV-specific T-cell responses before and after DAA or interferon-based therapy in acute or chronic HCV were compared to those of participants with spontaneous clearance of infection, using Enzyme-linked Immunospot (ELISPOT). PBMCs were available for 55 patients comprising 4 groups: spontaneous clearance (n = 17), acute interferon (n = 14), acute DAA (n = 13) and chronic DAA (n = 11). After controlling for sex, the magnitude of post-treatment HCV-specific responses after acute DAA treatment was greater than after chronic DAA or acute IFN treatment and similar to those found in spontaneous clearers. However, spontaneous clearers responded to more HCV peptide pools indicating greater breadth of response. In conclusion, early treatment with DAAs may prevent or reverse some degree of immune exhaustion and result in stronger HCV-specific responses post-treatment. However, individuals with spontaneous clearance had broader HCV-specific responses.
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Affiliation(s)
- Julia L Casey
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Gregory J Dore
- The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Jason Grebely
- The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Gail V Matthews
- The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Vera Cherepanov
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | | | - Philippa Marks
- The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.,Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Rupert Kaul
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, University Health Network, Toronto, Ontario, Canada
| | - Sonya A MacParland
- Departments of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Adam J Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.,Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.,Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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Carvalho-Gomes Â, Cubells A, Pallarés C, Corpas-Burgos F, Berenguer M, Aguilera V, López-Labrador FX. Cytomegalovirus specific polyfunctional T-cell responses expressing CD107a predict control of CMV infection after liver transplantation. Cell Immunol 2021; 371:104455. [PMID: 34864514 DOI: 10.1016/j.cellimm.2021.104455] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/16/2021] [Accepted: 11/04/2021] [Indexed: 11/03/2022]
Abstract
Cytomegalovirus (CMV) viral load after liver transplantation (LT) is controlled by cell mediated immune responses (CMI). Quantification of CMV-specific T-cells may identify patients who control CMV spontaneously and avoid expensive and potentially toxic antiviral therapies. Prospective post-LT clinical, virological and immunological monitoring was carried out up to 1-year post-LT in a cohort of adult recipients. The CMV-specific T-cell response was characterized using flow cytometry intracellular cytokine staining in 49 LT recipients-R (79.6% R+, 20.4% R-). CMV infection occurred in 24 patients (18 D+/R+ and 6 D+/R-). Only patients with undetectable polyfunctional CMV-specific CD4+ T-cells developed CMV infection. Predictive models showed that polyfunctional CMV-specific CD4+ T-cells pre-existing before LT are protective for CMV reactivation posttransplantation. Quantitation of CD4+ T-cell responses to CMV may be a useful marker for spontaneous control of viral replication to tailor antiviral prophylaxis after LT.
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Affiliation(s)
- Ângela Carvalho-Gomes
- Liver Transplantation and Hepatology Laboratory, Hepatology, HBP Surgery and Transplant Unit, Instituto Investigación Sanitaria La Fe, Hospital U. y P. La Fe, València, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Spain.
| | - Almudena Cubells
- Liver Transplantation and Hepatology Laboratory, Hepatology, HBP Surgery and Transplant Unit, Instituto Investigación Sanitaria La Fe, Hospital U. y P. La Fe, València, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Spain
| | - Carmina Pallarés
- Liver Transplantation and Hepatology Laboratory, Hepatology, HBP Surgery and Transplant Unit, Instituto Investigación Sanitaria La Fe, Hospital U. y P. La Fe, València, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Spain
| | - Francisca Corpas-Burgos
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO-Public Health), Av. Catalunya, 21, 46020 Valencia, Spain; CIBEResp, Instituto de Salud Carlos III, Madrid, Spain
| | - Marina Berenguer
- Liver Transplantation and Hepatology Laboratory, Hepatology, HBP Surgery and Transplant Unit, Instituto Investigación Sanitaria La Fe, Hospital U. y P. La Fe, València, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Spain; Liver Transplantation and Hepatology Unit, Hospital Universitario y Politécnico La Fe, València, Spain; Department of Medicine, University of Valencia Medical School, Valencia, Spain
| | - Victoria Aguilera
- Liver Transplantation and Hepatology Laboratory, Hepatology, HBP Surgery and Transplant Unit, Instituto Investigación Sanitaria La Fe, Hospital U. y P. La Fe, València, Spain; CIBERehd, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Spain; Liver Transplantation and Hepatology Unit, Hospital Universitario y Politécnico La Fe, València, Spain
| | - F Xavier López-Labrador
- CIBEResp, Instituto de Salud Carlos III, Madrid, Spain; Virology Laboratory, Genomics and Health Area, Centro Superior de Salud Pública, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunidad Valenciana (FISABIO-Public Health), Conselleria de Sanitat, València, Spain
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5
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Kuriry H, Casey J, Krassenburg L, La D, Kuczynski M, Shah H, Janssen HLA, Hansen BE, Feld JJ. Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection. Clin Gastroenterol Hepatol 2021; 19:2398-2406.e1. [PMID: 32629131 DOI: 10.1016/j.cgh.2020.06.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/11/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Direct-acting antivirals (DAAs) cure most cases of chronic hepatitis C virus (HCV) infection. However, a small percentage of patients relapse with reappearance of viremia after a full course of therapy. Although most who relapse require retreatment, some patients spontaneously clear HCV without additional therapy. We studied patients who relapsed with detectable HCV RNA after a full course of DAA therapy and then spontaneously cleared the HCV infection without retreatment. METHODS We performed a case-control study of patients who spontaneously cleared chronic HCV infection following a documented relapse after DAA therapy at the Toronto Centre for Liver Disease, from January 2014 through December 2017. We collected clinical information at baseline, 12 weeks after treatment, and 6 months after relapse and compared data among spontaneous clearers, patients with persistent relapse, and patients who achieved a sustained virologic response to therapy 12 weeks after treatment (SVR12). The strength and breadth of interferon gamma cytokine secretion by HCV-specific T cells from peripheral blood were quantified using the ELISPOT assay. RESULTS Of the 1032 individuals with chronic HCV infection who were treated with DAAs, 93 patients had a documented relapse. Of these patients, 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy. The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse, much like patients with an SVR12. There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses. CONCLUSIONS In a case-control study of patients who spontaneously cleared chronic HCV infection following a relapse after DAA therapy, we found that it is important to confirm viremia prior to retreatment after the relapse-particularly for individuals with low levels of HCV RNA and normal or near-normal levels of alanine aminotransferase after treatment.
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Affiliation(s)
- Hadi Kuriry
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Julia Casey
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Lisette Krassenburg
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Danie La
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Magdalena Kuczynski
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, Toronto, Ontario, Canada
| | - Hemant Shah
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, Toronto, Ontario, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Toronto Viral Hepatitis Care Network, Toronto, Ontario, Canada.
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6
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Memory-like HCV-specific CD8 + T cells retain a molecular scar after cure of chronic HCV infection. Nat Immunol 2021; 22:229-239. [PMID: 33398179 DOI: 10.1038/s41590-020-00817-w] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/06/2020] [Indexed: 01/05/2023]
Abstract
In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8+ T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor-progeny relationship between memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8+ T cell response. However, an exhausted core signature of memory-like CD8+ T cells was still detectable, including, to a smaller extent, in HCV-specific CD8+ T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8+ T cells even after the cessation of chronic antigen stimulation.
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7
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Thimme R. T cell immunity to hepatitis C virus: Lessons for a prophylactic vaccine. J Hepatol 2021; 74:220-229. [PMID: 33002569 DOI: 10.1016/j.jhep.2020.09.022] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/22/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022]
Abstract
There is consensus that HCV-specific T cells play a central role in the outcome (clearance vs. persistence) of acute infection and that they contribute to protection against the establishment of persistence after reinfection. However, these T cells often fail and the virus can persist, largely as a result of T cell exhaustion and the emergence of viral escape mutations. Importantly, HCV cure by direct-acting antivirals does not lead to a complete reversion of T cell exhaustion and thus HCV reinfections can occur. The current lack of detailed knowledge about the immunological determinants of viral clearance, persistence and protective immunity is a major roadblock to the development of a prophylactic T cell vaccine. This minireview highlights the basic concepts of successful T cell immunity, major mechanisms of T cell failure and how our understanding of these concepts can be translated into a prophylactic vaccine.
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Affiliation(s)
- Robert Thimme
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Medical Center - University of Freiburg, Faculty of Medicine, Germany.
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Perpiñán E, Pérez-Del-Pulgar S, Londoño MC, Mariño Z, Lens S, Leonel T, Bartres C, García-López M, Rodriguez-Tajes S, Forns X, Koutsoudakis G. Chronic genotype 1 hepatitis C along with cirrhosis drives a persistent imprint in virus-specific CD8 + T cells after direct-acting antiviral therapies. J Viral Hepat 2020; 27:1408-1418. [PMID: 32812325 DOI: 10.1111/jvh.13370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/03/2020] [Accepted: 07/18/2020] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis C virus (HCV) infection impairs HCV CD8+ T-cell responses, while it could influence immune responses towards unrelated viruses/vaccines (e.g. cytomegalovirus, CMV, and influenza, Flu). The aim of our study was to delineate whether restoration of these virus-specific CD8+ T cells occurs after direct-acting antiviral (DAA) therapies and particularly in patients with cirrhosis. We performed longitudinal analysis (baseline, week 4, follow-up [FU] 12 and FU48) of virus-specific CD8+ T cells by multicolour flow cytometry in HCV-cirrhotic patients undergoing DAA therapy (n = 26) after in vitro expansion with immunodominant HCV, CMV and Flu epitopes restricted by HLA-A*02. HCV noncirrhotic patients (n = 9) and healthy individuals (n = 10) served as controls. We found that the proliferative capacity of HCV-specific CD8+ T cells increased from baseline up to FU48 in a significant proportion of cirrhotic and noncirrhotic patients. Nevertheless, these cells remained poor cytokine producers in both patient groups, regardless of the down-regulation of inhibitory co-regulatory receptors in HCV-cirrhotic patients at FU48. Likewise, high expression levels of these exhaustion markers were detected in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients at all time points, albeit without affecting their proliferative capacity or cytokine production. We conclude that DAA therapies induce restoration of the proliferative capacity of HCV-specific CD8+ T cells. However, these cells remain phenotypically and functionally impaired. Contrarily, the 'exhausted' phenotype in CMV-/Flu-specific CD8+ T cells in HCV-cirrhotic patients did not associate with their functions. Larger studier with longer follow-up may elucidate whether this complex interplay influences the outcome of cirrhotic patients.
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Affiliation(s)
- Elena Perpiñán
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Sofía Pérez-Del-Pulgar
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - María-Carlota Londoño
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Thais Leonel
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Concepción Bartres
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Mireia García-López
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Sergio Rodriguez-Tajes
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - George Koutsoudakis
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
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9
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Kemming J, Thimme R, Neumann-Haefelin C. Adaptive Immune Response against Hepatitis C Virus. Int J Mol Sci 2020; 21:ijms21165644. [PMID: 32781731 PMCID: PMC7460648 DOI: 10.3390/ijms21165644] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 12/18/2022] Open
Abstract
A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.
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Affiliation(s)
- Janine Kemming
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
- Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104 Freiburg im Breisgau, Germany
| | - Robert Thimme
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79102 Freiburg im Breisgau, Germany; (J.K.); (R.T.)
- Correspondence: ; Tel.: +49-761-270-32800
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Osuch S, Metzner KJ, Caraballo Cortés K. Reversal of T Cell Exhaustion in Chronic HCV Infection. Viruses 2020; 12:v12080799. [PMID: 32722372 PMCID: PMC7472290 DOI: 10.3390/v12080799] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022] Open
Abstract
The long-term consequences of T cell responses’ impairment in chronic HCV infection are not entirely characterized, although they may be essential in the context of the clinical course of infection, re-infection, treatment-mediated viral clearance and vaccine design. Furthermore, it is unclear whether a complete reinvigoration of HCV-specific T cell response may be feasible. In most studies, attempting to reverse the effects of compromised immune response quality by specific blockades of negative immune regulators, a restoration of functional competence of HCV-specific T cells was shown. This implies that HCV-induced immune dysfunction may be reversible. The advent of highly successful, direct-acting antiviral treatment (DAA) for chronic HCV infection instigated investigation whether the treatment-driven elimination of viral antigens restores T cell function. Most of studies demonstrated that DAA treatment may result in at least partial restoration of T cell immune function. They also suggest that a complete restoration comparable to that seen after spontaneous viral clearance may not be attained, pointing out that long-term antigenic stimulation imprints an irreversible change on the T cell compartment. Understanding the mechanisms of HCV-induced immune dysfunction and barriers to immune restoration following viral clearance is of utmost importance to diminish the possible long-term consequences of chronic HCV infection.
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Affiliation(s)
- Sylwia Osuch
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-091 Warsaw, Poland;
| | - Karin J. Metzner
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland;
- Institute of Medical Virology, University of Zurich, CH-8057 Zurich, Switzerland
| | - Kamila Caraballo Cortés
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Correspondence: ; Tel.: +48-22-572-07-09; Fax: +48-22-883-10-60
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11
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Coss SL, Torres-Cornejo A, Prasad MR, Moore-Clingenpeel M, Grakoui A, Lauer GM, Walker CM, Honegger JR. CD4+ T cell restoration and control of hepatitis C virus replication after childbirth. J Clin Invest 2020; 130:748-753. [PMID: 31904583 PMCID: PMC6994162 DOI: 10.1172/jci123623] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 10/24/2019] [Indexed: 12/28/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is characterized by persistent high-level viremia and defective cellular immunity, including a lack of functional HCV-specific CD4+ T cells. We previously described an exceptional period of viral control that occurs in some chronically infected women after childbirth. Here, we investigated whether reduced HCV replication after pregnancy is associated with recovery of CD4+ T cell immunity. Class II tetramer analysis revealed significantly greater frequencies of circulating HCV-specific CD4+ T cells at 3 months postpartum in women with concurrent declines in viremia compared with those with stable viremia. These HCV-specific CD4+ T cells had an effector-memory phenotype. Inhibitory coreceptor expression on these cells corresponded to the degree of viral control. Circulating CD4+ T cells produced IL-2 and IFN-γ after HCV antigen stimulation, demonstrating Th1 functionality. These data provide direct evidence that the profound loss of HCV-specific CD4+ T cell help that results in chronic infection is reversible following pregnancy, and this recovery of CD4+ T cells is associated with at least transient control of persistent viral replication.
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Affiliation(s)
- Samantha L. Coss
- The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Almudena Torres-Cornejo
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Mona R. Prasad
- The Ohio State University College of Medicine, Columbus, Ohio, USA
| | | | | | - Georg M. Lauer
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Christopher M. Walker
- The Ohio State University College of Medicine, Columbus, Ohio, USA
- Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Jonathan R. Honegger
- The Ohio State University College of Medicine, Columbus, Ohio, USA
- Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA
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12
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Hakim MS, Rahmadika N, Jariah ROA. Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy. Rev Med Virol 2019; 30:e2094. [DOI: 10.1002/rmv.2094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/06/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Mohamad S. Hakim
- Department of Microbiology, Faculty of Medicine, Public Health and NursingUniversitas Gadjah Mada Yogyakarta Indonesia
| | - Nofri Rahmadika
- Infectious Disease Research Center, Faculty of MedicineUniversitas Padjadjaran Bandung Indonesia
| | - Rizka O. A. Jariah
- Department of Health Science, Faculty of Vocational StudiesUniversitas Airlangga Surabaya Indonesia
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13
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Vranjkovic A, Deonarine F, Kaka S, Angel JB, Cooper CL, Crawley AM. Direct-Acting Antiviral Treatment of HCV Infection Does Not Resolve the Dysfunction of Circulating CD8 + T-Cells in Advanced Liver Disease. Front Immunol 2019; 10:1926. [PMID: 31456810 PMCID: PMC6700371 DOI: 10.3389/fimmu.2019.01926] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 07/30/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection disrupts immune functions, including that of cytotoxic CD8+ T-cells which are important mediators of immune response. While HCV cure aims to eliminate long term sequelae of infection, whether direct-acting antiviral (DAA) treatment results in immune reconstitution remains unclear. We and others have reported generalized CD8+ T-cell dysfunction in chronic HCV infection and our research suggests that the degree of liver damage is a factor in this process. Our recent research indicates that liver fibrosis is not readily reversed after DAA-mediated clearance of chronic HCV infection. We therefore examined the function of circulating CD8+ T-cell subsets in chronic HCV infection in the context of liver fibrosis severity, determined by ultrasound elastography and Metavir F-score system. We observed progressive shifts in CD8+ T-cell subset distribution in HCV-infected individuals with advanced liver fibrosis (F4) compared to minimal fibrosis (F0-1) or uninfected controls, and this remained unchanged after viral cure. Impaired CD8+ T-cell function was observed as a reduced proportion of CD107+ and perforin+ late effector memory cells in HCV+(F4) and HCV+(F0-1) individuals, respectively. In HCV+(F4) individuals, nearly all CD8+ T-cell subsets had an elevated proportion of perforin+ cells while naïve cells had increased proportions of IFN-γ+ and CD107+ cells. These exaggerated CD8+ T-cell activities were not resolved when evaluated 24 weeks after completion of DAA therapy and HCV clearance. This was further supported by sustained, high levels of cell proliferation and cytolytic activity. Furthermore, DAA therapy had no effect on elevated concentrations of systemic inflammatory cytokines and decreased levels of inhibitory TGF-β in the plasma of HCV+(F4) individuals, suggesting HCV infection and advanced liver disease result in a long-lasting immune activating microenvironment. These data demonstrate that in chronic HCV infection, liver fibrosis severity is associated with generalized hyperfunctional CD8+ T-cells, particularly with perforin production and cytotoxicity, and this persists after viral clearance. Whether DAA therapy will eliminate other related long-term sequelae in HCV+(F4) individuals remains an important research question.
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Affiliation(s)
- Agatha Vranjkovic
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Felicia Deonarine
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Shaima Kaka
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Jonathan B Angel
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada
| | - Curtis L Cooper
- Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada.,School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada.,Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Angela M Crawley
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.,Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada.,Department of Biology, Carleton University, Ottawa, ON, Canada
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14
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Casey JL, Feld JJ, MacParland SA. Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection. Cells 2019; 8:cells8040317. [PMID: 30959825 PMCID: PMC6523849 DOI: 10.3390/cells8040317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022] Open
Abstract
Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.
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Affiliation(s)
- Julia L Casey
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Jordan J Feld
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
| | - Sonya A MacParland
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
- Departments of Laboratory Medicine & Pathobiology and Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada.
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15
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Abdel-Hakeem MS. Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries. Viruses 2019; 11:E106. [PMID: 30691215 PMCID: PMC6410308 DOI: 10.3390/v11020106] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/16/2022] Open
Abstract
Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.
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Affiliation(s)
- Mohamed S Abdel-Hakeem
- Penn Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt.
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16
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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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17
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Luxenburger H, Neumann-Haefelin C, Thimme R, Boettler T. HCV-Specific T Cell Responses During and After Chronic HCV Infection. Viruses 2018; 10:v10110645. [PMID: 30453612 PMCID: PMC6265781 DOI: 10.3390/v10110645] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/14/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV)-specific T cell responses are closely linked to the clinical course of infection. While T cell responses in self-limiting infection are typically broad and multi-specific, they display several distinct features of functional impairment in the chronic phase. Moreover, HCV readily adapts to immune pressure by developing escape mutations within epitopes targeted by T cells. Much of our current knowledge on HCV-specific T cell responses has been gathered under the assumption that this might eventually pave the way for a therapeutic vaccine. However, with the development of highly efficient direct acting antivirals (DAAs), there is less interest in the development of a therapeutic vaccine for HCV and the scope of T cell research has shifted. Indeed, the possibility to rapidly eradicate an antigen that has persisted over years or decades, and has led to T cell exhaustion and dysfunction, provides the unique opportunity to study potential T cell recovery after antigen cessation in a human in vivo setting. Findings from such studies not only improve our basic understanding of T cell immunity but may also advance immunotherapeutic approaches in cancer or chronic hepatitis B and D infection. Moreover, in order to edge closer to the WHO goal of HCV elimination by 2030, a prophylactic vaccine is clearly required. Thus, in this review, we will summarize our current knowledge on HCV-specific T cell responses and also provide an outlook on the open questions that require answers in this field.
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Affiliation(s)
- Hendrik Luxenburger
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Robert Thimme
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Tobias Boettler
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
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18
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Shrivastava S, Bhatta M, Ward H, Romani S, Lee R, Rosenthal E, Osinusi A, Kohli A, Masur H, Kottilil S, Wilson E. Multitarget Direct-Acting Antiviral Therapy Is Associated With Superior Immunologic Recovery in Patients Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus. Hepatol Commun 2018; 2:1451-1466. [PMID: 30556035 PMCID: PMC6287478 DOI: 10.1002/hep4.1258] [Citation(s) in RCA: 21] [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: 04/23/2018] [Accepted: 08/24/2018] [Indexed: 12/13/2022] Open
Abstract
Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have higher levels of immune activation, impaired antigen‐specific responses, and accelerated fibrogenesis compared to patients monoinfected with HCV. Whether different direct‐acting antiviral (DAA) combinations have differential effects on immunophenotypes and functions following successful HCV therapy remain unknown. Therefore, we aimed to assess the peripheral T‐cell immunophenotypes and functions in patients coinfected with HIV/HCV who were successfully treated with combination DAA treatment regimens. We analyzed peripheral blood mononuclear cells (PBMCs) at baseline and at the time of sustained viral response (SVR) from subjects treated with three different combination DAA regimens: daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks (CONQUER 2‐DAA), DCV/ASV/beclabuvir (BCV) for 12 weeks (CONQUER 3‐DAA), and sofosbuvir (SOF) and ledipasvir (LDV) for 12 weeks (ERADICATE study). We used flow cytometry to assess T‐cell phenotypes (activation and exhaustion) and HCV‐specific T‐cell functions (cytokine secretion and cytotoxicity). Statistical analyses were conducted using the Wilcoxon matched‐pairs signed‐rank test with P < 0.05 considered significant. Overall, there was an improvement in T‐cell exhaustion markers, a decrease in T‐cell activation, an increase in the effector memory population, and improved T‐cell function after achieving SVR, with the largest effects noted with CONQUER 3‐DAA treatment. Conclusion: Treatment with DCV/ASV/BCV in patients coinfected with HIV/HCV resulted in greater restoration of the T‐cell impairments and perturbations associated with HIV/HCV coinfection to an extent that was greater than that observed in either two‐drug regimens. We showed that different DAA‐based therapies have different immunologic outcomes after successful HCV treatment in patients coinfected with HIV/HCV. This information will be beneficial for providers when selecting the regimens for patients coinfected with HIV/HCV.
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Affiliation(s)
- Shikha Shrivastava
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD
| | - Manasa Bhatta
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD.,Critical Care Medicine Department, Clinical Center National Institutes of Health Bethesda MD
| | - Haley Ward
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD.,Critical Care Medicine Department, Clinical Center National Institutes of Health Bethesda MD
| | - Sara Romani
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD
| | - Rebecca Lee
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD
| | - Elana Rosenthal
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD
| | | | - Anita Kohli
- Critical Care Medicine Department, Clinical Center National Institutes of Health Bethesda MD
| | - Henry Masur
- Critical Care Medicine Department, Clinical Center National Institutes of Health Bethesda MD
| | - Shyam Kottilil
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD
| | - Eleanor Wilson
- Institute of Human Virology University of Maryland School of Medicine Baltimore MD
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19
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Mazouz S, Boisvert M, Shoukry NH, Lamarre D. Reversing immune dysfunction and liver damage after direct-acting antiviral treatment for hepatitis C. CANADIAN LIVER JOURNAL 2018; 1:78-105. [DOI: 10.3138/canlivj.1.2.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 12/12/2022]
Abstract
The introduction of small molecules targeting viral functions has caused a paradigm shift in hepatitis C virus (HCV) treatment. Administration of these direct-acting antivirals (DAAs) achieves a complete cure in almost all treated patients with short-duration therapy and minimal side effects. Although this is a major improvement over the previous pegylated interferon plus ribavirin (PEG-IFNα/RBV) standard-of-care treatment for HCV, remaining questions address several aspects of the long-term benefits of DAA therapy. Interferon (IFN)-based treatment with successful outcome was associated with substantial reduction in liver disease–related mortality. However, emerging data suggest a complex picture and several confounding factors that influence the effect of both IFN-based and DAA therapies on immune restoration and limiting liver disease progression. We review current knowledge of restoration of innate and HCV-specific immune responses in DAA-mediated viral elimination in chronic HCV infection, and we identify future research directions to achieve long-term benefits in all cured patients and reduce HCV-related liver disease morbidity and mortality.
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Affiliation(s)
- Sabrina Mazouz
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Maude Boisvert
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
| | - Daniel Lamarre
- Centre de Recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
- Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
- Département de médecine, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada
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20
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Lampejo T, Agarwal K, Carey I. Interferon-free direct-acting antiviral therapy for acute hepatitis C virus infection in HIV-infected individuals: A literature review. Dig Liver Dis 2018; 50:113-123. [PMID: 29233687 DOI: 10.1016/j.dld.2017.11.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 10/29/2017] [Accepted: 11/15/2017] [Indexed: 02/07/2023]
Abstract
Dramatic rises in hepatitis C virus (HCV) coinfection rates in human immunodeficiency virus (HIV)-infected individuals have been observed recently, largely attributable to increasing recreational drug use combined with increased testing for HCV. In the era of direct-acting antiviral (DAA) therapy, treatment of acute HCV infection in HIV-infected individuals with short durations of these drugs may potentially reduce the disease and economic burden associated with HCV infection as well as reducing the likelihood of onward HCV transmission. We performed an extensive literature search of PubMed, Embase and Google Scholar up to 05 September 2017 for clinical trials of acute HCV infection in HIV-infected individuals. In the studies identified, rates of sustained virologic response at 12 weeks post-treatment (SVR12) ranged from 21% with 6 weeks of therapy up to 92% with 12 weeks of therapy with sofosbuvir and ribavirin. Ledipasvir/sofosbuvir for 6 weeks achieved an SVR of 77%. No HIV-related events occurred regardless of whether patients were receiving antiretroviral therapy (ART) and DAAs were well tolerated. Data is currently limited with regards to optimal regimens and durations of therapy, which need to be tailored based on potential interactions with concurrent ART and consideration for the fact that patients with higher baseline HCV RNA levels may require an extended duration of treatment.
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Affiliation(s)
- Temi Lampejo
- Institute of Liver Studies, King's College Hospital, London, United Kingdom.
| | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Ivana Carey
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
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21
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Tan WG, Zubkova I, Kachko A, Wells F, Adler H, Sutter G, Major ME. Qualitative differences in cellular immunogenicity elicited by hepatitis C virus T-Cell vaccines employing prime-boost regimens. PLoS One 2017; 12:e0181578. [PMID: 28732046 PMCID: PMC5521799 DOI: 10.1371/journal.pone.0181578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 07/03/2017] [Indexed: 12/31/2022] Open
Abstract
T-cell based vaccines have been considered as attractive candidates for prevention of hepatitis C virus (HCV) infections. In this study we compared the magnitude and phenotypic characteristics of CD8+ T-cells induced by three commonly used viral vectors, Adenovirus-5 (Ad5), Vaccinia virus (VV) and Modified Vaccinia Ankara (MVA) expressing the HCV NS3/4A protein. C57/BL6 mice were primed with DNA expressing NS3/4A and boosted with each of the viral vectors in individual groups of mice. We then tracked the vaccine-induced CD8+ T-cell responses using pentamer binding and cytokine production analysis. Overall, our data indicate that the memory cells induced by Ad5 were inferior to those induced by VV or MVA. We found that Ad5 boosting resulted in rapid expansion and significantly higher frequencies of NS3-specific T-cells compared to VV and MVA boosting. However, the functional profiles, assessed through analysis of the memory cell marker CD127 and the anti-apoptotic molecule Bcl-2 in the blood, spleen, and liver; and measurements of interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 production indicated significantly lower frequencies of long-lived memory T-cells following Ad5 boosting compared to VV and MVA. This same set of analyses suggested that the memory cells induced following boosting with MVA were superior to those induced by both Ad5 and VV. This superiority of the MVA-induced CD8+ T-cells was confirmed following surrogate challenge of mice with a recombinant mouse herpes virus expressing the HCV NS3 protein. Higher levels of NS3-specific CD8+ T-cells displaying the functional markers CD69, Ki67 and Granzyme B were found in the spleens of mice boosted with MVA compared to VV and Ad5, both alone and in combination. These data suggest that MVA may be a more successful viral vector for induction of effective CD8+ T-cell responses against hepatitis C virus.
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Affiliation(s)
- Wendy G. Tan
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Iryna Zubkova
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Alla Kachko
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Frances Wells
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Heiko Adler
- Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München—German Research Center for Environmental Health (GmbH), Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Gerd Sutter
- Institute for Infectious Diseases and Zoonoses, LMU University of Munich, Munich, Germany
| | - Marian E. Major
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
- * E-mail:
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22
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Li BJ, He Y, Zhang Y, Guo YH, Zhou Y, Zhang PX, Wang W, Zhao JR, Li JG, Zuo WZ, Fan C, Jia ZS. Interferon-α-induced CD100 on naïve CD8 + T cells enhances antiviral responses to hepatitis C infection through CD72 signal transduction. J Int Med Res 2017; 45:89-100. [PMID: 28222623 PMCID: PMC5536608 DOI: 10.1177/0300060516676136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Objectives We investigated the effects of CD100 on naïve CD8+ T cells during hepatitis C virus (HCV) infection after interferon-α (IFN-α) therapy to clarify the mechanism underlying the effect of IFN-α in enhancing the antiviral response. Methods The CD100 molecules on subsets of CD8+ T cells were analysed with flow cytometry. The effects of CD100-overexpressing naïve CD8+ T cells were determined with ELISAs and an MTT cytotoxicity assay. The role of CD100-CD72 signal transduction was analysed with a neutralization and transwell assays. Results HCV infection reduced CD100 expression on CD8+ T cells, whereas IFN-α treatment significantly increased CD100 expression on naïve CD8+ T cells. The increased CD100 interacted with the CD72 receptor and enhanced PBMC cytokine secretion (IFN-γ and tumour necrosis factor-α) and cytotoxicity. Conclusions IFN-α-induced CD100 on naïve CD8+ T cells promotes PBMC cytokine secretion and cytotoxicity through CD100-CD72 signalling during HCV infection.
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Affiliation(s)
- Bing Jie Li
- 2 First Affiliated Hospital, School of Medicine, Shihezi University, Xinjiang, China
| | - Yu He
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Ying Zhang
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Yong Hong Guo
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Yun Zhou
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Pei Xin Zhang
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Wei Wang
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Jie Ru Zhao
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Jin Ge Li
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Wei Ze Zuo
- 2 First Affiliated Hospital, School of Medicine, Shihezi University, Xinjiang, China
| | - Chao Fan
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
| | - Zhan Sheng Jia
- 1 Department of Infectious Diseases and Center of Liver Diseases, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China
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Murira A, Lamarre A. Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection. Front Immunol 2016; 7:609. [PMID: 28066419 PMCID: PMC5165262 DOI: 10.3389/fimmu.2016.00609] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 12/01/2016] [Indexed: 12/11/2022] Open
Abstract
Type I interferons (IFN-I) have long been heralded as key contributors to effective antiviral responses. More widely understood in the context of acute viral infection, the role of this pleiotropic cytokine has been characterized as triggering antiviral states in cells and potentiating adaptive immune responses. Upon induction in the innate immune response, IFN-I triggers the expression of interferon-stimulated genes (ISGs), which upregulate the effector function of immune cells (e.g., dendritic cells, B cells, and T cells) toward successful resolution of infections. However, emerging lines of evidence reveal that viral persistence in the course of chronic infections could be driven by deleterious immunomodulatory effects upon sustained IFN-I expression. In this setting, elevation of IFN-I and ISGs is directly correlated to viral persistence and elevated viral loads. It is important to note that the correlation among IFN-I expression, ISGs, and viral persistence may be a cause or effect of chronic infection and this is an important distinction to make toward establishing the dichotomous nature of IFN-I responses. The aim of this mini review is to (i) summarize the interaction between IFN-I and downstream effector responses and therefore (ii) delineate the function of this cytokine on positive and negative immunoregulation in chronic infection. This is a significant consideration given the current therapeutic administration of IFN-I in chronic viral infections whose therapeutic significance is projected to continue despite emergence of increasingly efficacious antiviral regimens. Furthermore, elucidation of the interplay between virus and the antiviral response in the context of IFN-I will elucidate avenues toward more effective therapeutic and prophylactic measures against chronic viral infections.
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Affiliation(s)
- Armstrong Murira
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier , Laval, QC , Canada
| | - Alain Lamarre
- Immunovirology Laboratory, Institut national de la recherche scientifique (INRS), INRS-Institut Armand-Frappier , Laval, QC , Canada
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Hartling HJ, Ballegaard VC, Nielsen NS, Gaardbo JC, Nielsen SD. Immune regulation in chronic hepatitis C virus infection. Scand J Gastroenterol 2016; 51:1387-97. [PMID: 27436030 DOI: 10.3109/00365521.2016.1170875] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The immunological result of infection with Hepatitis C virus (HCV) depends on the delicate balance between a vigorous immune response that may clear the infection, but with a risk of unspecific inflammation and, or a less inflammatory response that leads to chronic infection. In general, exhaustion and impairment of cytotoxic function of HCV-specific T cells and NK cells are found in patients with chronic HCV infection. In contrast, an increase in immune regulatory functions is found primarily in form of increased IL-10 production possibly due to increased level and function of anti-inflammatory Tregs. Thus, the major immune players during chronic HCV infection are characterized by a decrease of cytotoxic function and increase of inhibitory functions. This may be an approach to diminish intrahepatic and systemic inflammation. Finally, there has been increasing awareness of regulatory functions of epigenetic changes in chronic HCV infection. A vast amount of studies have revealed the complexity of immune regulation in chronic HCV infection, but the interplay between immune regulation in virus and host remains incompletely understood. This review provides an overview of regulatory functions of HCV-specific T cells, NK cells, Tregs, IL-10, and TGF-β, as well as epigenetic changes in the setting of chronic HCV infection.
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Affiliation(s)
- Hans Jakob Hartling
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Vibe Cecilie Ballegaard
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Nick Schou Nielsen
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Julie Christine Gaardbo
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
| | - Susanne Dam Nielsen
- a Viro-Immunology Research Unit, Department of Infectious Diseases , University of Copenhagen , Rigshospitalet , Denmark
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25
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Abdelwahab SF. Cellular immune response to hepatitis-C-virus in subjects without viremia or seroconversion: is it important? Infect Agent Cancer 2016; 11:23. [PMID: 27186234 PMCID: PMC4867533 DOI: 10.1186/s13027-016-0070-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 03/30/2016] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C Virus (HCV) causes chronic infection and represents a global health burden. To date, there is no licensed vaccine for HCV. The high viral replication rate and the existence of several HCV genotypes and quasispecies hamper the development of an effective universal vaccine. In this regard, the current HCV vaccine candidates show genotype-specific protection or narrow cross reactivity against other genotypes. Importantly, HCV spontaneous clearance occurs in 15-50 % of infected subjects, indicating that natural resistance to chronic infection exists. This phenomenon was demonstrated among humans and chimpanzees and continues to motivate researchers attempting to develop an effective HCV vaccine. However, what constitutes a protective immune response or correlate of protection against HCV infection is still vague. Additionally, the mechanisms behind successful HCV clearance suggest the coordination of several arms of the immune system, with cell-mediated immunity (CMI) playing a crucial role in this process. By contrast, although neutralizing antibodies have been identified, they are isolate-specific and poorly correlate with viral clearance. Antigen-specific CD4 T cells, instead, correlate with transient decline in HCV viremia and long-lasting control of the infection. Unfortunately, HCV has been very successful in evading host immune mechanisms, leading to complications such as liver fibrosis, cirrhosis and hepatocellular carcinoma. Interestingly, CMI to HCV antigens were shown among exposed individuals without viremia or seroconversion, suggesting the clearance of prior HCV infection(s). These individuals include family members living with HCV-infected subjects, healthcare workers, IV drug users, and sexual contacts. The correlates of protection could be closely monitored among these individuals. This review provides a summary of HCV-specific immune responses in general and of CMI in particular in these cohorts. The importance of these CMI responses are discussed.
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Affiliation(s)
- Sayed F. Abdelwahab
- />Departement of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, 61511 Egypt
- />Department of Microbiology, College of Pharmacy, Taif University, Taif, 21974 Kingdom of Saudi Arabia
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26
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Saab S, Rheem J, Jimenez M, Bau S, Choi G, Durazo F, El Kabany M, Han S, Farid A, Jamal N, Grotts J, Elashoff D, Busuttil RW. Curing Hepatitis C in Liver Transplant Recipients Is Associated with Changes in Immunosuppressant Use. J Clin Transl Hepatol 2016; 4:32-8. [PMID: 27047770 PMCID: PMC4807141 DOI: 10.14218/jcth.2016.00001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/19/2016] [Accepted: 02/24/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS All-oral interferon-free antivirals are highly effective in treating recurrent hepatitis C (HCV) infection in liver transplant (LT) recipients. The aim of the study was to assess immunosuppression needs after achieving a sustained viral response (SVR). METHODS We compared immunosuppression needs before and after achieving a SVR in adult LT recipients treated for recurrent HCV infection with all-oral direct acting agents. RESULTS We identified 52 liver LT treated recipients who achieved a SVR. The median (25th and 75th percentile interquartile range [IQR]) age was 62 years (57.75, 65). Most recipients received tacrolimus (TAC) for their immunosuppressant regimen. After achieving SVR, there was no statistically significant difference in daily dose of TAC unadjusted per weight (p > 0.05). However, there was a statistically significant decrease in daily dose of TAC adjusted per weight, serum levels of TAC, and the product of glomerular filtration rate and TAC. No statistically significant differences in cyclosporine unadjusted/adjusted per weight daily dose or serum levels were noted. CONCLUSIONS Immunosuppression needs were increased for those patients treated with TAC but not cyclosporine. LT recipients prescribed TAC require close monitoring after treatment completion to avoid potential risk of acute rejection.
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Affiliation(s)
- Sammy Saab
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
- Correspondence to: Sammy Saab, Pfleger Liver Institute, UCLA Medical Center, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA. Tel: +1-310-206-6705, Fax: +1-310-206-4197, E-mail:
| | - Justin Rheem
- Department of Medicine at Harbor-University of California at Los Angeles Medical Center, Torrance, California, USA
| | - Melissa Jimenez
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - Sherona Bau
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Gina Choi
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Francisco Durazo
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Mohammed El Kabany
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Steven Han
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
| | - Alexander Farid
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - Naadir Jamal
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - Jonathan Grotts
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
| | - David Elashoff
- Departments of Medicine at the University of California at Los Angeles, Los Angeles, California, USA
- Department of Biostatistics at the University of California at Los Angeles, Los Angeles, California, USA
| | - Ronald W. Busuttil
- Department of Surgery at the University of California at Los Angeles, Los Angeles, California, USA
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27
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Burchill MA, Golden-Mason L, Wind-Rotolo M, Rosen HR. Memory re-differentiation and reduced lymphocyte activation in chronic HCV-infected patients receiving direct-acting antivirals. J Viral Hepat 2015; 22:983-91. [PMID: 26482547 DOI: 10.1111/jvh.12465] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 08/12/2015] [Indexed: 12/14/2022]
Abstract
Recently, the treatment of HCV has advanced significantly due to the introduction of direct-acting antivirals (DAAs). Studies using interferon (IFN)-containing regimens failed to consistently show restoration of immunologic responses. Therefore, IFN-free DAA formulations provide a unique opportunity to dissect the immunologic effect of HCV cure. This study investigates the restoration of the immune compartment as a consequence of rapid viral clearance in patients successfully treated with DAAs and in the absence of IFN and ribavirin. Here, we evaluate the immunologic changes that occurred following DAA-mediated HCV cure. Peripheral blood from nineteen previously treatment-naïve patients with chronic HCV genotype 1a/1b who received an IFN and ribavirin-free regimen of daclatasvir, asunaprevir and BMS-791325 was evaluated. Immune reconstitution occurs in patients in whom HCV was successfully eradicated via DAA therapy. Restoration of the CD4(+) T-cell compartment in the peripheral blood and a re-differentiation of the T lymphocyte memory compartment resulted in a more effector memory cell population and a reduction in expression in the co-inhibitory molecule TIGIT in bulk T lymphocytes. Furthermore, we observed a partial reversal of the exhausted phenotype in HCV-specific CD8(+) T cells and a dampening of the activation state in peripheral NK cells. Collectively, our data provide the groundwork for dissecting the effect of DAA therapy on the immune system and identifying novel mechanisms by which chronic HCV infection exerts immunosuppressive effects on T cells through the recently described co-inhibitory molecule TIGIT.
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Affiliation(s)
- M A Burchill
- Department of Medicine, Division of GI/Heaptology, University of Colorado-Denver, Aurora, CO, USA
| | - L Golden-Mason
- Department of Medicine, Division of GI/Heaptology, University of Colorado-Denver, Aurora, CO, USA
| | - M Wind-Rotolo
- Bristol-Myers Squibb, Exploratory Clinical and Translational Research, Lawrenceville, NJ, USA
| | - H R Rosen
- Department of Medicine, Division of GI/Heaptology, University of Colorado-Denver, Aurora, CO, USA
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28
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Kachko A, Frey SE, Sirota L, Ray R, Wells F, Zubkova I, Zhang P, Major ME. Antibodies to an interfering epitope in hepatitis C virus E2 can mask vaccine-induced neutralizing activity. Hepatology 2015; 62:1670-82. [PMID: 26251214 PMCID: PMC4681649 DOI: 10.1002/hep.28108] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 08/03/2015] [Indexed: 12/13/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) neutralization occurring at the E2 region 412-426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434-446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here, we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred twelve blinded serum samples from a phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in enzyme-linked immunosorbent assay for binding reactivity to peptides representing the E2 regions 412-426 (EP-I) and 434-446 (EP-II). All samples were subsequently tested for neutralizing activity using cell-culture HCV 1a(H77)/2a chimera, HCV pseudotype particles (HCVpp) H77, and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples, we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only, and 70 double negative. Depleting EP-II antibodies from double-positive serum samples increased 50% inhibitory dose (ID50) neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (P ≤ 0.0005), contrasting with ID50 neutralization titer increases in 2 of 70 double-negative samples (2.9%; P > 0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (P < 0.0003). CONCLUSION These data show that antibodies to the region 434-446 are induced during immunization of individuals with recombinant E1E2 proteins, and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP-II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins.
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Affiliation(s)
- Alla Kachko
- Division of Viral ProductsCBER/FDASilver SpringMD
| | - Sharon E. Frey
- Division of Infectious Diseases, Allergy and ImmunologySaint Louis University School of MedicineSt LouisMO
| | - Lev Sirota
- Division of Biostatistics, Office of Biostatistics and EpidemiologyCBER/FDASilver SpringMD
| | - Ranjit Ray
- Division of Infectious Diseases, Allergy and ImmunologySaint Louis University School of MedicineSt LouisMO
| | | | | | - Pei Zhang
- Division of HematologyCBER/FDASilver SpringMD
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Sun J, Rajsbaum R, Yi M. Immune and non-immune responses to hepatitis C virus infection. World J Gastroenterol 2015; 21:10739-10748. [PMID: 26478666 PMCID: PMC4600576 DOI: 10.3748/wjg.v21.i38.10739] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/06/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The host innate and adaptive immune systems are involved in nearly every step of hepatitis C virus (HCV) infection. In patients, the outcome is determined by a series of complex host-virus interactions, whether it is a natural infection or results from clinical intervention. Strong and persistent CD8+ and CD4+ T-cell responses are critical in HCV clearance, as well as cytokine-induced factors that can directly inhibit virus replication. Newly available direct-acting antivirals (DAAs) are very effective in viral clearance in patients. DAA treatment may further result in the down-regulation of programmed death-1, leading to rapid restoration of HCV-specific CD8+ T cell functions. In this review, we focus on recent studies that address the host responses critical for viral clearance and disease resolution. Additional discussion is devoted to the prophylactic vaccine development as well as to current efforts aimed at understanding the host innate responses against HCV infection. Current theories on how the ubiquitin system and interferon-stimulated genes may affect HCV replication are also discussed.
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30
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Echevarria D, Gutfraind A, Boodram B, Major M, Del Valle S, Cotler SJ, Dahari H. Mathematical Modeling of Hepatitis C Prevalence Reduction with Antiviral Treatment Scale-Up in Persons Who Inject Drugs in Metropolitan Chicago. PLoS One 2015; 10:e0135901. [PMID: 26295805 PMCID: PMC4546683 DOI: 10.1371/journal.pone.0135901] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 07/10/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIM New direct-acting antivirals (DAAs) provide an opportunity to combat hepatitis C virus (HCV) infection in persons who inject drugs (PWID). Here we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago. METHODS To estimate the HCV antibody and HCV-RNA (chronic infection) prevalence among the metropolitan Chicago PWID population, we used empirical data from three large epidemiological studies. Cost of DAAs is assumed $50,000 per person. RESULTS Approximately 32,000 PWID reside in metropolitan Chicago with an estimated HCV-RNA prevalence of 47% or 15,040 cases. Approximately 22,000 PWID (69% of the total PWID population) attend harm reduction (HR) programs, such as syringe exchange programs, and have an estimated HCV-RNA prevalence of 30%. There are about 11,000 young PWID (<30 years old) with an estimated HCV-RNA prevalence of 10% (PWID in these two subpopulations overlap). The model suggests that the following treatment scale-up is needed to reduce the baseline HCV-RNA prevalence by one-half over 10 years of treatment [cost per year, min-max in millions]: 35 per 1,000 [$50-$77] in the overall PWID population, 19 per 1,000 [$20-$26] for persons in HR programs, and 5 per 1,000 [$3-$4] for young PWID. CONCLUSIONS Treatment scale-up could dramatically reduce the prevalence of chronic HCV infection among PWID in Chicago, who are the main reservoir for on-going HCV transmission. Focusing treatment on PWID attending HR programs and/or young PWID could have a significant impact on HCV prevalence in these subpopulations at an attainable cost.
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MESH Headings
- Adult
- Age Factors
- Antiviral Agents/economics
- Antiviral Agents/therapeutic use
- Chicago/epidemiology
- Cost-Benefit Analysis
- Harm Reduction/ethics
- Hepatitis C Antibodies/blood
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/economics
- Hepatitis C, Chronic/epidemiology
- Humans
- Middle Aged
- Models, Statistical
- Prevalence
- RNA, Viral/antagonists & inhibitors
- RNA, Viral/blood
- Substance Abuse, Intravenous/complications
- Substance Abuse, Intravenous/drug therapy
- Substance Abuse, Intravenous/economics
- Substance Abuse, Intravenous/epidemiology
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Affiliation(s)
- Desarae Echevarria
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Chicago, Medical Center, Maywood, Illinois, United States of America
| | - Alexander Gutfraind
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Chicago, Medical Center, Maywood, Illinois, United States of America
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Basmattee Boodram
- Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Marian Major
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Sara Del Valle
- Energy and Infrastructure Analysis Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
| | - Scott J Cotler
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Chicago, Medical Center, Maywood, Illinois, United States of America
| | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Chicago, Medical Center, Maywood, Illinois, United States of America
- Theoretical and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
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Larrubia JR, Moreno-Cubero E, Miquel J, Sanz-de-Villalobos E. Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control. World J Gastroenterol 2015; 21:3480-3491. [PMID: 25834312 PMCID: PMC4375569 DOI: 10.3748/wjg.v21.i12.3480] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 12/10/2014] [Accepted: 02/05/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV)-specific cytotoxic T cell (CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response (SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients’ serum is still able to induce HCV infection in naïve chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatment-induced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferon-free regimes, based on direct-acting antivirals. Nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory α-interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed.
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Heim MH, Thimme R. Innate and adaptive immune responses in HCV infections. J Hepatol 2014; 61:S14-25. [PMID: 25443342 DOI: 10.1016/j.jhep.2014.06.035] [Citation(s) in RCA: 222] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 06/29/2014] [Accepted: 06/30/2014] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus has been identified a quarter of a decade ago as a leading cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously during acute infection. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses. However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response. The virus has developed several strategies to escape these immune responses. For example, to escape innate immunity, the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1 receptor-domain-containing adaptor-inducing IFN-β (TRIF). Despite these escape mechanisms, IFN-stimulated genes (ISGs) are induced in a large proportion of patients with chronic infection. Of note, chronically HCV infected patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cell compartments that are not accessible to anti-viral IFN-stimulated effector systems, or direct antagonism of effector systems by viral proteins. Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells. In addition, chronic infection is characterized by the presence of functionally and phenotypically altered NK and T cell responses that are unable to clear the virus but most likely contribute to the ongoing liver disease. In this review, we will summarize current knowledge about the role of innate and adaptive immune responses in determining the outcome of HCV infection.
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Affiliation(s)
- Markus H Heim
- Division of Gastroenterology and Hepatology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland.
| | - Robert Thimme
- Department of Medicine, Clinic for Gastroenterology, Hepatology, Endocrinology, Infectious Diseases, University Hospital Freiburg, Freiburg, Germany.
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Callendret B, Eccleston HB, Hall S, Satterfield W, Capone S, Folgori A, Cortese R, Nicosia A, Walker CM. T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee. Hepatology 2014; 60:1531-40. [PMID: 24975498 PMCID: PMC4242208 DOI: 10.1002/hep.27278] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/20/2014] [Indexed: 01/15/2023]
Abstract
UNLABELLED Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection. CONCLUSIONS The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection.
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Affiliation(s)
- Benoit Callendret
- Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, OH
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Abdel-Hakeem MS, Bédard N, Murphy D, Bruneau J, Shoukry NH. Signatures of protective memory immune responses during hepatitis C virus reinfection. Gastroenterology 2014; 147:870-881.e8. [PMID: 25038432 PMCID: PMC4170061 DOI: 10.1053/j.gastro.2014.07.005] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 06/12/2014] [Accepted: 07/07/2014] [Indexed: 01/18/2023]
Abstract
BACKGROUND & AIMS Development of a vaccine against hepatitis C virus (HCV) has been hindered by our limited understanding of immune correlates of protection during real-life exposure to the virus. We studied the immune response during HCV reinfection. METHODS We analyzed blood samples from participants in the Montreal Acute Hepatitis C Injection Drug User Cohort Study who were reinfected with HCV from 2009 to 2012. Five patients spontaneously resolved their second infection and 4 developed chronic infections. We monitored the phenotypic and functional dynamics of HCV-specific memory T cell responses in all subjects during natural re-exposure and re-infection. RESULTS Populations of CD4(+) and CD8(+) T cells with HCV-specific polyfunctional memory were expanded in all 5 individuals who resolved 2 successive HCV infections. We detected CD127(hi) HCV-specific memory CD8(+) T cells before reinfection regardless of a subject's ability to clear subsequent infections. Protection against viral persistence was associated with the expansion of a CD127(neg), PD1(lo) effector memory T cells at the peak of the response. We also observed broadening of T-cell response, indicating generation of de novo T-cell responses. The 4 individuals who failed to clear their subsequent infection had limited expansion of HCV-specific CD4(+) and CD8(+) memory T cells and expressed variable levels of the exhaustion marker PD1 on HCV-specific CD8(+) T cells. Dominant epitope regions of HCV strains isolated from patients with persistent reinfection had sequence variations that were not recognized by the pre-existing memory T cells. CONCLUSIONS Protection from persistent HCV reinfection depends on the magnitude, breadth, and quality of the HCV-specific memory T-cell response. Sequence homology among viruses and ability of T cells to recognize multiple strains of HCV are critical determinants of protective memory.
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Affiliation(s)
- Mohamed S. Abdel-Hakeem
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada,Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt,Département de microbiologie, infectiologie et immunologie, Montréal, Québec, Canada
| | - Nathalie Bédard
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada
| | - Donald Murphy
- Institut National de Santé Publique du Québec, Laboratoire de Santé Publique du Québec (LSPQ), Sainte-Anne-de-Bellevue, Québec, Canada
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada,Département de médecine familiale et de médecine d’urgence, Montréal, Québec, Canada
| | - Naglaa H. Shoukry
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, Québec, Canada,Département de médecine, Université de Montréal, Montréal, Québec, Canada,Correspondance: Dr. Naglaa H. Shoukry, Centre de Recherche du CHUM (CRCHUM), Tour Viger, Local R09.414, 900 rue St-Denis, Montréal, QC H2X 0A9, CANADA,
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Maini MK, Schurich A. Direct-acting antivirals trump interferon-alpha in their capacity to rescue exhausted T cells upon HCV clearance. J Hepatol 2014; 61:459-61. [PMID: 24953024 DOI: 10.1016/j.jhep.2014.06.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 06/14/2014] [Indexed: 12/20/2022]
Affiliation(s)
- Mala K Maini
- Division of Infection and Immunity, UCL, London, UK.
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Martin B, Hennecke N, Lohmann V, Kayser A, Neumann-Haefelin C, Kukolj G, Böcher WO, Thimme R. Restoration of HCV-specific CD8+ T cell function by interferon-free therapy. J Hepatol 2014; 61:538-43. [PMID: 24905492 DOI: 10.1016/j.jhep.2014.05.043] [Citation(s) in RCA: 193] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 05/26/2014] [Accepted: 05/26/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Chronic hepatitis C virus (HCV) infection is characterised by a failure of virus-specific CD8+ T cells that is mainly caused by viral escape and T cell exhaustion. Constant antigen stimulation has been suggested to contribute to HCV-specific CD8+ T cell exhaustion. However, IFN-based therapies failed to recover HCV-specific CD8+ T cell function suggesting that the damage to CD8+ T cells may be permanent even after antigen removal. It was therefore the objective of this study to analyse the impact of inhibition of ongoing viral replication by IFN-free therapy with direct acting antivirals (DAA) on the phenotype and function of HCV-specific CD8+ T cells. METHODS Virus-specific CD8+ T cells obtained from a patient cohort of 51 previously untreated chronically infected patients undergoing IFN-free therapy with a combination of faldaprevir (a protease inhibitor) and deleobuvir (a non-nucleoside polymerase inhibitor) with or without ribavirin were analysed ex vivo and after in vitro expansion at baseline, wk4, wk 12, and after treatment. RESULTS Our results show the rapid restoration of proliferative HCV-specific CD8+ T cells in the majority of patients with SVR12 within 4 weeks of therapy suggesting that IFN-free therapy mediated antigen removal may restore CD8+ T cell function. CONCLUSIONS This study indicates a specific restoration of proliferative HCV-specific CD8+ T cells under IFN-free therapy. This is in contrast to PegIFN-based therapies that have been shown not to restore T cell function during and after chronic infection.
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Affiliation(s)
- Bianca Martin
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
| | - Nadine Hennecke
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
| | - Volker Lohmann
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany
| | - Antonin Kayser
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
| | | | | | | | - Robert Thimme
- Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
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Rodrigue-Gervais IG, Rigsby H, Jouan L, Willems B, Lamarre D. Intact dendritic cell pathogen-recognition receptor functions associate with chronic hepatitis C treatment-induced viral clearance. PLoS One 2014; 9:e102605. [PMID: 25033043 PMCID: PMC4102513 DOI: 10.1371/journal.pone.0102605] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 06/20/2014] [Indexed: 12/17/2022] Open
Abstract
Although studies have addressed the exhaustion of the host's immune response to HCV and its role in treatment, there is little information about the possible contribution of innate immunity to treatment-induced clearance. We hypothesized that because intact myeloid dendritic cell (MDC) pathogen sensing functions are associated with improved HCV-specific CD8+ T cell functionality in some chronically infected patients, it might enhance HCV clearance rate under standard interferon therapy. To investigate this hypothesis, TLR-induced MDC activation and HCV-specific CD8+ T cell response quality were monitored longitudinally at the single-cell level using polychromatic flow cytometry in chronically infected patients undergoing interferon therapy. We correlated the immunological, biochemical and virological data with response to treatment. We demonstrate that the clinical efficacy of interferon-induced viral clearance is influenced by the extent to which HCV inhibits MDC functions before treatment, rather than solely on a breakdown of the extrinsic T cell immunosuppressive environment. Thus, viral inhibition of MDC functions before treatment emerges as a co-determining factor in the clinical efficacy of interferon therapy during chronic HCV infection.
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Affiliation(s)
- Ian Gaël Rodrigue-Gervais
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
| | - Hawley Rigsby
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
| | - Loubna Jouan
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
| | - Bernard Willems
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
- Département de Médecine, Université de Montréal, Montréal, Québec, Canada
| | - Daniel Lamarre
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM), Montréal, Québec, Canada
- Département de Médecine, Université de Montréal, Montréal, Québec, Canada
- * E-mail:
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Abdel-Hakeem MS, Shoukry NH. Protective immunity against hepatitis C: many shades of gray. Front Immunol 2014; 5:274. [PMID: 24982656 PMCID: PMC4058636 DOI: 10.3389/fimmu.2014.00274] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 05/27/2014] [Indexed: 12/11/2022] Open
Abstract
The majority of individuals who become acutely infected with hepatitis C virus (HCV) develop chronic infection and suffer from progressive liver damage while approximately 25% are able to eliminate the virus spontaneously. Despite the recent introduction of new direct-acting antivirals, there is still no vaccine for HCV. As a result, new infections and reinfections will remain a problem in developing countries and among high risk populations like injection drug users who have limited access to treatment and who continue to be exposed to the virus. The outcome of acute HCV is determined by the interplay between the host genetics, the virus, and the virus-specific immune response. Studies in humans and chimpanzees have demonstrated the essential role of HCV-specific CD4 and CD8 T cell responses in protection against viral persistence. Recent data suggest that antibody responses play a more important role than what was previously thought. Individuals who spontaneously resolve acute HCV infection develop long-lived memory T cells and are less likely to become persistently infected upon reexposure. New studies examining high risk cohorts are identifying correlates of protection during real life exposures and reinfections. In this review, we discuss correlates of protective immunity during acute HCV and upon reexposure. We draw parallels between HCV and the current knowledge about protective memory in other models of chronic viral infections. Finally, we discuss some of the yet unresolved questions about key correlates of protection and their relevance for vaccine development against HCV.
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Affiliation(s)
- 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, Faculté de Médecine, Université de Montréal , Montréal, QC , Canada ; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University , Cairo , Egypt
| | - 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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Stone AEL, Mitchell A, Brownell J, Miklin DJ, Golden-Mason L, Polyak SJ, Gale MJ, Rosen HR. Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression. PLoS One 2014; 9:e95627. [PMID: 24788809 PMCID: PMC4006833 DOI: 10.1371/journal.pone.0095627] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 03/28/2014] [Indexed: 12/11/2022] Open
Abstract
Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell population in the defense against viruses. pDCs detect viral pathogen associated molecular patterns (PAMPs) through pattern recognition receptors (PRR). PRR/PAMP interactions trigger signaling events that induce interferon (IFN) production to initiate local and systemic responses. pDCs produce Type I and Type III (IFNL) IFNs in response to HCV RNA. Extracellular HCV core protein (Core) is found in the circulation in chronic infection. This study defined how Core modulates PRR signaling in pDCs. Type I and III IFN expression and production following exposure to recombinant Core or β-galactosiade was assessed in human GEN2.2 cells, a pDC cell line. Core suppressed type I and III IFN production in response to TLR agonists and the HCV PAMP agonist of RIG-I. Core suppression of IFN induction was linked with decreased IRF-7 protein levels and increased non-phosphorylated STAT1 protein. Circulating Core protein interferes with PRR signaling by pDCs to suppress IFN production. Strategies to define and target Core effects on pDCs may serve to enhance IFN production and antiviral actions against HCV.
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Affiliation(s)
- Amy E. L. Stone
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Angela Mitchell
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Jessica Brownell
- Department of Global Health, University of Washington, Seattle, Washington, United States of America
| | - Daniel J. Miklin
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Lucy Golden-Mason
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Stephen J. Polyak
- Department of Global Health, University of Washington, Seattle, Washington, United States of America
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
| | - Michael J. Gale
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Hugo R. Rosen
- Integrated Department in Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado, United States of America
- Division of Gastroenterology & Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
- Denver Veteran’s Affairs Medical Center, Denver, Colorado, United States of America
- * E-mail:
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Grady BP, Schinkel J, Thomas XV, Dalgard O. Hepatitis C virus reinfection following treatment among people who use drugs. Clin Infect Dis 2014; 57 Suppl 2:S105-10. [PMID: 23884057 DOI: 10.1093/cid/cit301] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Most new cases of hepatitis C virus (HCV) infections in the developed world are associated with injection drug use. However, treatment for people who inject drugs (PWID) is controversial, as successful treatment risks being followed by new infection. Reinfection after sustained virologic response has been reported, but is the risk so great that treatment should be withheld from this large HCV population? Preliminary evidence suggests that the reinfection incidence is low, but studies to date have been limited by small sample size and few cases of reinfection. In this review, we assess data from studies among PWID of HCV reinfection following treatment to give a reasonable estimate on how frequently reinfection appears and try to characterize those most at risk, The observation that spontaneous clearance of HCV reinfection following treatment occurs is suggestive of a partial protective immunity against persistent infection.
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Affiliation(s)
- Bart P Grady
- Department of Infectious Diseases, Center for Infection and Immunity Amsterdam (CINIMA), Amsterdam, the Netherlands
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Amador-Cañizares Y, Martínez-Donato G, Álvarez-Lajonchere L, Vasallo C, Dausá M, Aguilar-Noriega D, Valenzuela C, Raíces I, Dubuisson J, Wychowski C, Cinza-Estévez Z, Castellanos M, Núñez M, Armas A, González Y, Revé I, Guerra I, Pérez Aguiar &A, Dueñas-Carrera S. HCV-specific immune responses induced by CIGB-230 in combination with IFN-α plus ribavirin. World J Gastroenterol 2014; 20:148-162. [PMID: 24415868 PMCID: PMC3886004 DOI: 10.3748/wjg.v20.i1.148] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Revised: 06/14/2013] [Accepted: 07/13/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze hepatitis C virus (HCV)-specific immune responses in chronically infected patients under triple therapy with interferon-α (IFN-α) plus ribavirin and CIGB-230.
METHODS: CIGB-230 was administered in different schedules with respect to IFN-α plus ribavirin therapy. Paired serum and peripheral blood mononuclear cells (PBMC) samples from baseline and end of treatment were analyzed. The HCV-specific humoral response was tested by enzyme-linked immunosorbent assay, neutralizing antibodies were evaluated by cell culture HCV neutralization assays, PBMC proliferation was assayed by carboxyfluorescein succinimidyl ester staining and IFN-γ secretion was assessed by enzyme-linked immunospot. Data on virological and histological response and their association with immune variables are also provided.
RESULTS: From week 12 to week 48, all groups of patients showed a significant reduction in mean leukocyte counts. Statistically significant reductions in antibody titers were frequent, but only individuals immunized with CIGB-230 as early add-on treatment sustained the core-IgG response, and the neutralizing antibody response was enhanced only in patients receiving CIGB-230. Cell-mediated immune responses also tended to decline, but significant reductions in IFN-γ secretion and total absence of core-specific lymphoproliferation were exclusive of the control group. Only CIGB-230-immunized individuals showed de novo induced lymphoproliferative responses against the structural antigens. Importantly, it was demonstrated that the quality of the CIGB-230-induced immune response depended on the number of doses and timing of administration in relation to the antiviral therapy. Specifically, the administration of 6 doses of CIGB-230 as late add-on to therapy increased the neutralizing antibody activity and the de novo core-specific IFN-γ secretion, both of which were associated with the sustained virological response.
CONCLUSION: CIGB-230, combined with IFN-α-based therapy, modifies the immune response in chronic patients. The study provides evidence for the design of more effective therapeutic vaccine interventions against HCV.
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MESH Headings
- Adult
- Antiviral Agents/administration & dosage
- Antiviral Agents/adverse effects
- Biomarkers/blood
- Cells, Cultured
- Cuba
- Double-Blind Method
- Drug Administration Schedule
- Drug Therapy, Combination
- Female
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepatitis C Antibodies/blood
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Humans
- Immunity, Cellular/drug effects
- Immunity, Humoral/drug effects
- Immunization Schedule
- Interferon alpha-2
- Interferon-alpha/administration & dosage
- Interferon-alpha/adverse effects
- Interferon-gamma/metabolism
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/virology
- Male
- Middle Aged
- Recombinant Proteins/administration & dosage
- Recombinant Proteins/adverse effects
- Ribavirin/administration & dosage
- Ribavirin/adverse effects
- Time Factors
- Treatment Outcome
- Vaccines, DNA/administration & dosage
- Vaccines, DNA/adverse effects
- Viral Hepatitis Vaccines/administration & dosage
- Viral Hepatitis Vaccines/adverse effects
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Hakim MS, Spaan M, Janssen HLA, Boonstra A. Inhibitory receptor molecules in chronic hepatitis B and C infections: novel targets for immunotherapy? Rev Med Virol 2013; 24:125-38. [DOI: 10.1002/rmv.1779] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Mohamad S. Hakim
- Liver Unit, Department of Gastroenterology and Hepatology; Erasmus MC, University Medical Center Rotterdam; Rotterdam The Netherlands
| | - Michelle Spaan
- Liver Unit, Department of Gastroenterology and Hepatology; Erasmus MC, University Medical Center Rotterdam; Rotterdam The Netherlands
| | - Harry L. A. Janssen
- Liver Unit, Department of Gastroenterology and Hepatology; Erasmus MC, University Medical Center Rotterdam; Rotterdam The Netherlands
- Liver Clinic University Health Network, Division of Gastroenterology; University of Toronto; Toronto Canada
| | - Andre Boonstra
- Liver Unit, Department of Gastroenterology and Hepatology; Erasmus MC, University Medical Center Rotterdam; Rotterdam The Netherlands
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Flynn JK, Dore GJ, Hellard M, Yeung B, Rawlinson WD, White PA, Kaldor JM, Lloyd AR, Ffrench RA. Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment. J Gastroenterol Hepatol 2013; 28:1770-81. [PMID: 23663030 PMCID: PMC3808486 DOI: 10.1111/jgh.12265] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM T-cell responses against hepatitis C are believed to be critical in achieving both natural and treatment-induced clearance. However, rapid clearance of antigen with early treatment of primary infection may result in reduced or poorly sustained cellular immunity. This study longitudinally examined Th1 and Th2 hepatitis C virus (HCV)-specific cytokine production and T-cell effector function from subjects enrolled in the Australian Trial in Acute Hepatitis C comparing three groups: treatment-induced clearance (sustained virological response [SVR]), treatment non-response, and untreated spontaneous clearance. METHODS HCV-specific T-cell responses were characterized by HCV peptide ELISpot, in vitro cytokine production, and T-cell flow cytometry assays. RESULTS Treated subjects with a sustained virological response (SVR) displayed a better maintenance of HCV-specific Th1 responses compared to treatment non-responders (higher interferon [IFN]-γ and interleukin (IL)-2 magnitude at week 24, broader IFN-γ responses at weeks 24 and 48, P < 0.05) and significantly increased IFN-γ responses between screening and week 48 (magnitude P = 0.026, breadth P = 0.009). Treatment-induced viral clearance was also associated with a trend toward decreased IL-10 responses (screening to week 48, P = 0.070), higher expression of CD45RO (P = 0.042) and CD38 (P = 0.088) on CD4+ T cells, and higher IFN-γR expression (CD56+ IFN-γR+ P = 0.033) compared to treatment non-responders. Untreated subjects with viral clearance also displayed high magnitude and broad HCV-specific IFN-γ and IL-2 responses early in infection; however, IFN-γ responses were not as well maintained compared to treated subjects with a SVR (week 48 magnitude, breadth P = 0.064). CONCLUSION Treatment-induced viral clearance of recent HCV infection is associated with maintenance of HCV-specific Th1 responses.
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Affiliation(s)
- Jacqueline K Flynn
- Centre for Biomedical Research, Burnet Institute, Melbourne, Australia,Department of Immunology, Monash University, Melbourne, Australia
| | - Gregory J Dore
- The Kirby Institute for Infection and Immunity in Society, University of New South Wales (UNSW), Sydney, Australia
| | - Margaret Hellard
- Centre for Population Health, Burnet Institute, Melbourne, Australia
| | - Barbara Yeung
- The Kirby Institute for Infection and Immunity in Society, University of New South Wales (UNSW), Sydney, Australia
| | - William D Rawlinson
- Virology Division, Southern Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, Australia
| | - Peter A White
- School of Biotechnology and Biomedical Sciences, University of New South Wales, Sydney, Australia
| | - John M Kaldor
- The Kirby Institute for Infection and Immunity in Society, University of New South Wales (UNSW), Sydney, Australia
| | - Andrew R Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Rosemary A Ffrench
- Centre for Biomedical Research, Burnet Institute, Melbourne, Australia,Department of Immunology, Monash University, Melbourne, Australia
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Pasetto A, Aleman S, Chen M. Functional attributes of responding T cells in HCV infection: the recent advances in engineering functional antiviral T cells. Arch Immunol Ther Exp (Warsz) 2013; 62:23-30. [PMID: 23955531 DOI: 10.1007/s00005-013-0248-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 08/05/2013] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus (HCV) is one of the major causes of hepatocellular carcinoma (HCC) around the world. HCV promotes characteristics of cancer stem cells and the infected cells are insensitive to apoptotic signals, which lead to persistent antigen stimulation and T cell exhaustion in the host. In spite of new effective antiviral drugs, new challenges are around the corner as drug-resistant viral strains and drug-drug interactions have already been reported. Considering that there are few effective treatments available for HCC, novel immunotherapies to prevent HCC and late stage HCV-related liver diseases should be considered. Given that adoptive immunotherapy with antigen-specific T lymphocytes has emerged as an effective therapeutic strategy for combating cancer, there is, therefore, reason to examine the possibility of using highly functional HCV-reactive T cells in immunotherapy. This review aims to provide the current understanding of natural HCV responding T cells in HCV infection and to give an update on the novel approaches that have the capacity to ex vivo generate functional T cells for potential adoptive cell therapy. Approaches based on the pMHC tetramer-associated magnetic enrichment, exogenous HCV T cell receptor transfer, and induced pluripotent stem cell technologies are described herein. Their potentials as immunotherapeutic against HCV-related diseases are discussed.
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Affiliation(s)
- Anna Pasetto
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
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Seigel B, Bengsch B, Lohmann V, Bartenschlager R, Blum HE, Thimme R. Factors that determine the antiviral efficacy of HCV-specific CD8(+) T cells ex vivo. Gastroenterology 2013; 144:426-436. [PMID: 23142136 DOI: 10.1053/j.gastro.2012.10.047] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 10/03/2012] [Accepted: 10/31/2012] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Dysfunctional CD8(+) T cells are believed to contribute to the ability of hepatitis C virus (HCV) to evade the immune response. Most studies have focused on the effector functions of HCV-specific CD8(+) T cells or their surface expression of inhibitory receptors. There is currently no information available about the ex vivo ability of HCV-specific CD8(+) T cells to inhibit viral replication (antiviral efficacy). METHODS To analyze the antiviral efficacy of virus-specific CD8(+) T cells ex vivo, we used an immunologic model based on a cell line that expresses HLA-A*02 and contains a stably replicating HCV reporter replicon. We isolated HCV-specific CD8(+) T cells from 18 HLA-A*02-positive patients with chronic HCV infection and 15 subjects with resolved HCV infection (7 spontaneous, 8 after therapy). Replicon cells were labeled with virus-specific peptides; inhibition of HCV replication was determined by measuring luciferase activity after 72 hours of coculture with virus-specific CD8(+) T cells. RESULTS HCV-specific CD8(+) T cells from patients with chronic HCV infection had a significantly lower antiviral efficacy than influenza-, Epstein-Barr virus-, and cytomegalovirus-specific CD8(+) T cells. Antiviral efficacy was associated with the ability of virus-specific CD8(+) T cells to secrete interferon gamma. The antiviral efficacy of HCV-specific CD8(+) T cells was linked to surface expression of CD127 and PD-1. The cytokines interleukin-2, interleukin-7, and interleukin-15 increased the antiviral efficacy of CD127-positive but not of CD127-negative, HCV-specific CD8(+) T cells. Spontaneous, but not antiviral therapy-induced, viral clearance was associated with increased antiviral efficacy. CONCLUSIONS The ability of CD8(+) T cells to inhibit HCV replication ex vivo is associated with their ability to secrete interferon gamma and their surface expression of CD127 and PD-1.
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Affiliation(s)
- Bianca Seigel
- Department of Medicine II, University Hospital of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany
| | - Bertram Bengsch
- Department of Medicine II, University Hospital of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany
| | - Volker Lohmann
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany
| | - Ralf Bartenschlager
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany
| | - Hubert E Blum
- Department of Medicine II, University Hospital of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Medicine II, University Hospital of Freiburg, Freiburg, Germany.
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Boni C, Laccabue D, Lampertico P, Giuberti T, Viganò M, Schivazappa S, Alfieri A, Pesci M, Gaeta GB, Brancaccio G, Colombo M, Missale G, Ferrari C. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012; 143:963-73.e9. [PMID: 22796241 DOI: 10.1053/j.gastro.2012.07.014] [Citation(s) in RCA: 298] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Revised: 06/29/2012] [Accepted: 07/03/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control. METHODS We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa-induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen-negative patients with chronic infections. RESULTS Although HBV-specific T cells from nucleos(t)ide analogue-treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue-treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection. CONCLUSIONS In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.
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Affiliation(s)
- Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
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Zhang Y, Liu Y, Zhao Y, Shi L, Ma L, Yan H, Wu H, Wei L, Dong T, Chen X. Hepatitis C virus nonstructural protein specific T cells are associated with virological responses to combination therapy in chronic HCV patients. Liver Int 2012; 32:102-9. [PMID: 22098382 DOI: 10.1111/j.1478-3231.2011.02652.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2011] [Accepted: 08/26/2011] [Indexed: 02/13/2023]
Abstract
BACKGROUND Virus-specific T-cell responses play a major role in antiviral immune response. However, the effect of hepatitis C virus (HCV)-specific T-cell responses on combination therapy still remains controversial. AIMS To identify the association between HCV-specific T cell responses and efficiency of combination therapy. METHODS To address this issue, a longitudinal analysis of HCV-specific T-cell responses to overlapping peptides covering HCV-nonstructural protein (NS) was performed using ELISpot assay in 48 chronically infected HCV-1b patients during combination treatment with peginterferon-alfa and ribavirin. RESULTS Fifty-two percent of chronic HCV patients showed detectable HCV-NS3, NS4 or NS5A specific T-cell responses before therapy, with NS3 appearing to be the most immunodominant protein followed by NS5A and NS4. In addition, the percentage of patients responding to peptide stimulation was higher in patients with sustained virological response (SVR) when compared with those without SVR. Dynamics of HCV-NS-specific T-cell responses were further analysed; we found that HCV-specific T-cell responses maintained higher levels at 12 weeks into treatment in patients with SVR. In contrast, HCV-specific T-cell responses in patients without SVR declined significantly at 4 weeks into treatment and maintained low levels at 12 weeks. CONCLUSION We found that the HCV-specific T-cell responses were associated with good viral control in patients with combination therapy.
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Affiliation(s)
- Yonghong Zhang
- Beijing You'an Hospital, Capital Medical University, Beijing, China
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Abstract
HCV has the tendency to persist in the majority of infected patients despite the presence of virus-specific CD8+ T-cell responses. The HCV-specific CD8+ T-cell pool consists of heterogenous subsets that can be elegantly distinguished by CD127 expression. Indeed, HCV-specific CD8+ T cells with high levels of CD127 expression are characterized by features consistent with memory differentiation, while HCV-specific CD8+ T cells with low levels of CD127 expression display an exhausted phenotype characterized by the coexpression of PD-1 and other inhibitory receptors. In this article, the current knowledge about the phenotypes and differentiation profiles of HCV-specific CD8+ T cells is summarized. Clearly, the differentiation of HCV-specific CD8+ T cells in chronic HCV infection results from complex virus–host interactions, and both viral and immunological factors shape the HCV-specific CD8+ T-cell pool.
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Affiliation(s)
- Bertram Bengsch
- University of Freiburg, Freiburg, Germany; Uniklinik Freiburg, Hugstetter Street, 55, 79106 Freiburg, Germany
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