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Magri A, Manfredi GF, Smirne C, Pigni S, Burlone ME, Bellan M, Vercellino N, Minisini R, Pirisi M. Impact of Age and Sex on Viral Load in Hepatitis C Virus Infection. Viruses 2024; 17:21. [PMID: 39861810 PMCID: PMC11769058 DOI: 10.3390/v17010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/24/2024] [Accepted: 12/26/2024] [Indexed: 01/27/2025] Open
Abstract
The determinants of hepatitis C virus (HCV) viral load remain incompletely understood and may differ in females, who are relatively protected from the consequences of HCV infection during their reproductive years. We aimed to evaluate how age affects the relationship between sex and viral load. n = 922 patients (males n = 497, median age 62 years), all naïve to direct antiviral agents, were studied. Females were older (median age 68 vs. 57, p < 0.001) and had a higher prevalence of genotype 2 (33% vs. 20%, p < 0.001) than males; there was no difference between sexes regarding the METAVIR stage. The median HCV RNA concentration was 1.017 × 106 IU/mL (interquartile range, 0.286-2.400). Among males, the METAVIR stage was the strongest independent predictor of a high viral load (defined as the highest two quartiles), with advanced stages inversely associated with viral load (p = 0.008). In females, age was the only independent predictor, with women aged ≥55 years exhibiting higher loads (p = 0.009). These findings are consistent with data showing that estrogens exert an antiviral effect in in vitro models of HCV. Their declining levels after the menopause may explain the "catch-up" phase of HCV-related liver disease, observed in older women.
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Affiliation(s)
- Andrea Magri
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7JT, UK
| | - Giulia Francesca Manfredi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Silvia Pigni
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Michela Emma Burlone
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Nicole Vercellino
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy; (A.M.); (G.F.M.); (C.S.); (S.P.); (M.E.B.); (M.B.); (N.V.); (R.M.)
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Bengu N, Cromhout G, Adland E, Govender K, Herbert N, Lim N, Fillis R, Sprenger K, Vieira V, Kannie S, van Lobenstein J, Chinniah K, Kapongo C, Bhoola R, Krishna M, Mchunu N, Pascucci GR, Cotugno N, Palma P, Tagarro A, Rojo P, Roider J, Garcia-Guerrero MC, Ochsenbauer C, Groll A, Reddy K, Giaquinto C, Rossi P, Hong S, Dong K, Ansari MA, Puertas MC, Ndung'u T, Capparelli E, Lichterfeld M, Martinez-Picado J, Kappes JC, Archary M, Goulder P. Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission. Nat Med 2024; 30:2796-2804. [PMID: 38843818 PMCID: PMC11485204 DOI: 10.1038/s41591-024-03105-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 06/03/2024] [Indexed: 07/04/2024]
Abstract
After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.
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Affiliation(s)
- Nomonde Bengu
- Queen Nandi Regional Hospital, Empangeni, South Africa
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Gabriela Cromhout
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Department of Paediatrics, University of KwaZulu-Natal, Durban, South Africa
| | - Emily Adland
- Department of Paediatrics, University of Oxford, Oxford, UK
| | | | | | - Nicholas Lim
- Department of Paediatrics, University of Oxford, Oxford, UK
| | - Rowena Fillis
- Harry Gwala Regional Hospital, Pietermaritzburg, South Africa
| | - Kenneth Sprenger
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | | | - Samantha Kannie
- General Justice Gizenga Mpanza Regional Hospital, Stanger, South Africa
| | | | | | | | - Roopesh Bhoola
- Harry Gwala Regional Hospital, Pietermaritzburg, South Africa
| | - Malini Krishna
- Harry Gwala Regional Hospital, Pietermaritzburg, South Africa
| | - Noxolo Mchunu
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Giuseppe Rubens Pascucci
- Clinical Immunology and Vaccinology Unit, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy
- Probiomics S.r.l., Rome, Italy
| | - Nicola Cotugno
- Clinical Immunology and Vaccinology Unit, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy
- University of Rome Tor Vergata, Rome, Italy
| | - Paolo Palma
- Clinical Immunology and Vaccinology Unit, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy
- University of Rome Tor Vergata, Rome, Italy
| | - Alfredo Tagarro
- Fundación de Investigación Biomédica Hospital 12 de Octubre, Instituto de Investigación 12 de Octubre (imas12), Madrid, Spain
- Department of Pediatrics, Infanta Sofia University Hospital and Henares University Hospital Foundation for Biomedical Research and Innovation, Madrid, Spain
- Universidad Europea de Madrid, Madrid, Spain
| | - Pablo Rojo
- Fundación de Investigación Biomédica Hospital 12 de Octubre, Instituto de Investigación 12 de Octubre (imas12), Madrid, Spain
| | | | | | | | | | - Kavidha Reddy
- Africa Health Research Institute, Durban, South Africa
| | | | - Paolo Rossi
- Clinical Immunology and Vaccinology Unit, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy
- University of Rome Tor Vergata, Rome, Italy
| | - Seohyun Hong
- Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA
| | - Krista Dong
- Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA
| | - M Azim Ansari
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Maria C Puertas
- IrsiCaixa AIDS Research Institute, Barcelona, Spain
- Consorcio Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Thumbi Ndung'u
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
- Africa Health Research Institute, Durban, South Africa
- Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA
- Division of Infection and Immunity, University College London, London, UK
| | | | | | - Javier Martinez-Picado
- IrsiCaixa AIDS Research Institute, Barcelona, Spain
- Consorcio Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
- Infectious Diseases and Immunity Department, University of Vic-Central University of Catalonia, Vic, Spain
| | - John C Kappes
- University of Alabama at Birmingham, Birmingham, AL, USA
- Birmingham Veterans Affairs Medical Center, Research Service, Birmingham, AL, USA
| | - Moherndran Archary
- Department of Paediatrics, University of KwaZulu-Natal, Durban, South Africa
| | - Philip Goulder
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
- Department of Paediatrics, University of Oxford, Oxford, UK.
- Africa Health Research Institute, Durban, South Africa.
- Ragon Institute of MGH, MIT and Harvard, Boston, MA, USA.
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Sallam M, Khalil R. Contemporary Insights into Hepatitis C Virus: A Comprehensive Review. Microorganisms 2024; 12:1035. [PMID: 38930417 PMCID: PMC11205832 DOI: 10.3390/microorganisms12061035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis C virus (HCV) remains a significant global health challenge. Approximately 50 million people were living with chronic hepatitis C based on the World Health Organization as of 2024, contributing extensively to global morbidity and mortality. The advent and approval of several direct-acting antiviral (DAA) regimens significantly improved HCV treatment, offering potentially high rates of cure for chronic hepatitis C. However, the promising aim of eventual HCV eradication remains challenging. Key challenges include the variability in DAA access across different regions, slightly variable response rates to DAAs across diverse patient populations and HCV genotypes/subtypes, and the emergence of resistance-associated substitutions (RASs), potentially conferring resistance to DAAs. Therefore, periodic reassessment of current HCV knowledge is needed. An up-to-date review on HCV is also necessitated based on the observed shifts in HCV epidemiological trends, continuous development and approval of therapeutic strategies, and changes in public health policies. Thus, the current comprehensive review aimed to integrate the latest knowledge on the epidemiology, pathophysiology, diagnostic approaches, treatment options and preventive strategies for HCV, with a particular focus on the current challenges associated with RASs and ongoing efforts in vaccine development. This review sought to provide healthcare professionals, researchers, and policymakers with the necessary insights to address the HCV burden more effectively. We aimed to highlight the progress made in managing and preventing HCV infection and to highlight the persistent barriers challenging the prevention of HCV infection. The overarching goal was to align with global health objectives towards reducing the burden of chronic hepatitis, aiming for its eventual elimination as a public health threat by 2030.
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Affiliation(s)
- Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Roaa Khalil
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan
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Mota GD, Marques CL, Ribeiro SL, Albuquerque C, Castro G, Fernandino D, Omura F, Ranzolin A, Resende G, Silva N, Souza M, Studart S, Xavier R, Yazbek M, Pinheiro MM. HLA-B27 did not protect against COVID-19 in patients with axial spondyloarthritis - data from the ReumaCov-Brasil Registry. Adv Rheumatol 2023; 63:56. [PMID: 38031143 DOI: 10.1186/s42358-023-00340-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 11/20/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Some studies have suggested the HLA-B27 gene may protect against some infections, as well as it could play a benefit role on the viral clearance, including hepatitis C and HIV. However, there is lack of SARS-CoV-2 pandemic data in spondyloarthritis (SpA) patients. AIM To evaluate the impact of HLA-B27 gene positivity on the susceptibility and severity of COVID-19 and disease activity in axial SpA patients. METHODS The ReumaCoV-Brasil is a multicenter, observational, prospective cohort designed to monitor immune-mediated rheumatic diseases patients during SARS-CoV-2 pandemic in Brazil. Axial SpA patients, according to the ASAS classification criteria (2009), and only those with known HLA-B27 status, were included in this ReumaCov-Brasil's subanalysis. After pairing them to sex and age, they were divided in two groups: with (cases) and without (control group) COVID-19 diagnosis. Other immunodeficiency diseases, past organ or bone marrow transplantation, neoplasms and current chemotherapy were excluded. Demographic data, managing of COVID-19 (diagnosis, treatment, and outcomes, including hospitalization, mechanical ventilation, and death), comorbidities, clinical details (disease activity and concomitant medication) were collected using the Research Electronic Data Capture (REDCap) database. Data are presented as descriptive analysis and multiple regression models, using SPSS program, version 20. P level was set as 5%. RESULTS From May 24th, 2020 to Jan 24th, 2021, a total of 153 axial SpA patients were included, of whom 85 (55.5%) with COVID-19 and 68 (44.4%) without COVID-19. Most of them were men (N = 92; 60.1%) with mean age of 44.0 ± 11.1 years and long-term disease (11.7 ± 9.9 years). Regarding the HLA-B27 status, 112 (73.2%) patients tested positive. There were no significant statistical differences concerning social distancing, smoking, BMI (body mass index), waist circumference and comorbidities. Regarding biological DMARDs, 110 (71.8%) were on TNF inhibitors and 14 (9.15%) on IL-17 antagonists. Comparing those patients with and without COVID-19, the HLA-B27 positivity was not different between groups (n = 64, 75.3% vs. n = 48, 48%, respectively; p = 0.514). In addition, disease activity was similar before and after the infection. Interestingly, no new episodes of arthritis, enthesitis or extra-musculoskeletal manifestations were reported after the COVID-19. The mean time from the first symptoms to hospitalization was 7.1 ± 3.4 days, and although the number of hospitalization days was numerically higher in the B27 positive group, no statistically significant difference was observed (5.7 ± 4.11 for B27 negative patients and 13.5 ± 14.8 for B27 positive patients; p = 0.594). Only one HLA-B27 negative patient died. No significant difference was found regarding concomitant medications, including conventional or biologic DMARDs between the groups. CONCLUSIONS No significant difference of COVID-19 frequency rate was observed in patients with axial SpA regarding the HLA-B27 positivity, suggesting a lack of protective effect with SARS-CoV-2 infection. In addition, the disease activity was similar before and after the infection. TRIAL REGISTRATION This study was approved by the Brazilian Committee of Ethics in Human Research (CONEP), CAAE 30186820.2.1001.8807, and was registered at the Brazilian Registry of Clinical Trials - REBEC, RBR-33YTQC. All patients read and signed the informed consent form before inclusion.
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Affiliation(s)
- G D Mota
- UNIFESP, Rua Borges Lagoa, 913/ 51-53 - Vila Clementino, São Paulo, CEP: 04038-034, SP, Brazil
| | | | | | | | | | | | - F Omura
- Clinica Omura, S?o Paulo, Brazil
| | | | | | | | - M Souza
- SCBH, Belo Horizonte, Brazil
| | | | | | | | - Marcelo M Pinheiro
- UNIFESP, Rua Borges Lagoa, 913/ 51-53 - Vila Clementino, São Paulo, CEP: 04038-034, SP, Brazil.
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Maunye TK, Gededzha MP, Blackard JT, Rakgole JN, Selabe SG. Hepatitis C Virus Genotype 5 Variability in Treatment-Naïve Patients in South Africa. Intervirology 2023; 66:77-87. [PMID: 37231989 PMCID: PMC10353306 DOI: 10.1159/000528178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/14/2022] [Indexed: 05/27/2023] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) genotype 5 was originally identified in South Africa, where it represents 35-60% of all HCV infections. There are limited data on resistance-associated variants (RAVs) in South Africa. Thus, we investigated variability within the NS3/NS4A, NS5A, and NS5B genes of treatment-naïve individuals with HCV genotype 5 infection at the Dr. George Mukhari Academic Hospital (DGMAH) in Pretoria, South Africa. METHODS Nested PCR was performed to amplify the NS3/4A, NS5A, and NS5B genes. RAVs were evaluated using the Geno2pheno tool. RESULTS In the NS3/4A gene, F56S and T122A were detected in one sample each. The D168E mutation was detected in 7 samples. Within the NS5A gene, the T62M mutation was detected in 2 individuals. In the NS5B gene, 8 of 12 individuals (67%) had the A421V mutation, while all 12 individuals (100%) had the S486A mutation. DISCUSSION RAVs were detected frequently among treatment-naïve individuals with HCV genotype 5 infection in South Africa. Thus, resistance testing may be prudent when initiating treatment of patients with genotype 5 infection. Additional population-based studies are needed to understand the prevalence of these RAVs during HCV genotype 5 infection.
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Affiliation(s)
- Tshegofatso K Maunye
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University, Pretoria, South Africa
- National Health Laboratory Service, Pretoria, South Africa
| | - Maemu P Gededzha
- Department of Immunology, Faculty of Health Sciences, University of Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa
| | - Jason T Blackard
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University, Pretoria, South Africa,
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA,
| | - Johnny N Rakgole
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University, Pretoria, South Africa
| | - Selokela G Selabe
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University, Pretoria, South Africa
- National Health Laboratory Service, Pretoria, South Africa
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Mechanisms and Consequences of Genetic Variation in Hepatitis C Virus (HCV). Curr Top Microbiol Immunol 2023; 439:237-264. [PMID: 36592248 DOI: 10.1007/978-3-031-15640-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Chronic infection with hepatitis C virus (HCV) is an important contributor to the global incidence of liver diseases, including liver cirrhosis and hepatocellular carcinoma. Although common for single-stranded RNA viruses, HCV displays a remarkable high level of genetic diversity, produced primarily by the error-prone viral polymerase and host immune pressure. The high genetic heterogeneity of HCV has led to the evolution of several distinct genotypes and subtypes, with important consequences for pathogenesis, and clinical outcomes. Genetic variability constitutes an evasion mechanism against immune suppression, allowing the virus to evolve epitope escape mutants that avoid immune recognition. Thus, heterogeneity and variability of the HCV genome represent a great hindrance for the development of vaccines against HCV. In addition, the high genetic plasticity of HCV allows the virus to rapidly develop antiviral resistance mutations, leading to treatment failure and potentially representing a major hindrance for the cure of chronic HCV patients. In this chapter, we will present the central role that genetic diversity has in the viral life cycle and epidemiology of HCV. Incorporation errors and recombination, both the result of HCV polymerase activity, represent the main mechanisms of HCV evolution. The molecular details of both mechanisms have been only partially clarified and will be presented in the following sections. Finally, we will discuss the major consequences of HCV genetic diversity, namely its capacity to rapidly evolve antiviral and immunological escape variants that represent an important limitation for clearance of acute HCV, for treatment of chronic hepatitis C and for broadly protective vaccines.
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Osuch S, Laskus T, Perlejewski K, Berak H, Bukowska-Ośko I, Pollak A, Zielenkiewicz M, Radkowski M, Caraballo Cortés K. CD8 + T-Cell Exhaustion Phenotype in Chronic Hepatitis C Virus Infection Is Associated With Epitope Sequence Variation. Front Immunol 2022; 13:832206. [PMID: 35386708 PMCID: PMC8977521 DOI: 10.3389/fimmu.2022.832206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Background and Aims During chronic hepatitis C virus (HCV) infection, CD8+ T-cells become functionally exhausted, undergoing progressive phenotypic changes, i.e., overexpression of “inhibitory” molecules such as PD-1 (programmed cell death protein 1) and/or Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3). The extreme intrahost genetic diversity of HCV is a major mechanism of immune system evasion, facilitating epitope escape. The aim of the present study was to determine whether T-cell exhaustion phenotype in chronic HCV infection is related to the sequence repertoire of NS3 viral immunodominant epitopes. Methods The study population was ninety prospective patients with chronic HCV genotype 1b infection. Populations of peripheral blood CD8+ T-cells expressing PD-1/Tim-3 were assessed by multiparametric flow cytometry, including HCV-specific T-cells after magnetic-based enrichment using MHC-pentamer. Autologous epitope sequences were inferred from next-generation sequencing. The correction of sequencing errors and genetic variants reconstruction was performed using Quasirecomb. Results There was an interplay between the analyzed epitopes sequences and exhaustion phenotype of CD8+ T-cells. A predominance of NS31406 epitope sequence, representing neither prototype KLSGLGLNAV nor cross-reactive variants (KLSSLGLNAV, KLSGLGINAV or KLSALGLNAV), was associated with higher percentage of HCV-specific CD8+PD-1+Tim-3+ T-cells, P=0.0102. Variability (at least two variants) of NS31406 epitope sequence was associated with increased frequencies of global CD8+PD-1+Tim-3+ T-cells (P=0.0197) and lower frequencies of CD8+PD-1−Tim-3− T-cells (P=0.0079). In contrast, infection with NS31073 dominant variant epitope (other than prototype CVNGVCWTV) was associated with lower frequency of global CD8+PD-1+Tim-3+ T-cells (P=0.0054). Conclusions Our results indicate that PD-1/Tim-3 receptor expression is largely determined by viral epitope sequence and is evident for both HCV-specific and global CD8+ T-cells, pointing to the importance of evaluating autologous viral epitope sequences in the investigation of CD8+ T-cell exhaustion in HCV infection.
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Affiliation(s)
- Sylwia Osuch
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Hanna Berak
- Outpatient Clinic, Warsaw Hospital for Infectious Diseases, Warsaw, Poland
| | - Iwona Bukowska-Ośko
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Agnieszka Pollak
- Department of Human Genetics, Medical University of Warsaw, Warsaw, Poland
| | | | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Kamila Caraballo Cortés
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
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Echeverría N, Comas V, Aldunate F, Perbolianachis P, Moreno P, Cristina J. In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet? World J Hepatol 2021; 13:1234-1268. [PMID: 34786164 PMCID: PMC8568586 DOI: 10.4254/wjh.v13.i10.1234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/14/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is responsible for no less than 71 million people chronically infected and is one of the most frequent indications for liver transplantation worldwide. Despite direct-acting antiviral therapies fuel optimism in controlling HCV infections, there are several obstacles regarding treatment accessibility and reinfection continues to remain a possibility. Indeed, the majority of new HCV infections in developed countries occur in people who inject drugs and are more plausible to get reinfected. To achieve global epidemic control of this virus the development of an effective prophylactic or therapeutic vaccine becomes a must. The coronavirus disease 19 (COVID-19) pandemic led to auspicious vaccine development against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which has renewed interest on fighting HCV epidemic with vaccination. The aim of this review is to highlight the current situation of HCV vaccine candidates designed to prevent and/or to reduce HCV infectious cases and their complications. We will emphasize on some of the crossroads encountered during vaccine development against this insidious virus, together with some key aspects of HCV immunology which have, so far, hampered the progress in this area. The main focus will be on nucleic acid-based as well as recombinant viral vector-based vaccine candidates as the most novel vaccine approaches, some of which have been recently and successfully employed for SARS-CoV-2 vaccines. Finally, some ideas will be presented on which methods to explore for the design of live-attenuated vaccines against HCV.
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Affiliation(s)
- Natalia Echeverría
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Victoria Comas
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay
| | - Fabián Aldunate
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Paula Perbolianachis
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Pilar Moreno
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay
| | - Juan Cristina
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
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Mutational escape from cellular immunity in viral hepatitis: variations on a theme. Curr Opin Virol 2021; 50:110-118. [PMID: 34454351 DOI: 10.1016/j.coviro.2021.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/05/2021] [Indexed: 12/19/2022]
Abstract
Approx. 320 million individuals worldwide are chronically infected with hepatitis viruses, contributing to viral hepatitis being one of the 10 leading causes of death. Cellular adaptive immunity, namely CD4+ and CD8+ T cells, plays an important role in viral clearance and control. Two main mechanisms, however, may lead to failure of the virus-specific T-cell response: T-cell exhaustion and mutational viral escape. Viral escape has been studied in detail in hepatitis C virus (HCV) infection, where it is thought to affect approx. 50% of virus-specific CD8+ T-cell responses in persistent infection, to influence natural infection outcome and to contribute to failure of preventive vaccination strategies. In hepatitis B virus (HBV) as well as HBV/hepatitis D virus (HDV) co-infection, the impact of viral escape has been studied in detail only recently.
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10
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Saraceni C, Birk J. A Review of Hepatitis B Virus and Hepatitis C Virus Immunopathogenesis. J Clin Transl Hepatol 2021; 9:409-418. [PMID: 34221927 PMCID: PMC8237136 DOI: 10.14218/jcth.2020.00095] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/21/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Despite the advances in therapy, hepatitis B virus (HBV) and hepatitis C virus (HCV) still represent a significant global health burden, both as major causes of cirrhosis, hepatocellular carcinoma, and death worldwide. HBV is capable of incorporating its covalently closed circular DNA into the host cell's hepatocyte genome, making it rather difficult to eradicate its chronic stage. Successful viral clearance depends on the complex interactions between the virus and host's innate and adaptive immune response. One encouraging fact on hepatitis B is the development and effective distribution of the HBV vaccine. This has significantly reduced the spread of this virus. HCV is a RNA virus with high mutagenic capacity, thus enabling it to evade the immune system and have a high rate of chronic progression. High levels of HCV heterogeneity and its mutagenic capacity have made it difficult to create an effective vaccine. The recent advent of direct acting antivirals has ushered in a new era in hepatitis C therapy. Sustained virologic response is achieved with DAAs in 85-99% of cases. However, this still leads to a large population of treatment failures, so further advances in therapy are still needed. This article reviews the immunopathogenesis of HBV and HCV, their properties contributing to host immune system avoidance, chronic disease progression, vaccine efficacy and limitations, as well as treatment options and common pitfalls of said therapy.
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Affiliation(s)
- Corey Saraceni
- Correspondence to: Corey Saraceni, University of Connecticut School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, 263 Farmington Avenue, Farmington, CT 06030-8074, USA. Tel: +1-203-733-7408, Fax: +1-860-679-3159, E-mail:
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11
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Smith S, Honegger JR, Walker C. T-Cell Immunity against the Hepatitis C Virus: A Persistent Research Priority in an Era of Highly Effective Therapy. Cold Spring Harb Perspect Med 2021; 11:cshperspect.a036954. [PMID: 32205413 PMCID: PMC7778213 DOI: 10.1101/cshperspect.a036954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Approximately 70% of acute hepatitis C virus (HCV) infections become chronic, indicating that the virus is exceptionally well adapted to persist in humans with otherwise normal immune function. Robust, lifelong replication of this small RNA virus does not require a generalized failure of immunity. HCV effectively subverts innate and adaptive host defenses while leaving immunity against other viruses intact. Here, the role of CD4+ and CD8+ T-cell responses in control of HCV infection and their failure to prevent virus persistence in most individuals are reviewed. Two issues of practical importance remain priorities in an era of highly effective antiviral therapy for chronic hepatitis C. First, the characteristics of successful T-cell responses that promote resolution of HCV infection are considered, as they will underpin development of vaccines that prevent HCV persistence. Second, defects in T-cell immunity that facilitate HCV persistence and whether they are reversed after antiviral cure to provide protection from reinfection are also addressed.
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Affiliation(s)
- Stephanie Smith
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Jonathan R. Honegger
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Christopher Walker
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
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12
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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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13
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Diversity of the hepatitis C virus NS5B gene during HIV co-infection. PLoS One 2020; 15:e0237162. [PMID: 32750098 PMCID: PMC7402467 DOI: 10.1371/journal.pone.0237162] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/20/2020] [Indexed: 01/06/2023] Open
Abstract
Viral diversity is an important feature of hepatitis C virus (HCV) infection and an important predictor of disease progression and treatment response. HIV/HCV co-infection is associated with enhanced HCV replication, increased fibrosis, and the development of liver disease. HIV also increases quasispecies diversity of HCV structural genes, although limited data are available regarding the impact of HIV on non-structural genes of HCV, particularly in the absence of direct-acting therapies. The genetic diversity and presence of drug resistance mutations within the RNA-dependent RNA polymerase (NS5B) gene were examined in 3 groups of women with HCV genotype 1a infection, including those with HCV mono-infection, antiretroviral (ART)-naïve women with HIV/HCV co-infection and CD4 cell count <350 cells/mm3, and ART-naïve women with HIV/HCV co-infection and CD4 cell count ≥350 cells/mm3. None had ever been treated for HCV infection. There was evidence of significant diversity across the entire NS5B gene in all women. There were several nucleotides and amino acids with distinct distributions across the three study groups, although no obvious clustering of NS5B sequences was observed based on HIV co-infection or CD4 cell count. Polymorphisms at amino acid positions associated with resistance to dasabuvir and sofosbuvir were limited, although the Q309R variant associated with ribavirin resistance was present in 12 individuals with HCV mono-infection, 8 HIV/HCV co-infected individuals with CD4 <350 cells/mm3, and 12 HIV/HCV co-infected individuals with CD4 ≥350 cells/mm3. Previously reported fitness altering mutations were rare. CD8+ T cell responses against the human leukocyte antigen (HLA) B57-restricted epitopes NS5B2629-2637 and NS5B2936-2944 are critical for HCV control and were completely conserved in 44 (51.8%) and 70 (82.4%) study participants. These data demonstrate extensive variation across the NS5B gene. Genotypic variation may have a profound impact on HCV replication and pathogenesis and deserves careful evaluation.
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Barquera R, Hernández-Zaragoza DI, Bravo-Acevedo A, Arrieta-Bolaños E, Clayton S, Acuña-Alonzo V, Martínez-Álvarez JC, López-Gil C, Adalid-Sáinz C, Vega-Martínez MDR, Escobedo-Ruíz A, Juárez-Cortés ED, Immel A, Pacheco-Ubaldo H, González-Medina L, Lona-Sánchez A, Lara-Riegos J, Sánchez-Fernández MGDJ, Díaz-López R, Guizar-López GU, Medina-Escobedo CE, Arrazola-García MA, Montiel-Hernández GD, Hernández-Hernández O, Ramos-de la Cruz FDR, Juárez-Nicolás F, Pantoja-Torres JA, Rodríguez-Munguía TJ, Juárez-Barreto V, Delgado-Aguirre H, Escutia-González AB, Goné-Vázquez I, Benítez-Arvizu G, Arellano-Prado FP, García-Arias VE, Rodríguez-López ME, Méndez-Mani P, García-Álvarez R, González-Martínez MDR, Aquino-Rubio G, Escareño-Montiel N, Vázquez-Castillo TV, Uribe-Duarte MG, Ruíz-Corral MDJ, Ortega-Yáñez A, Bernal-Felipe N, Gómez-Navarro B, Arriaga-Perea AJ, Martínez-Bezies V, Macías-Medrano RM, Aguilar-Campos JA, Solís-Martínez R, Serrano-Osuna R, Sandoval-Sandoval MJ, Jaramillo-Rodríguez Y, Salgado-Adame A, Juárez-de la Cruz F, Novelo-Garza B, Pavón-Vargas MDLÁ, Salgado-Galicia N, Bortolini MC, Gallo C, Bedoya G, Rothhammer F, González-José R, Ruiz-Linares A, Canizales-Quinteros S, Romero-Hidalgo S, Krause J, Zúñiga J, Yunis EJ, Bekker-Méndez C, Granados J. The immunogenetic diversity of the HLA system in Mexico correlates with underlying population genetic structure. Hum Immunol 2020; 81:461-474. [PMID: 32651014 DOI: 10.1016/j.humimm.2020.06.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022]
Abstract
We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) allele groups and alleles by PCR-SSP based typing in a total of 15,318 mixed ancestry Mexicans from all the states of the country divided into 78 sample sets, providing information regarding allelic and haplotypic frequencies and their linkage disequilibrium, as well as admixture estimates and genetic substructure. We identified the presence of 4268 unique HLA extended haplotypes across Mexico and find that the ten most frequent (HF > 1%) HLA haplotypes with significant linkage disequilibrium (Δ'≥0.1) in Mexico (accounting for 20% of the haplotypic diversity of the country) are of primarily Native American ancestry (A*02~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*08~DQB1*04, A*68~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*14~DQB1*03:01, A*24~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*04~DQB1*03:02, A*02~B*40:02~DRB1*04~DQB1*03:02, A*68~B*35~DRB1*04~DQB1*03:02, A*02~B*15:01~DRB1*04~DQB1*03:02). Admixture estimates obtained by a maximum likelihood method using HLA-A/-B/-DRB1 as genetic estimators revealed that the main genetic components in Mexico as a whole are Native American (ranging from 37.8% in the northern part of the country to 81.5% in the southeastern region) and European (ranging from 11.5% in the southeast to 62.6% in northern Mexico). African admixture ranged from 0.0 to 12.7% not following any specific pattern. We were able to detect three major immunogenetic clusters correlating with genetic diversity and differential admixture within Mexico: North, Central and Southeast, which is in accordance with previous reports using genome-wide data. Our findings provide insights into the population immunogenetic substructure of the whole country and add to the knowledge of mixed ancestry Latin American population genetics, important for disease association studies, detection of demographic signatures on population variation and improved allocation of public health resources.
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Affiliation(s)
- Rodrigo Barquera
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany; Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico.
| | - Diana Iraíz Hernández-Zaragoza
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico; Immunogenetics Unit, Técnicas Genéticas Aplicadas a la Clínica (TGAC), Mexico City, Mexico
| | - Alicia Bravo-Acevedo
- Blood Bank, UMAE Hospital de Gineco Obstetricia No. 4 "Luis Castelazo Ayala", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | | | - Stephen Clayton
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany
| | - Víctor Acuña-Alonzo
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Julio César Martínez-Álvarez
- HLA Laboratory, Central Blood Bank, Hospital de Especialidades, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Concepción López-Gil
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | - Carmen Adalid-Sáinz
- Laboratory of Histocompatibility, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - María Del Rosario Vega-Martínez
- Molecular Biology and Histocompatibility Laboratory, Hospital Central Sur de Alta Especialidad, Petróleos Mexicanos (PEMEX), Mexico City, Mexico
| | - Araceli Escobedo-Ruíz
- Histocompatibility Laboratory, Hospital de Especialidades, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Eva Dolores Juárez-Cortés
- Histocompatibility Laboratory, Central Blood Bank, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Alexander Immel
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany; Institute of Clinical Molecular Biology (IKMB), Kiel University, University Hospital, Schleswig-Holstein, Germany
| | - Hanna Pacheco-Ubaldo
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Liliana González-Medina
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Abraham Lona-Sánchez
- Molecular Genetics Laboratory, Escuela Nacional de Antropología e Historia (ENAH), Mexico City, Mexico
| | - Julio Lara-Riegos
- Chemistry Faculty, Universidad Autónoma de Yucatán (UADY), Mérida, Yucatán, Mexico
| | - María Guadalupe de Jesús Sánchez-Fernández
- Department of Nephrology and Transplantation Unit, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Rosario Díaz-López
- Molecular Biology Laboratory, Hospital Central Militar, Secretaría de la Defensa Nacional (SEDENA), Mexico City, Mexico
| | - Gregorio Ulises Guizar-López
- Molecular Biology Laboratory, Hospital Central Militar, Secretaría de la Defensa Nacional (SEDENA), Mexico City, Mexico
| | - Carolina Elizabeth Medina-Escobedo
- Unit of Research and Education in Health, Unidad Médica de Alta Especialidad (UMAE) # 10, Instituto Mexicano del Seguro Social (IMSS), Mérida, Yucatán, Mexico
| | - María Araceli Arrazola-García
- HLA Laboratory, Central Blood Bank, Hospital de Especialidades, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | | | | | - Flor Del Rocío Ramos-de la Cruz
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | | | - Jorge Arturo Pantoja-Torres
- Immunology Division, Unidad Médica de Alta Especialidad (UMAE) # 1, Instituto Mexicano del Seguro Social (IMSS), León, Guanajuato, Mexico
| | - Tirzo Jesús Rodríguez-Munguía
- Molecular Biology Laboratory, Hospital General "Norberto Treviño Zapata", Dirección de Servicios de Salud de Tamaulipas, Ciudad Victoria, Tamaulipas, Mexico
| | | | - Héctor Delgado-Aguirre
- Laboratory of Histocompatibility, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | | | - Isis Goné-Vázquez
- Histocompatibility Laboratory, Hospital de Especialidades, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Gamaliel Benítez-Arvizu
- HLA Laboratory, Central Blood Bank, Hospital de Especialidades, Unidad Médica de Alta Especialidad (UMAE), Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Francia Paulina Arellano-Prado
- Pediatrics Hospital, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Víctor Eduardo García-Arias
- Pediatrics Hospital, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Marla Estefanía Rodríguez-López
- Pediatrics Hospital, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Patricia Méndez-Mani
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | - Raquel García-Álvarez
- Pharmacology Laboratory, Research Unit, Instituto Nacional de Pediatría (INP), Mexico City, Mexico
| | | | - Guadalupe Aquino-Rubio
- Molecular Biology Laboratory, Hospital General "Norberto Treviño Zapata", Dirección de Servicios de Salud de Tamaulipas, Ciudad Victoria, Tamaulipas, Mexico
| | - Néstor Escareño-Montiel
- Department of Transplantation, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | | | - María Guadalupe Uribe-Duarte
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - María de Jesús Ruíz-Corral
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - Andrea Ortega-Yáñez
- Department of Development Genetics and Molecular Physiology, Instituto de Biotecnología (IBT), Universidad Nacional Autónoma de México (UNAM), Cuernavaca, Morelos, Mexico
| | | | - Benjamín Gómez-Navarro
- Central Office of Nephrology, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Agustín Jericó Arriaga-Perea
- Histocompatibility Laboratory, Central Blood Bank, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | | | - Rosa María Macías-Medrano
- Histocompatibility Laboratory, Central Blood Bank, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Jesús Abraham Aguilar-Campos
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - Raúl Solís-Martínez
- Department of Molecular Biology, Laboratorios Diagnóstica, Villahermosa, Tabasco, Mexico
| | - Ricardo Serrano-Osuna
- Clinical Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 2, Instituto Mexicano del Seguro Social (IMSS), Ciudad Obregón, Sonora, Mexico
| | - Mario J Sandoval-Sandoval
- Central Office of Transplantation, Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico; Health Research Division, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Yolanda Jaramillo-Rodríguez
- Direction of Health Education and Research, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Antonio Salgado-Adame
- Direction of Health Education and Research, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Federico Juárez-de la Cruz
- Department of Transplantation, Unidad Médica de Alta Especialidad (UMAE) # 71, Instituto Mexicano del Seguro Social (IMSS), Torreón, Coahuila, Mexico
| | - Bárbara Novelo-Garza
- Medical Infrastructure Planning Committee, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - María de Los Ángeles Pavón-Vargas
- Histocompatibility Laboratory, Unidad Médica de Alta Especialidad (UMAE) # 6, Instituto Mexicano del Seguro Social (IMSS), Puebla, Puebla, Mexico
| | - Norma Salgado-Galicia
- Molecular Biology and Histocompatibility Laboratory, Hospital Central Sur de Alta Especialidad, Petróleos Mexicanos (PEMEX), Mexico City, Mexico
| | - Maria Cátira Bortolini
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Carla Gallo
- Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Gabriel Bedoya
- Genética Molecular (GENMOL, Universidad de Antioquia, Medellín, Colombia
| | - Francisco Rothhammer
- Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Alta Investigación, Universidad de Tarapacá, Arica, Chile
| | - Rolando González-José
- Instituto Patagónico de Ciencias Sociales y Humanas-Centro Nacional Patagónico, CONICET, Puerto Madryn, Argentina
| | - Andrés Ruiz-Linares
- Ministry of Education Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China; Aix-Marseille Univ, CNRS, EFS, ADES, Marseille, France
| | - Samuel Canizales-Quinteros
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México e Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Sandra Romero-Hidalgo
- Department of Computational Genomics, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Johannes Krause
- Department of Archaeogenetics, Max Planck Institute for the Science of Human History (MPI-SHH), Jena, Germany
| | - Joaquín Zúñiga
- Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - Edmond J Yunis
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Carolina Bekker-Méndez
- Immunology and Infectology Research Unit, Infectology Hospital, Centro Médico Nacional "La Raza", Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Julio Granados
- Department of Transplantation, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" (INCMNSZ), Mexico City, Mexico.
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15
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ERAP1 allotypes shape the epitope repertoire of virus-specific CD8 + T cell responses in acute hepatitis C virus infection. J Hepatol 2019; 70:1072-1081. [PMID: 30769005 PMCID: PMC6527866 DOI: 10.1016/j.jhep.2019.01.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 01/30/2019] [Accepted: 01/31/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Endoplasmic reticulum aminopeptidase 1 (ERAP1) polymorphisms are linked with human leukocyte antigen (HLA) class I-associated autoinflammatory disorders, including ankylosing spondylitis and Behçet's disease. Disease-associated ERAP1 allotypes exhibit distinct functional properties, but it remains unclear how differential peptide trimming in vivo affects the repertoire of epitopes presented to CD8+ T cells. The aim of this study was to determine the impact of ERAP1 allotypes on the virus-specific CD8+ T cell epitope repertoire in an HLA-B*27:05+ individual with acute hepatitis C virus (HCV) infection. METHODS We performed genetic and functional analyses of ERAP1 allotypes and characterized the HCV-specific CD8+ T cell repertoire at the level of fine epitope specificity and HLA class I restriction, in a patient who had acquired an HCV genotype 1a infection through a needle-stick injury. RESULTS Two hypoactive allotypic variants of ERAP1 were identified in an individual with acute HCV infection. The associated repertoire of virus-derived epitopes recognized by CD8+ T cells was uncommon in a couple of respects. Firstly, reactivity was directed away from classically immunodominant epitopes, preferentially targeting either novel or subdominant epitopes. Secondly, reactivity was biased towards longer epitopes (10-11-mers). Despite the patient exhibiting favorable prognostic indicators, these atypical immune responses failed to clear the virus and the patient developed persistent low-level infection with HCV. CONCLUSIONS ERAP1 allotypes modify the virus-specific CD8+ T cell epitope repertoire in vivo, leading to altered immunodominance patterns that may contribute to the failure of antiviral immunity after infection with HCV. LAY SUMMARY Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in antigen presentation. Genetic variants of ERAP1 (leading to distinct allotypes) are linked with specific autoinflammatory disorders, such as ankylosing spondylitis and Behçet's disease. We found that ERAP1 allotypes modified the repertoire of virus-specific CD8+ T cell epitopes in a patient with hepatitis C virus, leading to an altered pattern of immunodominance that may have contributed to the failure of antiviral immunity in this patient.
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Abdel-Hakeem MS. Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries. Viruses 2019; 11:E106. [PMID: 30691215 PMCID: PMC6410308 DOI: 10.3390/v11020106] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 01/24/2019] [Accepted: 01/25/2019] [Indexed: 12/16/2022] Open
Abstract
Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.
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Affiliation(s)
- Mohamed S Abdel-Hakeem
- Penn Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt.
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17
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Hart GR, Ferguson AL. Computational design of hepatitis C virus immunogens from host-pathogen dynamics over empirical viral fitness landscapes. Phys Biol 2018; 16:016004. [PMID: 30484433 DOI: 10.1088/1478-3975/aaeec0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) afflicts 170 million people and kills 700 000 annually. Vaccination offers the most realistic and cost effective hope of controlling this epidemic, but despite 25 years of research, no vaccine is available. A major obstacle is HCV's extreme genetic variability and rapid mutational escape from immune pressure. Coupling maximum entropy inference with population dynamics simulations, we have employed a computational approach to translate HCV sequence databases into empirical landscapes of viral fitness and simulate the intrahost evolution of the viral quasispecies over these landscapes. We explicitly model the coupled host-pathogen dynamics by combining agent-based models of viral mutation with stochastically-integrated coupled ordinary differential equations for the host immune response. We validate our model in predicting the mutational evolution of the HCV RNA-dependent RNA polymerase (protein NS5B) within seven individuals for whom longitudinal sequencing data is available. We then use our approach to perform exhaustive in silico evaluation of putative immunogen candidates to rationally design tailored vaccines to simultaneously cripple viral fitness and block mutational escape within two selected individuals. By systematically identifying a small number of promising vaccine candidates, our empirical fitness landscapes and host-pathogen dynamics simulator can guide and accelerate experimental vaccine design efforts.
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Affiliation(s)
- Gregory R Hart
- Department of Physics, University of Illinois at Urbana-Champaign, 1110 West Green Street, Urbana, IL 61801, United States of America. Present address: Department of Therapeutic Radiology, Yale University, 202 LLCI, 15 York Street, New Haven, CT 96510, United States of America
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18
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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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19
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Tabernero D, Cortese MF, Buti M, Rodriguez-Frias F. HDV evolution-will viral resistance be an issue in HDV infection? Curr Opin Virol 2018; 32:100-107. [PMID: 30415162 DOI: 10.1016/j.coviro.2018.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 10/22/2018] [Accepted: 10/24/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis D virus (HDV) is a hepatotropic subviral infectious agent, obligate satellite of the Hepatitis B virus (HBV) and is highly related to viroids. HDV affects around 5% of the 257 million chronic HBV-carriers worldwide, leading to the most severe form of chronic viral hepatitis. Interferon alpha is the only approved treatment for chronic hepatitis D, albeit with low response rates (around 20%-30%). New antiviral strategies are currently under study. Due to the high viral evolution rates (10-3 to 10-4 substitutions/site/year) HDV forms an extremely complex viral population (quasispecies) that can be studied by Next-Generation Sequencing. Therefore, although specific viral resistance in HDV infection has not been reported, it cannot be completely discarded.
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Affiliation(s)
- David Tabernero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Maria Francesca Cortese
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain; Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona 08035, Spain
| | - Maria Buti
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona 08035, Spain
| | - Francisco Rodriguez-Frias
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain.
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20
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Lumley SF, McNaughton AL, Klenerman P, Lythgoe KA, Matthews PC. Hepatitis B Virus Adaptation to the CD8+ T Cell Response: Consequences for Host and Pathogen. Front Immunol 2018; 9:1561. [PMID: 30061882 PMCID: PMC6054973 DOI: 10.3389/fimmu.2018.01561] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/25/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic viral hepatitis infections are a major public health concern, with an estimated 290 million individuals infected with hepatitis B virus (HBV) globally. This virus has been a passenger in human populations for >30,000 years, and remains highly prevalent in some settings. In order for this endemic pathogen to persist, viral adaptation to host immune responses is pre-requisite. Here, we focus on the interplay between HBV infection and the CD8+ T cell response. We present the evidence that CD8+ T cells play an important role in control of chronic HBV infection and that the selective pressure imposed on HBV through evasion of these immune responses can potentially influence viral diversity, chronicity, and the outcome of infection, and highlight where there are gaps in current knowledge. Understanding the nature and mechanisms of HBV evolution and persistence could shed light on differential disease outcomes, including cirrhosis and hepatocellular carcinoma, and help reach the goal of global HBV elimination by guiding the design of new strategies, including vaccines and therapeutics.
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Affiliation(s)
- Sheila F. Lumley
- Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
| | - Anna L. McNaughton
- Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Paul Klenerman
- Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
- Oxford BRC, John Radcliffe Hospital, Oxford, United Kingdom
| | - Katrina A. Lythgoe
- Nuffield Department of Medicine, Big Data Institute, University of Oxford, Oxford, United Kingdom
| | - Philippa C. Matthews
- Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
- Oxford BRC, John Radcliffe Hospital, Oxford, United Kingdom
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21
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Karimzadeh H, Kiraithe MM, Kosinska AD, Glaser M, Fiedler M, Oberhardt V, Salimi Alizei E, Hofmann M, Mok JY, Nguyen M, van Esch WJE, Budeus B, Grabowski J, Homs M, Olivero A, Keyvani H, Rodríguez-Frías F, Tabernero D, Buti M, Heinold A, Alavian SM, Bauer T, Schulze Zur Wiesch J, Raziorrouh B, Hoffmann D, Smedile A, Rizzetto M, Wedemeyer H, Timm J, Antes I, Neumann-Haefelin C, Protzer U, Roggendorf M. Amino Acid Substitutions within HLA-B*27-Restricted T Cell Epitopes Prevent Recognition by Hepatitis Delta Virus-Specific CD8 + T Cells. J Virol 2018; 92:JVI.01891-17. [PMID: 29669837 PMCID: PMC6002722 DOI: 10.1128/jvi.01891-17] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 03/22/2018] [Indexed: 02/07/2023] Open
Abstract
Virus-specific CD8 T cell response seems to play a significant role in the outcome of hepatitis delta virus (HDV) infection. However, the HDV-specific T cell epitope repertoire and mechanisms of CD8 T cell failure in HDV infection have been poorly characterized. We therefore aimed to characterize HDV-specific CD8 T cell epitopes and the impacts of viral mutations on immune escape. In this study, we predicted peptide epitopes binding the most frequent human leukocyte antigen (HLA) types and assessed their HLA binding capacities. These epitopes were characterized in HDV-infected patients by intracellular gamma interferon (IFN-γ) staining. Sequence analysis of large hepatitis delta antigen (L-HDAg) and HLA typing were performed in 104 patients. The impacts of substitutions within epitopes on the CD8 T cell response were evaluated experimentally and by in silico studies. We identified two HLA-B*27-restricted CD8 T cell epitopes within L-HDAg. These novel epitopes are located in a relatively conserved region of L-HDAg. However, we detected molecular footprints within the epitopes in HLA-B*27-positive patients with chronic HDV infections. The variant peptides were not cross-recognized in HLA-B*27-positive patients with resolved HDV infections, indicating that the substitutions represent viral escape mutations. Molecular modeling of HLA-B*27 complexes with the L-HDAg epitope and its potential viral escape mutations indicated that the structural and electrostatic properties of the bound peptides differ considerably at the T cell receptor interface, which provides a possible molecular explanation for the escape mechanism. This viral escape from the HLA-B*27-restricted CD8 T cell response correlates with a chronic outcome of hepatitis D infection. T cell failure resulting from immune escape may contribute to the high chronicity rate in HDV infection.IMPORTANCE Hepatitis delta virus (HDV) causes severe chronic hepatitis, which affects 20 million people worldwide. Only a small number of patients are able to clear the virus, possibly mediated by a virus-specific T cell response. Here, we performed a systematic screen to define CD8 epitopes and investigated the role of CD8 T cells in the outcome of hepatitis delta and how they fail to eliminate HDV. Overall the number of epitopes identified was very low compared to other hepatotropic viruses. We identified, two HLA-B*27-restricted epitopes in patients with resolved infections. In HLA-B*27-positive patients with chronic HDV infections, however, we detected escape mutations within these identified epitopes that could lead to viral evasion of immune responses. These findings support evidence showing that HLA-B*27 is important for virus-specific CD8 T cell responses, similar to other viral infections. These results have implications for the clinical prognosis of HDV infection and for vaccine development.
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Affiliation(s)
- Hadi Karimzadeh
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Muthamia M Kiraithe
- University Hospital Freiburg, Department of Medicine II, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Anna D Kosinska
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich and Hannover Sites, Braunschweig, Germany
| | - Manuel Glaser
- Center for Integrated Protein Science Munich at the Department of Biosciences, Technische Universität München, Freising, Germany
| | - Melanie Fiedler
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Valerie Oberhardt
- University Hospital Freiburg, Department of Medicine II, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Elahe Salimi Alizei
- University Hospital Freiburg, Department of Medicine II, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Maike Hofmann
- University Hospital Freiburg, Department of Medicine II, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | | | | | | | - Bettina Budeus
- Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany
| | - Jan Grabowski
- German Center for Infection Research (DZIF), Munich and Hannover Sites, Braunschweig, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Maria Homs
- CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall d'Hebron Hospital, University Autònoma de Barcelona (UAB), Barcelona, Spain
| | | | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Francisco Rodríguez-Frías
- CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall d'Hebron Hospital, University Autònoma de Barcelona (UAB), Barcelona, Spain
| | - David Tabernero
- CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall d'Hebron Hospital, University Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Maria Buti
- CIBERehd and Departments of Biochemistry/Microbiology and Hepatology, Vall d'Hebron Hospital, University Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Andreas Heinold
- Institute of Transfusion Medicine, University of Duisburg-Essen, University Hospital, Essen, Germany
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Tanja Bauer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich and Hannover Sites, Braunschweig, Germany
| | - Julian Schulze Zur Wiesch
- Department of Medicine, Section of Infectious Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bijan Raziorrouh
- University Hospital Munich-Grosshadern, Department of Medicine II, Munich, Germany
| | - Daniel Hoffmann
- Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany
| | - Antonina Smedile
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Mario Rizzetto
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Heiner Wedemeyer
- German Center for Infection Research (DZIF), Munich and Hannover Sites, Braunschweig, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jörg Timm
- Institute of Virology, Heinrich-Heine-University, University Hospital, Duesseldorf, Germany
| | - Iris Antes
- Center for Integrated Protein Science Munich at the Department of Biosciences, Technische Universität München, Freising, Germany
| | - Christoph Neumann-Haefelin
- University Hospital Freiburg, Department of Medicine II, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich and Hannover Sites, Braunschweig, Germany
| | - Michael Roggendorf
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
- German Center for Infection Research (DZIF), Munich and Hannover Sites, Braunschweig, Germany
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22
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Crux NB, Elahi S. Human Leukocyte Antigen (HLA) and Immune Regulation: How Do Classical and Non-Classical HLA Alleles Modulate Immune Response to Human Immunodeficiency Virus and Hepatitis C Virus Infections? Front Immunol 2017; 8:832. [PMID: 28769934 PMCID: PMC5513977 DOI: 10.3389/fimmu.2017.00832] [Citation(s) in RCA: 134] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 06/30/2017] [Indexed: 12/13/2022] Open
Abstract
The genetic factors associated with susceptibility or resistance to viral infections are likely to involve a sophisticated array of immune response. These genetic elements may modulate other biological factors that account for significant influence on the gene expression and/or protein function in the host. Among them, the role of the major histocompatibility complex in viral pathogenesis in particular human immunodeficiency virus (HIV) and hepatitis C virus (HCV), is very well documented. We, recently, added a novel insight into the field by identifying the molecular mechanism associated with the protective role of human leukocyte antigen (HLA)-B27/B57 CD8+ T cells in the context of HIV-1 infection and why these alleles act as a double-edged sword protecting against viral infections but predisposing the host to autoimmune diseases. The focus of this review will be reexamining the role of classical and non-classical HLA alleles, including class Ia (HLA-A, -B, -C), class Ib (HLA-E, -F, -G, -H), and class II (HLA-DR, -DQ, -DM, and -DP) in immune regulation and viral pathogenesis (e.g., HIV and HCV). To our knowledge, this is the very first review of its kind to comprehensively analyze the role of these molecules in immune regulation associated with chronic viral infections.
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Affiliation(s)
- Nicole B. Crux
- Faculty of Medicine and Dentistry, Department of Dentistry, University of Alberta, Edmonton, AB, Canada
- Faculty of Medicine and Dentistry, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Shokrollah Elahi
- Faculty of Medicine and Dentistry, Department of Dentistry, University of Alberta, Edmonton, AB, Canada
- Faculty of Medicine and Dentistry, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
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23
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Prevalence of NS5B Resistance Mutations in Hepatitis C Virus (HCV) Treatment Naive South Africans. HEPATITIS MONTHLY 2017. [DOI: 10.5812/hepatmon.14248] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Merani S, Lucas M, Deshpande P, Pfafferott K, Chopra A, Cooper D, Leary S, Luciani F, Gaudieri S. Influence of Transmitted Virus on the Host's Immune Response: A Case Study. Viral Immunol 2017; 30:533-541. [PMID: 28530508 DOI: 10.1089/vim.2017.0001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Host hepatitis C virus (HCV)-specific T cell responses and the ability of the virus to escape this response are important correlates of infection outcome. Understanding this host-viral interplay has been difficult given the often asymptomatic nature of acute HCV infection. We studied a recent transmission case to determine whether adapted viral strains can be transmitted and influence the recipient's anti-HCV T cell response. The diversity of viral populations was examined using next-generation sequencing, and HCV-specific T cell interferon (IFN)-γ responses were assessed using a peptide panel representing the autologous viruses. HCV-specific T cell responses in the source were directed against peptides that did not match the dominant autologous virus but rather low-frequency variants, implying existing viral adaptation in the source strain. Most HCV T cell epitopes that elicited an IFN-γ response in the source did not in the recipient, despite the pair sharing human leukocyte antigen alleles that govern antigen presentation and similar autologous viruses. Intrahost HCV variation in the recipient fell within predicted T cell epitopes, suggesting alternative targets of the immune response. These data suggest that transmission of adapted viral species can direct the host's HCV-specific immune response profile during acute infection.
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Affiliation(s)
- Shahzma Merani
- 1 School of Human Sciences, University of Western Australia , Crawley, Australia
| | - Michaela Lucas
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia .,3 School of Medicine and Pharmacology, Harry Perkins Institute, University of Western Australia , Crawley, Australia .,4 School of Pathology and Laboratory Medicine, University of Western Australia , Crawley, Australia
| | - Pooja Deshpande
- 1 School of Human Sciences, University of Western Australia , Crawley, Australia
| | - Katja Pfafferott
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Abha Chopra
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Don Cooper
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Shay Leary
- 2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia
| | - Fabio Luciani
- 5 Systems Immunology, School of Medical Sciences, University of New South Wales , Sydney, Australia
| | - Silvana Gaudieri
- 1 School of Human Sciences, University of Western Australia , Crawley, Australia .,2 Institute of Immunology and Infectious Diseases, Murdoch University , Murdoch, Australia .,6 Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Centre , Nashville, Tennessee
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25
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Ansari MA, Pedergnana V, L C Ip C, Magri A, Von Delft A, Bonsall D, Chaturvedi N, Bartha I, Smith D, Nicholson G, McVean G, Trebes A, Piazza P, Fellay J, Cooke G, Foster GR, Hudson E, McLauchlan J, Simmonds P, Bowden R, Klenerman P, Barnes E, Spencer CCA. Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus. Nat Genet 2017; 49:666-673. [PMID: 28394351 PMCID: PMC5873514 DOI: 10.1038/ng.3835] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 03/10/2017] [Indexed: 12/11/2022]
Abstract
Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. We use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals chronically infected with HCV, predominately genotype 3. We show that both HLA alleles and interferon lambda innate immune system genes drive viral genome polymorphism, and that IFNL4 genotypes determine HCV viral load through a mechanism that is dependent on a specific polymorphism in the HCV polyprotein. We highlight the interplay between innate immune responses and the viral genome in HCV control.
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Affiliation(s)
- M Azim Ansari
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.,Oxford Martin School, University of Oxford, Oxford, UK.,Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - Vincent Pedergnana
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Camilla L C Ip
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.,Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - Andrea Magri
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - Annette Von Delft
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - David Bonsall
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - Nimisha Chaturvedi
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Istvan Bartha
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - David Smith
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | | | - Gilean McVean
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.,Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
| | - Amy Trebes
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Paolo Piazza
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Jacques Fellay
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Graham Cooke
- Wright-Fleming Institute, Imperial College London, London, UK
| | | | | | - Emma Hudson
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - John McLauchlan
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - Peter Simmonds
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - Rory Bowden
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the NIHR Oxford BRC, University of Oxford, Oxford, UK
| | - Chris C A Spencer
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
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Khan MA. An Update on the Genetic Polymorphism of HLA-B*27 With 213 Alleles Encompassing 160 Subtypes (and Still Counting). Curr Rheumatol Rep 2017; 19:9. [DOI: 10.1007/s11926-017-0640-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Ikram A, Obaid A, Awan FM, Hanif R, Naz A, Paracha RZ, Ali A, Janjua HA. Identification of drug resistance and immune-driven variations in hepatitis C virus (HCV) NS3/4A, NS5A and NS5B regions reveals a new approach toward personalized medicine. Antiviral Res 2017; 137:112-124. [PMID: 27984060 DOI: 10.1016/j.antiviral.2016.10.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 10/06/2016] [Accepted: 10/21/2016] [Indexed: 02/07/2023]
Abstract
Cellular immune responses (T cell responses) during hepatitis C virus (HCV) infection are significant factors for determining the outcome of infection. HCV adapts to host immune responses by inducing mutations in its genome at specific sites that are important for HLA processing/presentation. Moreover, HCV also adapts to resist potential drugs that are used to restrict its replication, such as direct-acting antivirals (DAAs). Although DAAs have significantly reduced disease burden, resistance to these drugs is still a challenge for the treatment of HCV infection. Recently, drug resistance mutations (DRMs) observed in HCV proteins (NS3/4A, NS5A and NS5B) have heightened concern that the emergence of drug resistance may compromise the effectiveness of DAAs. Therefore, the NS3/4A, NS5A and NS5B drug resistance variations were investigated in this study, and their prevalence was examined in a large number of protein sequences from all HCV genotypes. Furthermore, potential CD4+ and CD8+ T cell epitopes were predicted and their overlap with genetic variations was explored. The findings revealed that many reported DRMs within NS3/4A, NS5A and NS5B are not drug-induced; rather, they are already present in HCV strains, as they were also detected in HCV-naïve patients. This study highlights several hot spots in which HLA and drug selective pressure overlap. Interestingly, these overlapping mutations were frequently observed among many HCV genotypes. This study implicates that knowledge of the host HLA type and HCV subtype/genotype can provide important information in defining personalized therapy.
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Affiliation(s)
- Aqsa Ikram
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan
| | - Ayesha Obaid
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan
| | - Faryal Mehwish Awan
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan
| | - Rumeza Hanif
- Department of Healtcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan
| | - Anam Naz
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan
| | - Rehan Zafar Paracha
- Department of Computer Sciences, RCMS, National University of Sciences and Technology (NUST), Pakistan
| | - Amjad Ali
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan
| | - Hussnain Ahmed Janjua
- Department of Industrial Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Pakistan.
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Abstract
UNLABELLED Hepatitis C virus (HCV) afflicts 170 million people worldwide, 2%-3% of the global population, and kills 350 000 each year. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic in the developing world where expensive drug therapies are not available. Despite 20 years of research, the high mutability of the virus and lack of knowledge of what constitutes effective immune responses have impeded development of an effective vaccine. Coupling data mining of sequence databases with spin glass models from statistical physics, we have developed a computational approach to translate clinical sequence databases into empirical fitness landscapes quantifying the replicative capacity of the virus as a function of its amino acid sequence. These landscapes explicitly connect viral genotype to phenotypic fitness, and reveal vulnerable immunological targets within the viral proteome that can be exploited to rationally design vaccine immunogens. We have recovered the empirical fitness landscape for the HCV RNA-dependent RNA polymerase (protein NS5B) responsible for viral genome replication, and validated the predictions of our model by demonstrating excellent accord with experimental measurements and clinical observations. We have used our landscapes to perform exhaustive in silico screening of 16.8 million T-cell immunogen candidates to identify 86 optimal formulations. By reducing the search space of immunogen candidates by over five orders of magnitude, our approach can offer valuable savings in time, expense, and labor for experimental vaccine development and accelerate the search for a HCV vaccine. ABBREVIATIONS HCV-hepatitis C virus, HLA-human leukocyte antigen, CTL-cytotoxic T lymphocyte, NS5B-nonstructural protein 5B, MSA-multiple sequence alignment, PEG-IFN-pegylated interferon.
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Affiliation(s)
- Gregory R Hart
- Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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29
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Dietz J, Lutz T, Knecht G, Gute P, Berkowski C, Lange CM, Khaykin P, Stephan C, Brodt HR, Herrmann E, Zeuzem S, Sarrazin C. Evolution and function of the HCV NS3 protease in patients with acute hepatitis C and HIV coinfection. Virology 2015; 485:213-22. [PMID: 26295281 DOI: 10.1016/j.virol.2015.06.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 06/12/2015] [Accepted: 06/26/2015] [Indexed: 01/03/2023]
Abstract
Little is known about the importance of the hepatitis C virus (HCV) NS3 protease in acute hepatitis C. In this prospective study, 82 consecutive patients with acute hepatitis C and human immunodeficiency virus (HIV) coinfection were enrolled. Individuals were infected with highly related HCV strains and the baseline NS3 quasispecies diversity and complexity was higher compared to a chronic hepatitis C control group (P<0.0001). Both parameters were comparable in patients with spontaneous clearance (n=6) versus treatment-induced SVR (n=5) or development of chronic hepatitis C (n=9). Longitudinal NS3 quasispecies kinetics showed a trend to a decreasing diversity and complexity (P<0.05) within 4 weeks in patients with spontaneous clearance compared to the other groups. The innate immune signalling protein CARDIF was cleaved to a similar extent independent of the outcome. Together with a more pronounced viral load decline (P<0.05), an early decreasing NS3 quasispecies evolution indicates spontaneous clearance of acute hepatitis C.
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Affiliation(s)
- Julia Dietz
- Department of Internal Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | | | | | | | - Caterina Berkowski
- Department of Internal Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | | | - Pavel Khaykin
- Department of Internal Medicine 2, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Christoph Stephan
- Department of Internal Medicine 2, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Hans-Reinhard Brodt
- Department of Internal Medicine 2, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, J.W. Goethe University, Frankfurt, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany
| | - Christoph Sarrazin
- Department of Internal Medicine 1, J.W. Goethe University Hospital, Frankfurt, Germany.
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30
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Barth H. Hepatitis C virus: Is it time to say goodbye yet? Perspectives and challenges for the next decade. World J Hepatol 2015; 7:725-737. [PMID: 25914773 PMCID: PMC4404378 DOI: 10.4254/wjh.v7.i5.725] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 12/22/2014] [Accepted: 01/20/2015] [Indexed: 02/06/2023] Open
Abstract
The majority of individuals exposed to hepatitis C virus (HCV) establish a persistent infection, which is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Major progress has been made during the past twenty-five years in understanding the HCV life cycle and immune responses against HCV infection. Increasing evidence indicates that host genetic factors can significantly influence the outcome of HCV infection and the response to interferon alpha-based antiviral therapy. The arrival of highly effective and convenient treatment regimens for patients chronically infected with HCV has improved prospects for the eradication of HCV worldwide. Clinical trials are evaluating the best anti-viral drug combination, treatment doses and duration. The new treatments are better-tolerated and have shown success rates of more than 95%. However, the recent breakthrough in HCV treatment raises new questions and challenges, including the identification of HCV-infected patients and to link them to appropriate health care, the high pricing of HCV drugs, the emergence of drug resistance or naturally occurring polymorphism in HCV sequences which can compromise HCV treatment response. Finally, we still do not have a vaccine against HCV. In this concise review, we will highlight the progress made in understanding HCV infection and therapy. We will focus on the most significant unsolved problems and the key future challenges in the management of HCV infection.
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31
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Mutational escape of CD8+ T cell epitopes: implications for prevention and therapy of persistent hepatitis virus infections. Med Microbiol Immunol 2014; 204:29-38. [PMID: 25537849 PMCID: PMC4305108 DOI: 10.1007/s00430-014-0372-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 09/01/2014] [Indexed: 12/16/2022]
Abstract
Over the past two decades, much has been learned about how human viruses evade T cell immunity to establish persistent infection. The lessons are particularly relevant to two hepatotropic viruses, HBV and HCV, that are very significant global public health problems. Although HCV and HBV are very different, the natural history of persistent infections with these viruses in humans shares some common features including failure of T cell immunity. During recent years, large sequence studies of HCV have characterized intra-host evolution as well as sequence diversity between hosts in great detail. Combined with studies of CD8+ T cell phenotype and function, it is now apparent that the T cell response shapes viral evolution. In turn, HCV sequence diversity influences the quality of the CD8+ T cell response and thus infection outcome. Here, we review published studies of CD8+ T cell selection pressure and mutational escape of the virus. Potential consequences for therapeutic strategies to restore T cell immunity against persistent human viruses, most notably HBV, are discussed.
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32
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Baumert TF, Fauvelle C, Chen DY, Lauer GM. A prophylactic hepatitis C virus vaccine: a distant peak still worth climbing. J Hepatol 2014; 61:S34-44. [PMID: 25443345 DOI: 10.1016/j.jhep.2014.09.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 08/04/2014] [Accepted: 09/05/2014] [Indexed: 12/23/2022]
Abstract
Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end-stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus-host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward.
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Affiliation(s)
- Thomas F Baumert
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, USA; Inserm Unité 1110, France; Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
| | - Catherine Fauvelle
- Inserm Unité 1110, France; Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, France
| | - Diana Y Chen
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, USA
| | - Georg M Lauer
- Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, USA.
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33
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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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Reveille JD. An update on the contribution of the MHC to AS susceptibility. Clin Rheumatol 2014; 33:749-57. [PMID: 24838411 PMCID: PMC4488903 DOI: 10.1007/s10067-014-2662-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 03/24/2014] [Indexed: 11/24/2022]
Abstract
The 40-year-old association of HLA-B27 with ankylosing spondylitis is one of the best examples of disease association with a hereditary marker. Genomewide association and family studies suggest that other important major histocompatibility complex (MHC) influences are operative in ankylosing spondylitis (AS) susceptibility. HLA-B27 positive hepatitis C individuals are immunologically more efficient in combating viral infections such as HIV-1, hepatitis C, and influenza and less efficient in combating against certain bacteria (and perhaps other organisms) capable of surviving intracellularly. A recent representative population survey of the frequency of HLA-B27 in the USA found a lower frequency of HLA-B27 in older US adults, perhaps reflecting this. Other HLA class I and class II alleles have been implicated in AS susceptibility, the most consistent being HLA-B*40/B60 (B*40:01) but also B14, B15, A*0201, DRB1*04:04, and certain DPA1 and DPB1 alleles. Non-HLA MHC alleles have also been implicated, although many such studies have been inconsistent, likely due to power issues related to the low number of HLA-B27-negative AS patients examined. The best evidence is for major histocompatibility complex class I chain-related gene A (MICA) whose recognition by intestinal epithelial T cells expressing different V-delta-1 gamma/delta TCR further implicates the gut in AS pathogenesis. The HLA class I and class II and other non-HLA allelic associations underscore the importance of T cells in AS pathogenesis.
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Affiliation(s)
- John D Reveille
- Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston, MSB 5.270, 6431 Fannin, Houston, TX, 77030, USA,
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35
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Statistical linkage analysis of substitutions in patient-derived sequences of genotype 1a hepatitis C virus nonstructural protein 3 exposes targets for immunogen design. J Virol 2014; 88:7628-44. [PMID: 24760894 DOI: 10.1128/jvi.03812-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
UNLABELLED Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4(+) and cytotoxic CD8(+) T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing diverse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41. IMPORTANCE Despite much experimental work on HCV, a thorough statistical study of the HCV sequences for the purpose of immunogen design was missing in the literature. Such a study is vital to identify epistatic couplings among residues that can provide useful insights for designing a potent vaccine. In this work, ideas from random matrix theory were applied to characterize the statistics of substitutions within the diverse publicly available sequences of the genotype 1a HCV NS3 protein, leading to a group of sites for which HCV appears to resist simultaneous substitutions possibly due to deleterious effect on viral fitness. Our analysis leads to completely novel immunogen designs for HCV. In addition, the NS3 epitopes used in the recently proposed peptide-based vaccine IC41 were analyzed in the context of our framework. Our analysis predicts that alternative NS3 epitopes may be worth exploring as they might be more efficacious.
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HLA-B27-mediated protection in HIV and hepatitis C virus infection and pathogenesis in spondyloarthritis: two sides of the same coin? Curr Opin Rheumatol 2014; 25:426-33. [PMID: 23656712 DOI: 10.1097/bor.0b013e328362018f] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE OF REVIEW HLA-B27 is associated with low viral load and long-term nonprogression in HIV infection as well as spontaneous clearance of hepatitis C virus (HCV) infection. This review summarizes mechanisms that have been suggested to be involved in this protective effect of HLA-B27, and highlights possible lessons for the role of HLA-B27 in spondyloarthritis. RECENT FINDINGS Recent studies linked protection by HLA-B27 in HIV and HCV infection to virological mechanisms such as a complicated pathways of viral escape from immunodominant HLA-B27-restricted virus-specific CD8+ T-cell epitopes. In addition, several immunological mechanisms have been proposed, including CD8+ T-cell polyfunctionality and functional avidity, thymic selection of CD8+ T-cell precursors, specific T-cell receptor repertoires and clonotypes, efficient antigen processing, and evasion from regulatory T-cell-mediated suppression. SUMMARY Multiple virological and immunological mechanisms have been suggested to contribute to HLA-B27-mediated protection in HIV and HCV infection. Some of these mechanisms may also be involved in HLA-B27-associated pathogenesis in spondyloarthritis.
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Kim DW, Lee SA, Kim H, Won YS, Kim BJ. Naturally occurring mutations in the nonstructural region 5B of hepatitis C virus (HCV) from treatment-naïve Korean patients chronically infected with HCV genotype 1b. PLoS One 2014; 9:e87773. [PMID: 24489961 PMCID: PMC3906201 DOI: 10.1371/journal.pone.0087773] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 12/30/2013] [Indexed: 12/29/2022] Open
Abstract
The nonstructural 5B (NS5B) protein of the hepatitis C virus (HCV) with RNA-dependent RNA polymerase (RdRp) activity plays a pivotal role in viral replication. Therefore, monitoring of its naturally occurring mutations is very important for the development of antiviral therapies and vaccines. In the present study, mutations in the partial NS5B gene (492 bp) from 166 quasispecies of 15 genotype-1b (GT) treatment-naïve Korean chronic patients were determined and mutation patterns and frequencies mainly focusing on the T cell epitope regions were evaluated. The mutation frequency within the CD8+ T cell epitopes was significantly higher than those outside the CD8+ T cell epitopes. Of note, the mutation frequency within predicted CD4+ T cell epitopes, a particular mutational hotspot in Korean patients was significantly higher than it was in patients from other areas, suggesting distinctive CD4+ T cell-mediated immune pressure against HCV infection in the Korean population. The mutation frequency in the NS5B region was positively correlated with patients with carrier-stage rather than progressive liver disease (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma). Furthermore, the mutation frequency in four codons (Q309, A333, V338 and Q355) known to be related to the sustained virological response (SVR) and end-of treatment response (ETR) was also significantly higher in Korean patients than in patients from other areas. In conclusion, a high degree of mutation frequency in the HCV GT-1b NS5B region, particularly in the predicted CD4+ T cell epitopes, was found in Korean patients, suggesting the presence of distinctive CD4+ T cell pressure in the Korean population. This provides a likely explanation of why relatively high levels of SVR after a combined therapy of pegylated interferon (PEG-IFN) and ribavirin (RBV) in Korean chronic patients with GT-1b infections are observed.
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Affiliation(s)
- Dong-Won Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Seoung-Ae Lee
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Hong Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - You-Sub Won
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, College of Medicine, Seoul National University, Seoul, Korea
- * E-mail:
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38
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Nitschke K, Barriga A, Schmidt J, Timm J, Viazov S, Kuntzen T, Kim AY, Lauer GM, Allen TM, Gaudieri S, Rauch A, Lange CM, Sarrazin C, Eiermann T, Sidney J, Sette A, Thimme R, López D, Neumann-Haefelin C. HLA-B*27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope. J Hepatol 2014; 60:22-9. [PMID: 23978718 PMCID: PMC3867523 DOI: 10.1016/j.jhep.2013.08.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 07/29/2013] [Accepted: 08/02/2013] [Indexed: 01/17/2023]
Abstract
BACKGROUND & AIMS HLA-B*27 is associated with spontaneous HCV genotype 1 clearance. HLA-B*27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B*27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B*27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope. METHODS Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B*27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B*27:02 and 05. RESULTS The NS5B2820 epitope is only restricted by the HLA-B*27 subtype HLA-B*27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B*27 subtype B*27:05. Indeed, the epitope is very dominant in HLA-B*27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B*27:02+ chronically infected patients. CONCLUSIONS The NS5B2820 epitope is immunodominant in the context of HLA-B*27:02, but is not restricted by other HLA-B*27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines.
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Affiliation(s)
- Katja Nitschke
- Department of Medicine II, University of Freiburg, Freiburg, Germany,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | | | - Julia Schmidt
- Department of Medicine II, University of Freiburg, Freiburg, Germany
| | - Jörg Timm
- Institute of Virology, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Sergei Viazov
- Institute of Virology, University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Thomas Kuntzen
- Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA
| | - Arthur Y. Kim
- Division of Infectious Diseases, MGH, Boston, MA, USA
| | | | - Todd M. Allen
- Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA
| | - Silvana Gaudieri
- School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth Australia,Institute of Immunology and Infectious Disease, Murdoch University, Perth, Western Australia, Australia
| | - Andri Rauch
- Department of Infectious Diseases, Bern University Hospital and University of Bern, Switzerland
| | - Christian M. Lange
- Department of Medicine I, J. W. Goethe University Hospital, Frankfurt, Germany
| | - Christoph Sarrazin
- Department of Medicine I, J. W. Goethe University Hospital, Frankfurt, Germany
| | - Thomas Eiermann
- Transfusion Medicine, HLA-Laboratory, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - John Sidney
- La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Alessandro Sette
- La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
| | - Robert Thimme
- Department of Medicine II, University of Freiburg, Freiburg, Germany
| | - Daniel López
- Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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Abstract
Since the discovery of hepatitis C virus (HCV) by molecular cloning almost a quarter of a century ago, unprecedented at the time because the virus had never been grown in cell culture or detected serologically, there have been impressive strides in many facets of our understanding of the natural history of the disease, the viral life cycle, the pathogenesis, and antiviral therapy. It is apparent that the virus has developed multiple strategies to evade immune surveillance and eradication. This Review covers what we currently understand of the temporal and spatial immunological changes within the human innate and adaptive host immune responses that ultimately determine the outcomes of HCV infection.
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Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med 2013; 19:859-68. [PMID: 23836236 DOI: 10.1038/nm.3251] [Citation(s) in RCA: 374] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 05/30/2013] [Indexed: 02/08/2023]
Abstract
Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer worldwide and cause a million deaths per year. Although HBV and HCV differ in their genome structures, replication strategies and life cycles, they have common features, including their noncytopathic nature and their capacity to induce chronic liver disease, which is thought to be immune mediated. However, the rate of disease progression from chronic hepatitis to cirrhosis varies greatly among infected individuals, and the factors that regulate it are largely unknown. This review summarizes our current understanding of the roles of antigen-specific and nonspecific immune cells in the pathogenesis of chronic hepatitis B and C and discusses recent findings that identify natural killer cells as regulators of T cell function and liver inflammation.
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Affiliation(s)
- Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
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Neumann-Haefelin C, Thimme R. Adaptive immune responses in hepatitis C virus infection. Curr Top Microbiol Immunol 2013; 369:243-62. [PMID: 23463204 DOI: 10.1007/978-3-642-27340-7_10] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The adaptive immune response plays a central role in the outcome of hepatitis C virus (HCV) infection. Indeed, spontaneous viral clearance is associated with an early neutralizing antibody response as well as vigorous and sustained HCV-specific CD4+ and CD8+ T cell responses. In persistent HCV infection, however, all three components of the antiviral adaptive immune response fail due to different viral evasion strategies. In this chapter, we will describe the components of a successful immune response against HCV and summarize the mechanisms of immune failure. We will also highlight characteristics of protective CD8+ T cell responses which is the key factor to the design of an efficacious vaccine.
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Prabdial-Sing N, Puren AJ, Bowyer SM. Sequence-based in silico analysis of well studied hepatitis C virus epitopes and their variants in other genotypes (particularly genotype 5a) against South African human leukocyte antigen backgrounds. BMC Immunol 2012; 13:67. [PMID: 23227878 PMCID: PMC3552980 DOI: 10.1186/1471-2172-13-67] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Accepted: 11/30/2012] [Indexed: 02/07/2023] Open
Abstract
Background Host genetics influence the outcome of HCV disease. HCV is also highly mutable and escapes host immunity. HCV genotypes are geographically distributed and HCV subtypes have been shown to have distinct repertoires of HLA-restricted viral epitopes which explains the lack of cross protection across genotypes observed in some studies. Despite this, immune databases and putative epitope vaccines concentrate almost exclusively on HCV genotype 1 class I-epitopes restricted by the HLA-A*02 allele. While both genotype and allele predominate in developed countries, we hypothesise that HCV variation and population genetics will affect the efficacy of proposed epitope vaccines in South Africa. This in silico study investigates HCV viral variability within well-studied epitopes identified in genotype 1 and uses algorithms to predict the immunogenicity of their variants from other less studied genotypes and thus rate the most promising vaccine candidates for the South African population. Six class I- and seven class II- restricted epitope sequences within the core, NS3, NS4B and NS5B regions were compared across the six HCV genotypes using local genotype 5a sequence data together with global data. Common HLA alleles in the South African population are A30:01, A02:01, B58:02, B07:02; DRB1*13:01 and DRB1*03:01. Epitope binding to 13 class I- and 8 class –II alleles were described using web-based prediction servers, Immune Epitope Database, (IEDB) and Propred. Online population coverage tools were used to assess vaccine efficacy. Results Despite the homogeneity of genotype 1 and genotype 5 over the epitopes, there was limited promiscuity to local HLA-alleles.Host differences will make a putative vaccine less effective in South Africa. Of the 6 well-characterized class I- epitopes, only 2 class I- epitopes were promiscuous and 3 of the 7 class-II epitopes were better conserved and promiscuous. By fine tuning the putative vaccine using an optimal cocktail of genotype 1 and 5a epitopes and local HLA data, the coverage was raised from 65.85% to 91.87% in South African Blacks. Conclusion While in vivo and in vitro studies are needed to confirm immunogenic epitopes, in silico HCV epitope vaccine design which takes into account HCV variation and host allele frequency will maximize population coverage in different ethnic groups.
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Affiliation(s)
- Nishi Prabdial-Sing
- Specialized Molecular Diagnostics, Hepatitis Unit, National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa.
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Compensatory mutations restore the replication defects caused by cytotoxic T lymphocyte escape mutations in hepatitis C virus polymerase. J Virol 2011; 85:11883-90. [PMID: 21880756 DOI: 10.1128/jvi.00779-11] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
While human leukocyte antigen B57 (HLA-B57) is associated with the spontaneous clearance of hepatitis C virus (HCV), the mechanisms behind this control remain unclear. Immunodominant CD8(+) T cell responses against the B57-restricted epitopes comprised of residues 2629 to 2637 of nonstructural protein 5B (NS5B(2629-2637)) (KSKKTPMGF) and E2(541-549) (NTRPPLGNW) were recently shown to be crucial in the control of HCV infection. Here, we investigated whether the selection of deleterious cytotoxic T lymphocyte (CTL) escape mutations in the NS5B KSKKTPMGF epitope might impair viral replication and contribute to the B57-mediated control of HCV. Common CTL escape mutations in this epitope were identified from a cohort of 374 HCV genotype 1a-infected subjects, and their impact on HCV replication assessed using a transient HCV replicon system. We demonstrate that while escape mutations at residue 2633 (position 5) of the epitope had little or no impact on HCV replication in vitro, mutations at residue 2629 (position 1) substantially impaired replication. Notably, the deleterious mutations at position 2629 were tightly linked in vivo to upstream mutations at residue 2626, which functioned to restore the replicative defects imparted by the deleterious escape mutations. These data suggest that the selection of costly escape mutations within the immunodominant NS5B KSKKTPMGF epitope may contribute in part to the control of HCV replication in B57-positive individuals and that persistence of HCV in B57-positive individuals may involve the development of specific secondary compensatory mutations. These findings are reminiscent of the selection of deleterious CTL escape and compensatory mutations by HLA-B57 in HIV-1 infection and, thus, may suggest a common mechanism by which alleles like HLA-B57 mediate protection against these highly variable pathogens.
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