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Machraoui S, Errafii K, Oujamaa I, Belghali MY, Hakmaoui A, Lamjadli S, Eddehbi FE, Brahim I, Haida Y, Admou B. Frequency of the Main Human Leukocyte Antigen A, B, DR, and DQ Loci Known to Be Associated with the Clearance or Persistence of Hepatitis C Virus Infection in a Healthy Population from the Southern Region of Morocco: A Preliminary Study. Diseases 2024; 12:106. [PMID: 38785761 PMCID: PMC11120154 DOI: 10.3390/diseases12050106] [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: 01/17/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 05/25/2024] Open
Abstract
Hepatitis C Virus (HCV) infection represents a significant global health challenge, with its natural course largely influenced by the host's immune response. Human Leukocyte Antigen (HLA) molecules, particularly HLA class I and II, play a crucial role in the adaptive immune response against HCV. The polymorphism of HLA molecules contributes to the variability in immune response, affecting the outcomes of HCV infection. This study aims to investigate the frequency of HLA A, B, DR, and DQ alleles known to be associated with HCV clearance or persistence in a healthy Moroccan population. Conducted at the University Hospital Center Mohammed VI, Marrakech, this study spanned from 2015 to 2022 and included 703 healthy Moroccan individuals. HLA class I and II typing was performed using complement-dependent cytotoxicity and polymerase chain reaction-based methodologies. The results revealed the distinct patterns of HLA-A, B, DRB1, and DQB1 alleles in the Moroccan population. Notably, alleles linked to favorable HCV outcomes, such as HLA-DQB1*0301, DQB1*0501, and DRB1*1101, were more prevalent. Conversely, alleles associated with increased HCV susceptibility and persistence, such as HLA-DQB1*02 and DRB1*03, were also prominent. Gender-specific variations in allele frequencies were observed, providing insights into genetic influences on HCV infection outcomes. The findings align with global trends in HLA allele associations with HCV infection outcomes. The study emphasizes the role of host genetics in HCV infection, highlighting the need for further research in the Moroccan community, including HCV-infected individuals. The prevalence of certain HLA alleles, both protective and susceptibility-linked, underscores the potential for a national HLA data bank in Morocco.
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Affiliation(s)
- Safa Machraoui
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco;
| | - Khaoula Errafii
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco;
| | - Ider Oujamaa
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Moulay Yassine Belghali
- Department of Biology, Faculty of Sciences Dhar El Mahraz, Sidi Mohammed Ben Abdellah University, Fez 30003, Morocco;
| | - Abdelmalek Hakmaoui
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Saad Lamjadli
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Fatima Ezzohra Eddehbi
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Ikram Brahim
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Yasmine Haida
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
| | - Brahim Admou
- Laboratory of Immunology and HLA, Center of Clinical Research, Mohammed VI University Hospital, Marrakech 40080, Morocco; (I.O.); (A.H.); (S.L.); (F.E.E.); (I.B.); (Y.H.); (B.A.)
- Biosciences Research Laboratory, Faculty of Medicine and Pharmacy, Cadi Ayyad University, Marrakech 40080, Morocco
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Urakawa R, Isomura ET, Matsunaga K, Kubota K, Ike M. Impact of age, sex and medical history on adverse reactions to the first and second dose of BNT162b2 mRNA COVID-19 vaccine in Japan: a cross-sectional study. BMC Infect Dis 2022; 22:179. [PMID: 35197017 PMCID: PMC8864597 DOI: 10.1186/s12879-022-07175-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 02/17/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Vaccines for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being promoted worldwide. In this study, we analyzed the relationship between adverse reactions and the profile of vaccinated recipients. METHODS Vaccinated subjects who received two doses of BNT162b2 between May 17 and June 11, 2021, at Osaka University Dental Hospital were included in this study. Adverse reactions and profiles were collected by questionnaires, and the relationship between the presence of adverse reactions and the profiles of the vaccinated persons was analyzed by logistic regression analysis. The correlation between the severity of adverse reactions and age was analyzed by Spearman's rank correlation. RESULTS Logistic regression analysis showed that, for many kinds of adverse reactions, the incidence was significantly higher in females than in males and in younger than in older people. There was a very weak but significant negative correlation between age and the severity of many kinds of adverse reactions. The relationship between sex and the incidence of each adverse reaction was significant for injection site reactions and fatigue in the first vaccination, whereas significant relationships were found for fatigue, chills, fever, arthralgia, myalgia and headache in the second vaccination, all of which were clearly more likely to occur in females. CONCLUSION Adverse reactions to BNT162b2 were found to be more frequent and more intense in females and younger people in Japan, especially after the second vaccination.
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Affiliation(s)
- Ryuta Urakawa
- Department of Pharmacy, Osaka University Dental Hospital, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan. .,Department of Clinical Pharmacy Research and Education, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
| | - Emiko Tanaka Isomura
- First Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Kazuhide Matsunaga
- Second Department of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Kazumi Kubota
- Department of Healthcare Information Management, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Miho Ike
- Nursing Department, Osaka University Dental Hospital, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan
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Valencia A, Vergara C, Thio CL, Vince N, Douillard V, Grifoni A, Cox AL, Johnson EO, Kral AH, Goedert JJ, Mangia A, Piazzolla V, Mehta SH, Kirk GD, Kim AY, Lauer GM, Chung RT, Price JC, Khakoo SI, Alric L, Cramp ME, Donfield SM, Edlin BR, Busch MP, Alexander G, Rosen HR, Murphy EL, Wojcik GL, Carrington M, Gourraud PA, Sette A, Thomas DL, Duggal P. Trans-ancestral fine-mapping of MHC reveals key amino acids associated with spontaneous clearance of hepatitis C in HLA-DQβ1. Am J Hum Genet 2022; 109:299-310. [PMID: 35090584 PMCID: PMC8874224 DOI: 10.1016/j.ajhg.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 12/14/2021] [Indexed: 12/27/2022] Open
Abstract
Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.
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Affiliation(s)
- Ana Valencia
- Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Universidad Pontificia Bolivariana, Medellín, Antioquia 050031, Colombia
| | - Candelaria Vergara
- Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Chloe L Thio
- Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
| | - Nicolas Vince
- Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes 44000, France
| | - Venceslas Douillard
- Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes 44000, France
| | - Alba Grifoni
- Center for infectious Diseases and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Andrea L Cox
- Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
| | - Eric O Johnson
- GenOmics, Bioinformatics, and Translational Research Center, RTI International, Research Triangle Park, NC 27709, USA
| | - Alex H Kral
- GenOmics, Bioinformatics, and Translational Research Center, RTI International, Research Triangle Park, NC 27709, USA
| | - James J Goedert
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Alessandra Mangia
- Liver Unit, Medical Sciences Department, Fondazione "Casa Sollievo della Sofferenza" IRCCS, 71013 San Giovanni Rotondo, Italy
| | - Valeria Piazzolla
- Liver Unit, Medical Sciences Department, Fondazione "Casa Sollievo della Sofferenza" IRCCS, 71013 San Giovanni Rotondo, Italy
| | - Shruti H Mehta
- Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Gregory D Kirk
- Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA; Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Arthur Y Kim
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Georg M Lauer
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Jennifer C Price
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Francisco, CA 94143, USA
| | - Salim I Khakoo
- University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Laurent Alric
- Internal Medicine-Department of Digestive Diseases, Rangueil Hospital, Toulouse University, 1, 31400 Toulouse, France
| | | | | | - Brian R Edlin
- SUNY Downstate College of Medicine, Brooklyn, NY 11203, USA
| | - Michael P Busch
- University of California San Francisco and Vitalant Research Institute, San Francisco, CA 94118, USA
| | - Graeme Alexander
- UCL Institute for Liver and Digestive Health, The Royal Free Hospital, Pond St, Hampstead, London NW3 2QG, UK
| | | | - Edward L Murphy
- University of California San Francisco and Vitalant Research Institute, San Francisco, CA 94118, USA
| | - Genevieve L Wojcik
- Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA
| | - Mary Carrington
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA
| | - Pierre-Antoine Gourraud
- Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes 44000, France
| | - Alessandro Sette
- Center for infectious Diseases and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92093, USA
| | - David L Thomas
- Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA
| | - Priya Duggal
- Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
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Association of HLA Class II Alleles with Outcome of Hepatitis C Virus Infection: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2021. [DOI: 10.5812/hepatmon.109493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Context: Hepatitis C Virus (HCV) infection is a major cause of chronic cirrhosis and hepatocellular carcinoma. Approximately 30% of infected persons with HCV spontaneously clear the viral infection; but, some of the remaining patients develop chronic HCV. Studies show that HLA molecules play an important role in the outcome of HCV infection by influencing the efficiency of the antiviral immune response to HCV infection. It is now known that polymorphisms in HLA loci are associated with HCV susceptibility or clearance. The purpose of the present study was to systematically review the studies that reported the association of HLA class II alleles (HLA-DQ and HLA-DR) with the outcome of HCV infection. Evidence Acquisition: Studies were identified by searching electronic databases, including PubMed and Scopus. A total of 12,265 relevant studies were identified by the electronic search, of which a total of 19 eligible papers were identified that were meta-analyzed for the association between HLA class II alleles and the outcome of HCV infection. Results: Subjects carrying HLA-DQB1*0301, HLA-DQB1*0501, HLA-DRB1*1303, HLA-DRB1*1201, HLA-DRB1*0401, HLA-DRB1*0101, and HLA-DRB1*1101 alleles were significantly associated with higher spontaneous clearance of HCV infection. Conclusions: The data from the current study confirm that several polymorphisms in HLA-DQ and HLA-DR loci are correlated with the clearance of HCV infection. Identifying these polymorphisms may contribute to a better understanding of immune mechanisms of HCV clearance or persistence.
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Liu Y, Yang W, Smith C, Cheng C, Karol SE, Larsen EC, Winick N, Carroll WL, Loh ML, Raetz EA, Hunger SP, Winter SS, Dunsmore KP, Devidas M, Yang JJ, Evans WE, Jeha S, Pui CH, Inaba H, Relling MV. Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase Hypersensitivity. Clin Pharmacol Ther 2021; 110:794-802. [PMID: 33768542 PMCID: PMC8790808 DOI: 10.1002/cpt.2241] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/13/2021] [Indexed: 10/20/2023]
Abstract
We conducted the first human leukocyte antigen (HLA) allele and genome-wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children's Research Hospital's Total XVI (TXVI, n = 598) and Children's Oncology Group AALL0232 (n = 2,472) and AALL0434 (n = 1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7 × 10-5 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P < 5.0 × 10-5 ) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA-DQB1*02:02 was tagged by HLA-DQB1 rs1694129 in EAs (r2 = 0.96) and less so in non-EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome-wide significance in EAs were in class II HLA loci, and were partially replicated in non-EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P = 8.9 × 10-9 ) in non-EAs. The HLA-DQB1*02:02-DRB1*07:01-DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non-PEGylated asparaginase, even though the antigens differ between the two preparations.
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Affiliation(s)
- Yiwei Liu
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
| | - Wenjian Yang
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
| | - Colton Smith
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
| | - Cheng Cheng
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN
| | - Seth E. Karol
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | | | - Naomi Winick
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
| | | | - Mignon L. Loh
- Department of Pediatrics, University of California School of Medicine, San Francisco, CA
| | | | - Stephen P. Hunger
- Department of Pediatrics, Children’s Hospital of Philadelphia and the Perelman School of Medicine at The University of Pennsylvania, Philadelphia, PA
| | - Stuart S. Winter
- Children’s Minnesota Cancer and Blood Disorders Program, Children’s Minnesota, Minneapolis, MN
| | | | - Meenakshi Devidas
- Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN
| | - Jun J. Yang
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
| | - William E. Evans
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
| | - Sima Jeha
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Hiroto Inaba
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Mary V. Relling
- Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN
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Ding Y, Li G, Zhou Z, Deng T. Molecular mechanisms underlying hepatitis C virus infection-related diabetes. Metabolism 2021; 121:154802. [PMID: 34090869 DOI: 10.1016/j.metabol.2021.154802] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/27/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022]
Abstract
Diabetes is a noncommunicable widespread disease that poses the risk of severe complications in patients, with certain complications being life-threatening. Hepatitis C is an infectious disease that mainly causes liver damage, which is also a profound threat to human health. Hepatitis C virus (HCV) infection has many extrahepatic manifestations, including diabetes. Multiple mechanisms facilitate the strong association between HCV and diabetes. HCV infection can affect the insulin signaling pathway in liver and pancreatic tissue and change the profiles of circulating microRNAs, which may further influence the occurrence and development of diabetes. This review describes how HCV infection causes diabetes and discusses the current research progress with respect to HCV infection-related diabetes.
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Affiliation(s)
- Yujin Ding
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Guangdi Li
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Xiangya School of Public Health, Central South University, Changsha 410011, Hunan, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Tuo Deng
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Key Laboratory of Diabetes Immunology, Ministry of Education, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China; Clinical Immunology Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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Chang ML, Chang SW, Chen SC, Chien RN, Hsu CL, Chang MY, Fann CSJ. Genetic Association of Hepatitis C-Related Mixed Cryoglobulinemia: A 10-Year Prospective Study of Asians Treated with Antivirals. Viruses 2021; 13:464. [PMID: 33799903 PMCID: PMC7998980 DOI: 10.3390/v13030464] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 12/16/2022] Open
Abstract
Genetic profiles of hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) in Asians remain elusive. A 10-year prospective cohort study was conducted with 1043 consecutive HCV Ab-positive Taiwanese surveyed with 13 single nucleotide polymorphisms (SNPs). Of 1043, 589 (56.5%) had baseline MC, 934 (89.5%) had positive HCV RNA, 796 completed anti-HCV therapy, and 715 had sustained virological responses (SVRs). SNP associations were surveyed withgenotypic, allelic, trend, permutation and multivariate analyses. At baseline, higher male sex and MC rates were noted in HCV RNA-positive than RNA-negative patients; higher female sex and positive HCV RNA rates but lower HCV RNA levels were noted in patients with than those without MC. Baseline associations were: HLA II-rs9461776 A allele, IFNL3-rs12979860 T allele, SERPINE1-rs6976053 C allele and MC with HCV RNA positivity; IFNL3-rs12979860 C allele, ARNTL-rs6486122 T allele and HCV RNA positivity with baseline MC. In SVR patients, RETN-rs1423096 C allele and SERPINE1-rs6976053 T allele were associated with 24-week and 10-year post-therapy MC, respectively. Conclusions: HCV RNA, IFNL3-rs12979860 and ARNTL-rs6486122 were associated with baseline MC; RETN-rs1423096 and SERPINE1-rs6976053 were associated with short- and long-term post-therapy MC in SVR patients, respectively. Links with HCV RNA and immune-associated SNPs suggest MC an immune reaction to expel HCV.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
| | - Su-Wei Chang
- Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyua 333423, Taiwan;
- Division of Allergy, Asthma, and Rheumatology, Department of Paediatrics, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University, Taipei 11031, Taiwan;
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
| | - Chia-Lin Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan;
| | - Ming-Yu Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
- Division of Pediatric Neurologic Medicine, Chang Gung Children’s Hospital, Taoyuan 333423, Taiwan
- Division of Pediatrics, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Cathy S. J. Fann
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan;
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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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Oladejo BO, Adeboboye CF, Adebolu TT. Understanding the genetic determinant of severity in viral diseases: a case of SARS-Cov-2 infection. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020; 21:77. [PMID: 38624552 PMCID: PMC7773422 DOI: 10.1186/s43042-020-00122-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/08/2020] [Indexed: 12/16/2022] Open
Abstract
Background Numerous research studies have identified specific human gene variants that affect enhanced susceptibility to viral infections. More recently is the current pandemic where the SARS-CoV-2 infection has shown a high degree of person-to-person clinical variability. A wide range of disease severity occurs in the patients' experiences, from asymptomatic cases, mild infections to serious life threatening conditions requiring admission into the intensive care unit (ICU). Main body of the abstract Although, it is generally reported that age and co-morbidities contribute significantly to the variations in the clinical outcome of the scourge of COVID-19, a hypothetical question of the possibility of genetic involvement in the susceptibility and severity of the disease arose when some unique severe outcomes were seen among young patients with no co-morbidity. The role human genetics play in clinical response to the viral infections is scarcely understood; however, several ongoing researches all around the world are currently focusing on possible genetic factors. This review reports the possible genetic factors that have been widely studied in defining the severity of viral infections using SARS-CoV-2 as a case study. These involve the possible involvements of ACE2, HLA, and TLR genes such as TLR7 and TLR3 in the presentation of a more severe condition. Short conclusion Understanding these variations could help to inform efforts to identify people at increased risk of infection outbreaks through genetic diagnosis of infections by locating disease genes or mutations that predispose patients to severe infection. This will also suggest specific targets for therapy and prophylaxis.
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10
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Huang J, Xu R, Wang M, Liao Q, Huang K, Shan Z, You Q, Li C, Rong X, Fu Y. Association of HLA-DQB1*03:01 and DRB1*11:01 with spontaneous clearance of hepatitis C virus in Chinese Li ethnicity, an ethnic group genetically distinct from Chinese Han ethnicity and infected with unique HCV subtype. J Med Virol 2019; 91:1830-1836. [PMID: 31254396 DOI: 10.1002/jmv.25531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/21/2019] [Indexed: 01/14/2023]
Abstract
Specific human leukocyte antigen (HLA) class I and class II alleles have been associated with spontaneous clearance or persistent infection of hepatitis C virus (HCV), which seemed to be restricted by the host's ethnicity and viral genotype. Recently we reported a high prevalence and spontaneous clearance rate of HCV in a cohort of Chinese Li ethnicity who were infected with new variants of HCV genotype 6. In this study, we found that the distribution of HLA class I and class II alleles in HCV infected individuals of Chinese Li ethnicity (n = 143) was distinct from that of Chinese Han ethnicity which was reported in our previous study. HLA-DRB1*11:01 and DQB1*03:01 were more prevalent in Chinese Li subjects who cleared HCV spontaneously than those who were chronically infected (P = .036 and P = .024, respectively), which were consistent with our previous report regarding the Chinese Han population. Multivariate logistic regression analysis showed that DQB1*03:01 (odds ratio = 3.899, P = .017), but not DRB1*11:01, associated with HCV spontaneous clearance, independent of age, sex, and IFNL3 genotype. Because DQB1*03:01 and DRB1*11:01 were tightly linked because of linkage disequilibrium, our results clearly supported the associations of these two alleles with HCV spontaneous clearance in Chinese Li as well as Han ethnicity.
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Affiliation(s)
- Jieting Huang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
| | - Ru Xu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
| | - Min Wang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
| | - Qiao Liao
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
| | - Ke Huang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
| | - Zhengang Shan
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
| | - Qingzhu You
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Chengyao Li
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Xia Rong
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Yongshui Fu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Laboratory of Guangzhou, Guangzhou, Guangdong, China
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
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11
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Chigbu DI, Loonawat R, Sehgal M, Patel D, Jain P. Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence. Cells 2019; 8:cells8040376. [PMID: 31027278 PMCID: PMC6523734 DOI: 10.3390/cells8040376] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/25/2019] [Accepted: 04/17/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.
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Affiliation(s)
- DeGaulle I Chigbu
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
- Pennsylvania College of Optometry at Salus University, Elkins Park, PA 19027, USA.
| | - Ronak Loonawat
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Mohit Sehgal
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
| | - Dip Patel
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
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12
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Marques PI, Gonçalves JC, Monteiro C, Cavadas B, Nagirnaja L, Barros N, Barros A, Carvalho F, Lopes AM, Seixas S. Semen quality is affected by HLA class I alleles together with sexually transmitted diseases. Andrology 2019; 7:867-877. [PMID: 31002754 DOI: 10.1111/andr.12625] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/28/2019] [Accepted: 03/14/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND The human leukocyte antigen (HLA) locus includes several genes with key roles in antigen presentation and immune response, some of them inclusively found to be associated with non-obstructive azoospermia. Still, HLA connections to other infertility phenotypes such as semen hyperviscosity (SHV), asthenozoospermia (AST), and oligozoospermia (OLI) have been often neglected. OBJECTIVES In this work, we aimed to evaluate the association of HLA class I and II genes with SHV, AST, and OLI phenotypes while exploring a possible role in an adaptive immune response to sexually transmitted diseases (STD). MATERIALS AND METHODS Whole-exome sequencing was performed in a Portuguese cohort of 71 infertility cases and 68 controls, followed by HLA typing using a specific software-HLA*PRG:LA tool. Molecular screenings of seven STD were carried out in a subset of 72 samples (30 cases and 42 controls). RESULTS Statistical tests uncovered three protective alleles: HLA-A*11:01, associated with all forms of male infertility (p = 0.0006); HLA-DQB1*03:02 with SHV and OLI (PSHV = 0.0303, POLI = 0.0153); and HLA-A*29:02 with OLI (p = 0.0355), which was found to interfere in sperm number together with HPV (p = 0.0313). Five risk alleles were also identified: two linked with SHV (HLA-B*50:01, p = 0.0278; and HLA-C*06:02, p = 0.0461), another one with both SHV and OLI (HLA-DQA1*05:01, PSHV = 0.0444 and POLI =0.0265), and two with OLI (HLA-C*03:03, p = 0.0480; and HLA-DQB1*03:01, p = 0.0499). Here, HLA-C*03:03 carriers tend to be HPV infected. CONCLUSIONS The application of HLA*PRG:LA tool to the study of male infertility provided novel insights for an HLA correlation with semen quality, namely among SHV and OLI phenotypes. The discovery of an HLA-A*29:02/HPV crosstalk, together with former reports of HLA alleles conferring resistance-susceptibility to diverse human pathogens, raises the hypothesis of a mechanistic link between male infertility, HLA polymorphism, and host response to STD.
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Affiliation(s)
- P I Marques
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - J C Gonçalves
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - C Monteiro
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - B Cavadas
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
| | - L Nagirnaja
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
| | - N Barros
- Center for Reproductive Genetics Alberto Barros, Porto, Portugal
| | - A Barros
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Center for Reproductive Genetics Alberto Barros, Porto, Portugal.,Genetics, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - F Carvalho
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Genetics, Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - A M Lopes
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - S Seixas
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
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13
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Steba GS, Koekkoek SM, Tanck MWT, Vanhommerig JW, van der Meer JTM, Kwa D, Brinkman K, Prins M, Berkhout B, Pollakis G, Molenkamp R, Schinkel J, Paxton WA. SNP rs688 within the low-density lipoprotein receptor (LDL-R) gene associates with HCV susceptibility. Liver Int 2019; 39:463-469. [PMID: 30260075 PMCID: PMC6588020 DOI: 10.1111/liv.13978] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/17/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Despite high-risk behaviour, 10%-20% of HCV multiple exposed individuals remain uninfected (MEU), whilst the remainder become infected (MEI). We hypothesize that host factors play a role in HCV susceptibility. We aimed to identify polymorphisms in host genes that encode for proteins involved in viral entry: CD81, Scavenger receptor 1 (SR-1), Low-density lipoprotein receptor (LDL-R), Claudin-1 (CLDN1), Occludin (OCLN) and Niemann-Pick C1-like 1 (NPC1L1). METHODS Multiple exposed infected and MEU from two observational cohorts were selected. From the MSM study of acute infection with HCV (MOSAIC), HIV-1 infected MEU cases (n = 30) and HIV-1 infected MEI controls (n = 32) were selected based on reported high-risk behaviour. From the Amsterdam Cohorts Studies (ACS) injecting drug users (IDU) cohort, MEU cases (n = 40) and MEI controls (n = 22) were selected who injected drugs for ≥2 years, in the nineties, when HCV incidence was high. Selected single nucleotide polymorphisms (SNPs) were determined by sequencing or SNP assays. RESULTS No associations were found for SNPs within genes coding for CD81, SR-1, Claudin-1 or Occludin between the MEU and MEI individuals from either cohort. We did observe a significant association for rs688 within the LDL-R gene with HCV infection (OR: 0.41 P = 0.001), however, LDL cholesterol levels did not vary between individuals carrying the differential SNPs. Additionally, a marginal significant effect was found for rs217434 and rs2072183 (OR: 2.07 P = 0.032 and OR: 1.76 P = 0.039, respectively) within NPC1L1. CONCLUSIONS Our results demonstrate that the rs688 SNP within the LDL-R gene associates with HCV susceptibility through mucosal as well as intravenous exposure.
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Affiliation(s)
- Gaby S. Steba
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Sylvie M. Koekkoek
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Michael W. T. Tanck
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics (CEBB), Amsterdam UMCAcademic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Joost W. Vanhommerig
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands,Department of Infectious DiseasesPublic Health Service of AmsterdamAmsterdamThe Netherlands
| | - Jan T. M. van der Meer
- Division of Infectious Diseases, Tropical Medicine and AIDS, Department of Internal Medicine, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - David Kwa
- Department of MicrobiologyOnze Lieve Vrouwe GasthuisAmsterdamThe Netherlands
| | - Kees Brinkman
- Department of Internal MedicineOnze Lieve Vrouwe GasthuisAmsterdamThe Netherlands
| | - Maria Prins
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands,Department of Clinical Epidemiology, Biostatistics and Bioinformatics (CEBB), Amsterdam UMCAcademic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Ben Berkhout
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Georgios Pollakis
- Department of Clinical Infection, Microbiology and ImmunologyInstitute of Infection and Global HealthUniversity of LiverpoolLiverpoolUK
| | - Richard Molenkamp
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - Janke Schinkel
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
| | - William A. Paxton
- Department of Medical Microbiology, Amsterdam UMC, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands,Department of Clinical Infection, Microbiology and ImmunologyInstitute of Infection and Global HealthUniversity of LiverpoolLiverpoolUK
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14
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El-Bendary M, Neamatallah M, Elalfy H, Besheer T, Kamel E, Mousa H, Eladl AH, El-Setouhy M, El-Gilany AH, El-Waseef A, Esmat G. HLA Class II-DRB1 Alleles with Hepatitis C Virus Infection Outcome in Egypt: A Multicentre Family-based Study. Ann Hepatol 2019; 18:68-77. [PMID: 31113612 DOI: 10.5604/01.3001.0012.7864] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 12/11/2017] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Hepatitis C virus (HCV) infection is a global medical problem. HLA -DRB1 alleles have an important role in immune response against HCV. The aim of this study is to clarify the contribution of HLA -DRB1 alleles in HCV susceptibility in a multicentre family-based study. MATERIAL AND METHODS A total of 162 Egyptian families were recruited in this study with a total of 951 individuals (255 with chronic hepatitis C (CHC), 588 persons in the control group(-ve household contact to HCV) and 108 persons who spontaneously cleared the virus (SVC). All subjects were genotyped for HLA -DRB1 alleles by SSP-PCR and sequence based typing (SBT) methods. RESULTS The carriage of alleles 3:01:01 and 13:01:01 were highly significant in CHC when compared to that of control and SVC groups [OR of 3 family = 5.1289, PC (Bonferroni correction ) = 0.0002 and 5.9847, PC = 0.0001 and OR of 13 family = 4.6860, PC = 0.0002 and OR = 6.5987, PC = 0.0001 respectively]. While DRB1*040501, DRB1*040101, DRB1*7:01:01 and DRB1*110101 alleles were more frequent in SVC group than CHC patients (OR = 0.4052, PC = 0.03, OR: OR = 0.0916,PC = 0.0006, OR = 0.1833,PC = 0.0006 and OR = 0.4061, PC = 0.0001 respectively). CONCLUSIONS It was concluded that among the Egyptian families, HLA-DRB1*030101, and DRB1*130101 alleles associated with the risk of progression to CHC infection, while DRB1*040101, DRB1*040501, DRB1*7:01:01and DRB1*110101 act as protective alleles against HCV infection.
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Affiliation(s)
- Mahmoud El-Bendary
- Tropical Medicine & Hepatology, Mansoura Faculty Of Medicine, Mansoura University, Mansoura,Dakahlyia, Egypt.
| | - Mustafa Neamatallah
- Medical Biochemistry, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Dakahlyia, Egypt
| | - Hatem Elalfy
- Tropical Medicine & Hepatology, Mansoura Faculty Of Medicine, Mansoura University, Mansoura,Dakahlyia, Egypt
| | - Tarek Besheer
- Tropical Medicine & Hepatology, Mansoura Faculty Of Medicine, Mansoura University, Mansoura,Dakahlyia, Egypt
| | - Emily Kamel
- Public Health & Preventive Medicine, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Dakahlyia, Egypt
| | - Hend Mousa
- Biochemistry, Mansoura Faculty of Science, Mansoura University, Mansoura, Dakahlyia, Egypt
| | - Abdel-Hamid Eladl
- Internal Medicine Department, Alazhar Faculty of Medicine-Assiut University, Assiut, Egypt
| | - Maged El-Setouhy
- Department of Community and Occupational Medicine, Ain Shams Faculty of Medicine. Ain Shams University, Cairo, Egypt
| | - Abdel-Hady El-Gilany
- Public Health & Preventive Medicine, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Dakahlyia, Egypt
| | - Ahmed El-Waseef
- Biochemistry, Mansoura Faculty of Science, Mansoura University, Mansoura, Dakahlyia, Egypt
| | - Gamal Esmat
- Tropical Medicine & Hepatology, Cairo Faculty of Medicine
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15
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O'Brien TR, Yang HI, Groover S, Jeng WJ. Genetic Factors That Affect Spontaneous Clearance of Hepatitis C or B Virus, Response to Treatment, and Disease Progression. Gastroenterology 2019; 156:400-417. [PMID: 30287169 DOI: 10.1053/j.gastro.2018.09.052] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Over the past decade, studies of individuals infected with these viruses have established genetic associations with the probability of developing a chronic infection, risk of disease progression, and likelihood of treatment response. We review genetic and genomic methods that have been used to study risk of HBV and HCV infection and patient outcomes. For example, genome-wide association studies have linked a region containing the interferon lambda genes to spontaneous and treatment-induced clearance of HCV. We review the genetic variants associated with HCV and HBV infection, and how these variants affect specific expression or activities of their products. Further studies of these variants could provide insights into risk factors for and mechanisms of chronic infection and disease progression, as well as new strategies for treatment.
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Affiliation(s)
- Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Sarah Groover
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
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16
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Dominguez-Molina B, Ferrando-Martinez S, Tarancon-Diez L, Hernandez-Quero J, Genebat M, Vidal F, Muñoz-Fernandez MA, Leal M, Koup R, Ruiz-Mateos E. Immune Correlates of Natural HIV Elite Control and Simultaneous HCV Clearance-Supercontrollers. Front Immunol 2018; 9:2897. [PMID: 30619267 PMCID: PMC6295470 DOI: 10.3389/fimmu.2018.02897] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 11/26/2018] [Indexed: 12/14/2022] Open
Abstract
HIV-elite controllers are a minority group of HIV-infected patients with the ability to maintain undetectable HIV viremia for long time periods without antiretroviral treatment. A small group of HIV-controllers are also able to spontaneously clear the hepatitis C virus (HCV) whom we can refer to as "supercontrollers." There are no studies that explore immune correlates looking for the mechanisms implicated in this extraordinary phenomenon. Herein, we have analyzed HCV- and HIV-specific T-cell responses, as well as T, dendritic and NK cell phenotypes. The higher HCV-specific CD4 T-cell polyfunctionality, together with a low activation and exhaustion T-cell phenotype was found in supercontrollers. In addition, the frequency of CD8 CD161high T-cells was related with HIV- and HCV-specific T-cells polyfunctionality. Interesting features regarding NK and plasmacytoid dendritic cells (pDCs) were found. The study of the supercontroller's immune response, subjects that spontaneously controls both chronic viral infections, could provide further insights into virus-specific responses needed to develop immunotherapeutic strategies in the setting of HIV cure or HCV vaccination.
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Affiliation(s)
- Beatriz Dominguez-Molina
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain
- Laboratory of Immunovirology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - Sara Ferrando-Martinez
- Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Laura Tarancon-Diez
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain
- Laboratory of Immunovirology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | | | - Miguel Genebat
- Laboratory of Immunovirology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
| | - Francisco Vidal
- Hospital Universitari Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain
| | - Mª Angeles Muñoz-Fernandez
- Sección Inmunología, Laboratory InmunoBiología Molecular, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain
- Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain
| | - Manuel Leal
- Laboratory of Immunovirology, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain
- Servicio de Medicina Interna, Hospital Viamed, Santa Ángela de la Cruz, Seville, Spain
| | - Richard Koup
- Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Ezequiel Ruiz-Mateos
- Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain
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17
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El-Bendary M, Neamatallah M, Esmat G, Kamel E, Elalfy H, Besheer T, Eldeib D, Eladl AH, El-Setouhy M, El-Gilany AH, El-Waseef A. Associations of human leucocyte antigen class II-DQB1 alleles with hepatitis C virus infection in Egyptian population: a multicentre family-based study. J Viral Hepat 2016; 23:961-970. [PMID: 27599887 DOI: 10.1111/jvh.12573] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/07/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis C infection is a global pandemic. HLA-DQB1 alleles are believed to have an effective role in immune response against HCV including susceptibility to or protection from this infection. The aim of this study was to investigate the contribution of HLA-DQB1 alleles in the outcome of HCV genotype-4 infection through a family-based association study. Egyptian families with HCV (324) were recruited for this study (324 index positive for RNA-HCV, 225 positive relatives representing chronic hepatitis C cases and 582 family members negative for HCV-RNA [control], 63 of whom spontaneously cleared the virus. All subjects were genotyped for HLA-DQB1 alleles by sequence-specific primers (SSP-PCR) and sequence-based typing (SBT) methods. The frequency of DQB1*02:01:01 carriage was significantly higher in infected patients when compared to controls and those who spontaneously cleared virus (OR=5.47, P<.0001 and OR= 6.5234, P<.0001, respectively), and the carriage of the DQB1*03:01:01:01 allele was significantly higher in those who cleared and controls when compared to the infected patients (OR=0.2889, P<.0001 and OR=0.3016, P<.0001, respectively). On the other hand, the frequency of DQB1*06:01:01 and QB1*05:01:01:01 alleles was not associated with infection (comparison of infected and cleared patients showed OR of 2.1598 [P<.01]), but it becomes nonsignificant after adjustments with the Bonferroni formula (PC >0.05) and OR= 1.3523, P>.05, respectively. This study shows that clearance of HCV is associated with DQB1*03:01:01:01 allele and chronicity of HCV infection associated with the risk allele: DQB1*02:01:01.
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Affiliation(s)
- M El-Bendary
- Tropical Medicine & Hepatology, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - M Neamatallah
- Medical Biochemistry, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - G Esmat
- Tropical Medicine & Hepatology, Cairo Faculty of Medicine, Cairo, Egypt
| | - E Kamel
- Public Health & Preventive Medicine Department, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - H Elalfy
- Tropical Medicine & Hepatology, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - T Besheer
- Tropical Medicine & Hepatology, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - D Eldeib
- Biochemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - A-H Eladl
- Internal Medicine Department, Alazhar Faculty of Medicine- Assiut University, Assiut, Egypt
| | - M El-Setouhy
- Department of Community, Environmental and Occupational Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt
| | - A-H El-Gilany
- Public Health & Preventive Medicine Department, Mansoura Faculty of Medicine, Mansoura, Egypt
| | - A El-Waseef
- Biochemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
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18
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Huang J, Huang K, Xu R, Wang M, Liao Q, Xiong H, Li C, Tang X, Shan Z, Zhang M, Rong X, Nelson K, Fu Y. The Associations of HLA-A*02:01 and DRB1*11:01 with Hepatitis C Virus Spontaneous Clearance Are Independent of IL28B in the Chinese Population. Sci Rep 2016; 6:31485. [PMID: 27511600 PMCID: PMC4980596 DOI: 10.1038/srep31485] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 07/20/2016] [Indexed: 12/26/2022] Open
Abstract
Spontaneous clearance of hepatitis C virus (HCV) occurs in 10-40% of the infections. Specific human leukocyte antigen (HLA) alleles have been identified in associating with HCV clearance. However, data on the association of HLA with the spontaneous clearance of HCV are scarce in the Chinese population. In the current study we studied the HLA class I and class II genes in 231 Chinese voluntary blood donors who had cleared HCV infection spontaneously compared to 429 subjects with chronic HCV infections. We also studied their IL28B SNP (rs8099917) genotype, since a number of investigators have found a strong association of IL28B with spontaneous or treatment induced HCV clearance. We found that HLA-A*02:01 and DQB1*05:02 distributed differently between the two groups after Bonferroni correction (odds ratio [OR] = 1.839, Pc = 0.024 and OR = 0.547, Pc = 0.016, respectively). Multivariate logistic regression analysis suggested that A*02:01 and DRB1*11:01 (OR = 1.798, P = 0.008 and OR = 1.921, P = 0.005, respectively) were associated with HCV spontaneous clearance, independent of age, gender and IL28B polymorphism. We concluded that in the Chinese population, HLA-A*02:01 and DRB1*11:01 might be associated with the host capacity to clear HCV independent of IL28B, which suggesting that the innate and adaptive immune responses both play an important role in the control of HCV.
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Affiliation(s)
- Jieting Huang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Ke Huang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Ru Xu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Min Wang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Qiao Liao
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Huaping Xiong
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Chengyao Li
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Xi Tang
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengang Shan
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Ming Zhang
- Department of Epidemiology and Biostatistics, Faculty of Infectious Diseases, University of Georgia, Athens, GA, USA
| | - Xia Rong
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Kenrad Nelson
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Yongshui Fu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
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19
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Abstract
Hepatitis C infection is a common cause of cirrhosis and indication for liver transplantation in the United States. The incidence of chronic hepatitis C has been declining, but rates of cirrhosis and hepatocellular carcinoma are projected to increase. The outcome of chronic hepatitis C is variable. It is estimated that 20% to 25% will develop cirrhosis over a 25-year to 30-year period. The rate of disease progression is influenced by many host, viral, and environmental factors. Few can be modified.
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20
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Cheng CH, Chen HL, Lin IT, Wu CH, Lee YK, Wong MW, Bair MJ. The genotype distribution of hepatitis C in southeastern Taiwan: Clinical characteristics, racial difference, and therapeutic response. Kaohsiung J Med Sci 2015; 31:597-602. [PMID: 26678941 DOI: 10.1016/j.kjms.2015.09.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 09/04/2015] [Accepted: 09/14/2015] [Indexed: 02/07/2023] Open
Abstract
The genotypes of hepatitis C virus (HCV) are associated with the therapeutic response. The racial diversity of Taitung, Taiwan is heterogeneous and a distinguishing feature; how such racial differences influence the genotype distribution and treatment outcome has not been well studied. The objective of this study is to elucidate the HCV genotype distribution in southeastern Taiwan and to analyze the racial differences influencing genotypes and clinical implications. In this retrospective cohort study, we included 343 patients who had been treated with peginterferon-alpha plus ribavirin. The predominant HCV genotype in the southeastern area was type 1 (43.7%), followed by type 2 (37.0%). The proportion of patients mixed with genotype 1 was lower in indigenous vis-à-vis nonindigenous groups (46.1% and 60.2%, p = 0.02). The prevalence of genotype 6 (5.2%) seems higher than in the general population of Taiwan and showed no difference between indigenous and nonindigenous people. The sustained virological response rate was higher in patients without genotype 1, low baseline HCV RNA (≤ 400,000 IU/mL), and in patients who achieved rapid virological response. Racial differences did not influence the therapeutic response. In this retrospective study, the proportion of HCV genotype 6 appeared slightly higher in southeastern areas than in the general population in Taiwan. The prevalence of genotype 1 in indigenous people was statistically lower than in nonindigenous people. Sustained virological response rate did not show any significant difference between indigenous and nonindigenous people in the current study.
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Affiliation(s)
- Chun-Han Cheng
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan
| | - Huan-Lin Chen
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan
| | - I-Tsung Lin
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan
| | - Chia-Hsien Wu
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan
| | - Yuan-Kai Lee
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan
| | - Ming-Wun Wong
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung, Taiwan; Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
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21
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Hydes TJ, Moesker B, Traherne JA, Ashraf S, Alexander GJ, Dimitrov BD, Woelk CH, Trowsdale J, Khakoo SI. The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways. TISSUE ANTIGENS 2015; 86:267-75. [PMID: 26381047 PMCID: PMC4858811 DOI: 10.1111/tan.12650] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 08/05/2015] [Accepted: 08/10/2015] [Indexed: 12/15/2022]
Abstract
Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)-λ3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, χ(2) test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-λ3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA-B (TapG:HLA-B(114D) ) (P = 0.007) and HLA-DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (χ(2) test for trend P < 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-λ3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA-C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non-interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection.
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Affiliation(s)
- T J Hydes
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - B Moesker
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - J A Traherne
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - S Ashraf
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - G J Alexander
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - B D Dimitrov
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- Academic Unit of Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - C H Woelk
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - J Trowsdale
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - S I Khakoo
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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22
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Samimi-Rad K, Sadeghi F, Amirzargar A, Eshraghian MR, Alavian SM, Rahimnia R. Association of HLA class II alleles with hepatitis C virus clearance and persistence in thalassemia patients from Iran. J Med Virol 2015; 87:1565-72. [DOI: 10.1002/jmv.24211] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Katayoun Samimi-Rad
- Department of Virology, School of Public Health; Tehran University of Medical Sciences (TUMS); Tehran Iran
| | - Farzin Sadeghi
- Department of Virology, School of Public Health; Tehran University of Medical Sciences (TUMS); Tehran Iran
| | - Aliakbar Amirzargar
- Molecular Immunology Research Center, and Department of Immunology, School of Medicine; Tehran University of Medical Sciences (TUMS); Tehran Iran
| | - Mohamad Reza Eshraghian
- Department of Epidemiology and Biostatics, School of Public Health; Tehran University of Medical Sciences (TUMS); Tehran Iran
| | - Seyed-Moayed Alavian
- Research Center for Gastroenterology and Liver Disease; Baqiatallah University of Medical Sciences; Tehran Iran
| | - Ramin Rahimnia
- Department of Nanomedicine, School of Advanced Technologies in Medicine; Tehran University of Medical Sciences (TUMS); Tehran Iran
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23
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Fitzmaurice K, Hurst J, Dring M, Rauch A, McLaren PJ, Günthard HF, Gardiner C, Klenerman P. Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection. Gut 2015; 64:813-9. [PMID: 24996883 PMCID: PMC4392199 DOI: 10.1136/gutjnl-2013-306287] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 06/17/2014] [Accepted: 06/18/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. OBJECTIVE This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. DESIGN We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. RESULTS Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. CONCLUSIONS This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.
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Affiliation(s)
| | - Jacob Hurst
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Institute of Emerging Infection, The Oxford Martin School, University of Oxford, Oxford, UK
| | - Megan Dring
- Natural Killer Cell Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Andri Rauch
- University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland
| | - Paul J McLaren
- Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Huldrych F Günthard
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Clair Gardiner
- Natural Killer Cell Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland
| | - Paul Klenerman
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
- NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
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24
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Wang M, Li JS, Ping Y, Li ZQ, Wang LP, Guo Q, Zhang Z, Yue DL, Wang F, Zhang TF, Islam MS, Zhang Y. The host HLA-A*02 allele is associated with the response to pegylated interferon and ribavirin in patients with chronic hepatitis C virus infection. Arch Virol 2015; 160:1043-1054. [PMID: 25666200 DOI: 10.1007/s00705-015-2361-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 01/31/2015] [Indexed: 12/16/2022]
Abstract
Human leukocyte antigen (HLA) alleles are associated with both the progression of chronic hepatitis C (CHC) and the sustained virological response (SVR) to antiviral therapy. HLA-A*02 is the most common HLA allele in people of European/Caucasian descent and the Chinese and Japanese population. Therefore, we investigated whether HLA-A*02 expression is associated with disease outcome in Chinese CHC patients. Three hundred thirty-one treatment-naïve CHC patients were recruited in this study. The expression of HLA-A*02 was tested by FACS and LABType SSO assays. All patients were treated weekly with pegylated interferon plus ribavirin (PEG-IFN/RBV) according to a standard protocol. Virological response was assessed by TaqMan assay at the 4th, 12th, 24th, and 48th week of therapy, and again at the 24th week post-therapy. By the end of the study, 293 CHC patients, including 144 HLA-A*02-positive patients and 149 HLA-A*02-negative patients, were evaluable for analysis. There were no statistical differences in clinicopathological parameters between HLA-A*02-positive and negative patients before antiviral therapy (P > 0.05). The HLA-A*02-positive patients had a higher rapid virological response (RVR, 74.3 % versus 62.4 %, P = 0.03) and SVR (78.5 % versus 64.4 %, P = 0.01) and a lower relapse rate (4.2 % versus 11.9 %, P = 0.03) than HLA-A*02-negative patients. Multivariable logistic regression analysis showed that HLA-A*02 expression, liver fibrosis stages
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Affiliation(s)
- Meng Wang
- Department of Gastroenterology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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25
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Buchanan R, Hydes T, Khakoo SI. Innate and adaptive genetic pathways in HCV infection. TISSUE ANTIGENS 2015; 85:231-40. [PMID: 25708172 DOI: 10.1111/tan.12540] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes.
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Affiliation(s)
- R Buchanan
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
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26
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Papastergiou V, Karatapanis S. Current status and emerging challenges in the treatment of hepatitis C virus genotypes 4 to 6. World J Clin Cases 2015; 3:210-20. [PMID: 25789294 PMCID: PMC4360493 DOI: 10.12998/wjcc.v3.i3.210] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/01/2014] [Accepted: 12/29/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) genotypes 4, 5 and 6 are mainly present in Africa, the Middle East and Asia and they have been less extensively studied with respect to epidemiology, natural disease history and therapeutic endpoints. Response rates to a 48-wk combined peginterferon/ribavirin treatment range to 40%-69% for HCV 4, 55%-60% for HCV 5 and 60%-90% for HCV 6. Response-guided schedules are recommended to optimize the outcomes of peginterferon/ribavirin treatment in HCV 4 and, in form of preliminary data, for HCV 6, but no data are yet available to support such an individualization of therapy for HCV 5. Recently, the direct-acting antivirals (DAAs) with pan-genotypic activities simeprevir, sofosbuvir and daclatasvir have been recommended in triple regimens with peginterferon/ribavirin for the treatment of HCV genotypes 4 to 6 infections. In the future, DAA-based interferon-free therapies are awaited to drastically improve treatment outcomes in HCV. However, efforts to improve treatment outcomes with peginterferon/ribavirin should continue, as the HCV 4-6 infected population is mainly based in resource-limited settings with restricted access to the costly DAAs.
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27
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Rossi LMG, Escobar-Gutierrez A, Rahal P. Advanced molecular surveillance of hepatitis C virus. Viruses 2015; 7:1153-88. [PMID: 25781918 PMCID: PMC4379565 DOI: 10.3390/v7031153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 02/05/2015] [Accepted: 02/20/2015] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is an important public health problem worldwide. HCV exploits complex molecular mechanisms, which result in a high degree of intrahost genetic heterogeneity. This high degree of variability represents a challenge for the accurate establishment of genetic relatedness between cases and complicates the identification of sources of infection. Tracking HCV infections is crucial for the elucidation of routes of transmission in a variety of settings. Therefore, implementation of HCV advanced molecular surveillance (AMS) is essential for disease control. Accounting for virulence is also important for HCV AMS and both viral and host factors contribute to the disease outcome. Therefore, HCV AMS requires the incorporation of host factors as an integral component of the algorithms used to monitor disease occurrence. Importantly, implementation of comprehensive global databases and data mining are also needed for the proper study of the mechanisms responsible for HCV transmission. Here, we review molecular aspects associated with HCV transmission, as well as the most recent technological advances used for virus and host characterization. Additionally, the cornerstone discoveries that have defined the pathway for viral characterization are presented and the importance of implementing advanced HCV molecular surveillance is highlighted.
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Affiliation(s)
- Livia Maria Gonçalves Rossi
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
| | | | - Paula Rahal
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
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28
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Lokhande MU, Thimme R, Klenerman P, Semmo N. Methodologies for the Analysis of HCV-Specific CD4(+) T Cells. Front Immunol 2015; 6:57. [PMID: 25767470 PMCID: PMC4341113 DOI: 10.3389/fimmu.2015.00057] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 01/29/2015] [Indexed: 12/16/2022] Open
Abstract
Virus-specific CD4+ T cells play a major role in viral infections, such as hepatitis C virus (HCV). Viral clearance is associated with vigorous and multi-specific CD4+ T-cell responses, while chronic infection has been shown to be associated with weak or absent T-cell responses. Most of these studies have used functional assays to analyze virus-specific CD4+ T-cell responses; however, these and other detection methods have various limitations. Therefore, the important question of whether virus-specific CD4+ T cells are completely absent or primarily impaired in specific effector functions during chronic infection, has yet to be analyzed in detail. A novel assay, in which virus-specific CD4+ T-cell frequencies can be determined by de novo CD154 (CD40 ligand) expression in response to viral antigens, can help to overcome some of the limitations of functional assays and restrictions of multimer-based methods. This and other current established methods for the detection of HCV-specific CD4+ T cells will be discussed in this review.
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Affiliation(s)
- Megha U Lokhande
- Hepatology, Department of Clinical Research, University of Bern , Bern , Switzerland
| | - Robert Thimme
- Department of Gastroenterology and Hepatology, University Hospital of Freiburg , Freiburg , Germany
| | - Paul Klenerman
- NIHR Biomedical Research Centre, Oxford and Peter Medawar Building for Pathogen Research, University of Oxford , Oxford , UK
| | - Nasser Semmo
- Hepatology, Department of Clinical Research, University of Bern , Bern , Switzerland ; Department of Hepatology, University Clinic of Visceral Surgery and Medicine , Inselspital, Bern , Switzerland
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29
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Resistance to hepatitis C virus: potential genetic and immunological determinants. THE LANCET. INFECTIOUS DISEASES 2015; 15:451-60. [PMID: 25703062 DOI: 10.1016/s1473-3099(14)70965-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Studies of individuals who were highly exposed but seronegative (HESN) for HIV infection led to the discovery that homozygosity for the Δ32 deletion mutation in the CCR5 gene prevents viral entry into target cells, and is associated with resistance to infection. Additionally, evidence for protective immunity has been noted in some HESN groups, such as sex workers in The Gambia. Population studies of individuals at high risk for hepatitis C virus infection suggest that an HESN phenotype exists. The body of evidence, which suggests that protective immunity allows clearance of hepatitis C virus without seroconversion is growing. Furthermore, proof-of-principle evidence from in-vitro studies shows that genetic polymorphisms can confer resistance to establishment of infection. This Review discusses the possibility that genetic mutations confer resistance against hepatitis C virus, and also explores evidence for protective immunity, including via genetically programmed variations in host responses. The data generally strengthens the notion that investigations of naturally arising polymorphisms within the hepatitis C virus interactome, and genetic association studies of well characterised HESN individuals, could identify potential targets for vaccine design and inform novel therapies.
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Xiong H, Huang J, Rong X, Zhang M, Huang K, Xu R, Wang M, Li C, Liao Q, Xia W, Luo G, Ye X, Lu L, Fu Y, Guo T, Nelson K. HLA-B alleles B*15:01 and B*15:02: opposite association with hepatitis C virus infection in Chinese voluntary blood donors. Intervirology 2015; 58:80-7. [PMID: 25677350 DOI: 10.1159/000369209] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 10/18/2014] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Although human leukocyte antigens (HLA) have been shown in association with the outcomes of hepatitis C virus (HCV) infection among different ethnic groups, such studies remain absent in China, where the HCV prevalence is higher than the global average. METHODS In this study, 426 HCV-infected and 709 uninfected blood donors were analyzed, among whom the HLA alleles were sequenced using a high-resolution genotyping method. RESULTS At the 2-digit level, none of the alleles showed a statistical difference between the HCV-infected and uninfected groups. However, at the 4-digit level, the HLA-B alleles B*15:01 and B*15:02 showed an opposite association with HCV infection, i.e. B*15:01 was significantly higher in the HCV-infected group (odds ratio, OR = 1.561, p = 0.010), while B*15:02 was significantly higher in the uninfected group (OR = 0.778, p = 0.016). We also identified a higher frequency of B*13:02 in the HCV-infected group (OR = 1.515, p = 0.009) and a higher frequency of B*07:05 in the uninfected group (OR = 0.299, p = 0.001). CONCLUSIONS The frequencies of four HLA alleles, B*07:05, B*13:02, B*15:01, and B*15:02, were found to be significantly different between the HCV-infected and uninfected blood donors in China, revealing an inverse relation of B*15:01 and B*15:02 with HCV infection. This finding suggests that the ethnic genetic variations of HLA may greatly affect the host immune responses against HCV.
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Clausen LN, Lundbo LF, Benfield T. Hepatitis C virus infection in the human immunodeficiency virus infected patient. World J Gastroenterol 2014; 20:12132-12143. [PMID: 25232248 PMCID: PMC4161799 DOI: 10.3748/wjg.v20.i34.12132] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 04/02/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share the same transmission routes; therefore, coinfection is frequent. An estimated 5-10 million individuals alone in the western world are infected with both viruses. The majority of people acquire HCV by injection drug use and, to a lesser extent, through blood transfusion and blood products. Recently, there has been an increase in HCV infections among men who have sex with men. In the context of effective antiretroviral treatment, liver-related deaths are now more common than Acquired Immune Deficiency Syndrome-related deaths among HIV-HCV coinfected individuals. Morbidity and mortality rates from chronic HCV infection will increase because the infection incidence peaked in the mid-1980s and because liver disease progresses slowly and is clinically silent to cirrhosis and end-stage-liver disease over a 15-20 year time period for 15%-20% of chronically infected individuals. HCV treatment has rapidly changed with the development of new direct-acting antiviral agents; therefore, cure rates have greatly improved because the new treatment regimens target different parts of the HCV life cycle. In this review, we focus on the epidemiology, diagnosis and the natural course of HCV as well as current and future strategies for HCV therapy in the context of HIV-HCV coinfection in the western world.
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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
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Haralambieva IH, Ovsyannikova IG, Kennedy RB, Larrabee BR, Pankratz VS, Poland GA. Race and sex-based differences in cytokine immune responses to smallpox vaccine in healthy individuals. Hum Immunol 2013; 74:1263-6. [PMID: 23806267 PMCID: PMC4170575 DOI: 10.1016/j.humimm.2013.06.031] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 05/31/2013] [Accepted: 06/13/2013] [Indexed: 11/19/2022]
Abstract
We assessed the effects of sex, race and ethnicity on smallpox vaccine-induced immune responses in 1071 armed forces members after primary Dryvax(®) smallpox vaccination, including 790 males and 281 females; 580 Caucasians, 217 African-Americans, and 217 Hispanics. Analysis of vaccinia-specific cytokine responses revealed that Caucasians had higher total IFNγ ELISPOT responses (median 57 spot-forming units/SFUs per 200,000 cells, p=0.01) and CD8(+)IFNγ ELISPOT responses (12 SFUs, p<0.001) than African-Americans (51 and 4 SFUs, respectively) and Hispanics (47 and 8 SFUs, respectively). Similarly, Caucasians secreted higher levels of vaccinia-specific IL-2 (p=0.003) and IFNα (p<0.001) compared to other racial/ethnic groups. Males had higher total IFNγ ELISPOT responses (median 55 SFUs) compared to females (41 SFUs, p<0.001). We observed statistically significant sex-related differences in the secretion of IL-2 (p<0.001), IL-1β (p<0.001) and IL-10 (p=0.017). These data suggest that vaccinia-specific cytokine responses following primary smallpox vaccination are significantly influenced by race and sex of vaccinees.
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Affiliation(s)
- Iana H. Haralambieva
- Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN 55905 USA
- Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905 USA
| | - Inna G. Ovsyannikova
- Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN 55905 USA
- Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905 USA
| | - Richard B. Kennedy
- Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN 55905 USA
- Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905 USA
| | - Beth R. Larrabee
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA
| | - V. Shane Pankratz
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 USA
| | - Gregory A. Poland
- Mayo Vaccine Research Group, Mayo Clinic, Rochester, MN 55905 USA
- Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905 USA
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Wojcik G, Latanich R, Mosbruger T, Astemborski J, Kirk GD, Mehta SH, Goedert JJ, Kim AY, Seaberg EC, Busch M, Thomas DL, Duggal P, Thio CL. Variants in HAVCR1 gene region contribute to hepatitis C persistence in African Americans. J Infect Dis 2013; 209:355-9. [PMID: 23964107 DOI: 10.1093/infdis/jit444] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
To confirm previously identified polymorphisms in HAVCR1 that were associated with persistent hepatitis C virus (HCV) infection in individuals of African and of European descent, we studied 165 subjects of African descent and 635 subjects of European descent. Because the association was only confirmed in subjects of African descent (rs6880859; odds ratio, 2.42; P = .01), we then used 379 subjects of African descent (142 with spontaneous HCV clearance) to fine-map HAVCR1. rs111511318 was strongly associated with HCV persistence after adjusting for IL28B and HLA (adjusted P = 8.8 × 10(-4)), as was one 81-kb haplotype (adjusted P = .0006). The HAVCR1 genomic region is an independent genetic determinant of HCV persistence in individuals of African descent.
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Affiliation(s)
- Genevieve Wojcik
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore
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Association between human leukocyte antigen class I and II alleles and hepatitis C virus infection in high-risk hemodialysis patients awaiting kidney transplantation. Hum Immunol 2013; 74:1629-32. [PMID: 23974050 DOI: 10.1016/j.humimm.2013.08.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2013] [Revised: 07/29/2013] [Accepted: 08/10/2013] [Indexed: 02/06/2023]
Abstract
Recent evidences have shown that several host genetic factors influence susceptibility or protection to hepatitis C virus (HCV) infection. There are controversial data regarding the associations of human leukocyte antigens (HLA) and the clearance or progression of HCV. The aim of this study was to investigate whether particular HLA molecules were associated with HCV infection in recipients awaiting kidney transplantation considered at high-risk to infection due to protracted hemodialysis treatment. To this purpose, 301 kidney recipients with HCV infection and 1103 uninfected recipients were examined for HLA class I and II molecules. In our case-control study, HLA-A(*)26 is positively associated with HCV infection while HLA-A(*)29, -B(*)40 and -DRB1(*)01 are negatively associated with HCV infection. Multiple logistic regression analysis demonstrated that age (OR = 1.02; 95% CI = 1.01-1.04; p < 0.00), HLA-A(*)26, -A(*)29, -B(*)40 and -DRB1(*)01 [(OR = 1.54; 95% CI = 1.03-2.30; p = 0.03); (OR = 0.50; 95% CI = 0.26-0.99; p = 0.05); (OR = 0.42; 95% CI = 0.23-0, 7; p = 0.01); (OR = 0.62; 95% CI = 0.41-0, 94; p = 0.03); respectively] are independent predictors of HCV infection. Our results suggest that particular HLA molecules, as host genetic factors, may have a relationship with susceptibility or protection to HCV infection also in recipients awaiting kidney transplantation.
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Duggal P, Thio CL, Wojcik GL, Goedert JJ, Mangia A, Latanich R, Kim AY, Lauer GM, Chung RT, Peters MG, Kirk GD, Mehta SH, Cox AL, Khakoo SI, Alric L, Cramp ME, Donfield SM, Edlin BR, Tobler LH, Busch MP, Alexander G, Rosen HR, Gao X, Abdel-Hamid M, Apps R, Carrington M, Thomas DL. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann Intern Med 2013; 158:235-45. [PMID: 23420232 PMCID: PMC3638215 DOI: 10.7326/0003-4819-158-4-201302190-00003] [Citation(s) in RCA: 162] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
UNLABELLED Chinese translation BACKGROUND Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood. OBJECTIVE To evaluate the host genetic basis for spontaneous resolution of HCV infection. DESIGN 2-stage, genome-wide association study. SETTING 13 international multicenter study sites. PATIENTS 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence). MEASUREMENTS Frequencies of 792 721 single nucleotide polymorphisms (SNPs). RESULTS Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015). LIMITATION Epigenetic effects were not studied. CONCLUSION IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection.
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Affiliation(s)
- Priya Duggal
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Chloe L. Thio
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Genevieve L. Wojcik
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - James J. Goedert
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Alessandra Mangia
- Liver Unit IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy
| | - Rachel Latanich
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Arthur Y. Kim
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Warren 1019A, 55 Fruit Street, Boston MA, USA
- Ragon Institute of Harvard, Boston, MA, USA
| | - Georg M. Lauer
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Warren 1019A, 55 Fruit Street, Boston MA, USA
- Ragon Institute of Harvard, Boston, MA, USA
| | - Raymond T. Chung
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Warren 1019A, 55 Fruit Street, Boston MA, USA
- Ragon Institute of Harvard, Boston, MA, USA
| | - Marion G. Peters
- University of California San Francisco, 513 Parnassus Ave S357, San Francisco, CA, USA
| | - Greg D. Kirk
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Shruti H. Mehta
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Andrea L. Cox
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Salim I. Khakoo
- University of Southampton, Mailpoint 811, Level E South Academic Block, Southampton General Hospital, Tremona Road, Southampton, UK
| | | | | | | | | | - Leslie H Tobler
- Viral Reference Laboratory and Repository Core, Blood Systems Research Institute, San Francisco, CA, USA
| | - Michael P. Busch
- Viral Reference Laboratory and Repository Core, Blood Systems Research Institute, San Francisco, CA, USA
| | - Graeme Alexander
- Division of Gastroenetrology & Hepatology, University Department of Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Hill’s Road, Cambridge,, CB2 0QQ, United Kingdom
| | - Hugo R. Rosen
- Department of Medicine, University of Colorado, Denver, Colorado, USA
| | - Xiaojiang Gao
- Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Mohamed Abdel-Hamid
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University and Director, Viral Hepatitis Research Lab National Hepatology and Tropical Disease Research Institute
| | - Richard Apps
- Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Mary Carrington
- Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
| | - David L. Thomas
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Sehgal M, Khan ZK, Talal AH, Jain P. Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle? Virology (Auckl) 2013; 4:1-25. [PMID: 25512691 PMCID: PMC4222345 DOI: 10.4137/vrt.s11046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs’ potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV.
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Affiliation(s)
- Mohit Sehgal
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Andrew H Talal
- Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
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T cell epitope mapping of JC polyoma virus-encoded proteome reveals reduced T cell responses in HLA-DRB1*04:01+ donors. J Virol 2013; 87:3393-408. [PMID: 23302880 DOI: 10.1128/jvi.02803-12] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
JC polyomavirus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. It is only during immunocompromise and especially impaired CD4(+) T cell function in the brain, as seen in AIDS patients or natalizumab-treated multiple sclerosis patients, that JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4(+) T cells likely play an important role in controlling JCV infection, we here describe the T cell response to JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. We identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. We observed positive JCV-specific T cell responses in 28.6% to 77.6%, humoral immune response in 42.6% to 89.4%, and urinary viral shedding in 36.4% to 45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01(+), DRB1*07(+), DRB1*11(+), DRB1*13(+), DRB1*15(+), and DRB1*03(+) individuals. We show for the first time that JCV-specific T cell responses may be directed not only against JCV VP1 and large T antigen but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01(+) individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV.
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Marangon AV, Silva GF, de Moraes CFV, Grotto RMT, Pardini MIMC, de Pauli DS, Visentainer JEL, Sell AM, Moliterno RA. Protective effect of HLA-DRB1 11 and predisposition of HLA-C 04 in the development of severe liver damage in Brazilian patients with chronic hepatitis C virus infection. Scand J Immunol 2012; 76:440-7. [PMID: 22803655 DOI: 10.1111/j.1365-3083.2012.02755.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The objective of this study was to investigate human leucocyte antigen (HLA) genes in patients chronically infected with hepatitis C virus (HCV) and to analyse the possible role of these genes in the progression of chronic hepatitis C. One hundred and forty-five (145) Brazilian patients infected only with HCV genotype 1 were evaluated. HLA class I (A, B, C) and class II (DRB1, DQA1, DQB1) typing were carried out by PCR-SSO, through Luminex technology. Associations were found with protection against development of liver damage by both DRB1 11 (5.0% versus 18.2%, P=0.0016, OR=0.23, CI 95% = 0.09-0.58; Pc=0.0208) and DRB1 11-DQA1 05-DQB1 03 haplotype (4.2% versus 15.3%, P=0.0032; OR = 0.24, CI 95% = 0.08-0.64). Liver damage was associated with HLA-C 04 in patients with <20 years of infection (38.4% versus 9.1%, P = 0.002, OR = 6.25, CI 95%=1.97-19.7; Pc=0.0238). It is concluded that HLA alleles can influence the development of liver damage in HCV type-1 chronically infected Brazilian patients.
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Affiliation(s)
- A V Marangon
- Immunogenetics Laboratory, Maringá State University, UEM, Maringá, PR, Brazil.
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Papastergiou V, Dimitroulopoulos D, Skorda L, Lisgos P, Ketikoglou I, Kostas N, Karatapanis S. Predictors of sustained virological response in Greek and Egyptian patients with hepatitis C genotype 4: does ethnicity matter? J Med Virol 2012; 84:1217-23. [PMID: 22711349 DOI: 10.1002/jmv.23324] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus genotype 4 (HCV-4) is spreading beyond Africa and the Middle East but data regarding treatment with pegylated interferon alpha and ribavirin of European populations infected with HCV-4 remains limited. Interestingly, European (vs. Egyptian) origin has been associated with lower sustained virological response rates. Hence the aim of this study was to investigate the treatment outcomes of Greek (vs. Egyptian), treatment-naïve patients infected with HCV-4 (subtype a) and to identify factors influencing response rates. One hundred seventy-seven consecutive patients (mean age: 44.6 ± 10.2, males: 143/177; 80.8%, Egyptians: 76/177; 42.9%) treated over a 7-year period at the Hepatology clinics of three tertiary care hospitals in Greece were retrospectively evaluated. Overall, sustained virological response was achieved in 75/177 (42.4%) of the cohort without a significant difference between the two ethnic groups [Greek: 44/101 (43.6%); Egyptian 31/76 (40.8%), P = 0.7598]. In multivariate analysis, it was found that ethnicity was not associated with an impaired response but age ≥45 years [odds ratio (OR): 0.4225, 95% confidence interval (CI): 0.2135-0.8133; P = 0.0134], diabetes (OR: 0.2346, 95% CI: 0.0816-0.0674; P = 0.0071), advanced liver fibrosis (OR: 0.3964, 95% CI: 0.1933-0.8133; P = 0.0116), and treatment suspension (OR: 0.1738, 95% CI: 0.0482-0.6262; P = 0.0075) showed an independent negative association with response to antiviral treatment. In contrast to previous European data suggesting Egyptian ethnicity to be a positive predictor for a sustained virological response, there was no influence of Greek versus Egyptian ethnicity on treatment outcomes. Higher age, advanced liver fibrosis, and diabetes have been shown to reduce significantly response rates in patients infected with HCV-4.
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Ahmed R, Salama H, Abdallah ES, Ahmed SEDM, Sabry D, Omar D, Darwish T. Correlation between HCV viraemia and splenic volume in chronic HCV infected patients: an Egyptian study. Arab J Gastroenterol 2012; 13:58-64. [PMID: 22980593 DOI: 10.1016/j.ajg.2012.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2011] [Revised: 04/14/2012] [Accepted: 06/05/2012] [Indexed: 10/28/2022]
Abstract
BACKGROUND AND STUDY AIMS As HCV lymphotropism was ascertained, this study was carried out to verify the possible involvement of the spleen in HCV-related chronic hepatitis. PATIENTS AND METHODS A cross-sectional study was conducted on 97 HCV infected patients attending for treatment with interferon, categorised as follows; before treatment (group I, n=49), non-responders (group II, n=18), responders (group III, n=18) and group IV (n=12) including patients with HCV RNA below detection limit after 24 weeks of treatment. A control group of healthy blood donors (n=19) was enrolled in our study. Conventional ultrasonography was carried out on all participants. Splenic volume was measured and compared between the groups, and its relationship to HCV RNA concentration was investigated. RESULTS It was found that the splenic volume of patients of both groups I and II is significantly greater than that of the control group (p-values : 0.004 and 0.009, respectively) and, of patients of both groups III and IV. The latter are not significantly greater than that of the control group (p-value: 0.8 and 0.6, respectively). A significant positive relationship was detected between the splenic volume and the HCV RNA concentration in group I (r=0.56, p-value=0.00) but this is insignificant in group II. There is no significant relationship between the splenic longitudinal diameter and the HCV RNA concentration in any of the studied groups. CONCLUSION The splenic volume positively correlated with HCV RNA concentration in HCV positive patients, but this become insignificant in non-responders to interferon therapy. The successful response to interferon therapy matches with near normal splenic volume whilst non-responders to Interferon therapy matches with increased splenic volume. The change in the viral load leads to a corresponding change in the splenic volume and does not affect the splenic longitudinal diameter.
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Affiliation(s)
- Rasha Ahmed
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Understanding the T cell immune response in SARS coronavirus infection. Emerg Microbes Infect 2012; 1:e23. [PMID: 26038429 PMCID: PMC3636424 DOI: 10.1038/emi.2012.26] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Revised: 07/02/2012] [Accepted: 07/06/2012] [Indexed: 12/17/2022]
Abstract
The severe acute respiratory syndrome (SARS) epidemic started in late 2002 and swiftly spread across 5 continents with a mortality rate of around 10%. Although the epidemic was eventually controlled through the implementation of strict quarantine measures, there continues a need to investigate the SARS coronavirus (SARS-CoV) and develop interventions should it re-emerge. Numerous studies have shown that neutralizing antibodies against the virus can be found in patients infected with SARS-CoV within days upon the onset of illness and lasting up to several months. In contrast, there is little data on the kinetics of T cell responses during SARS-CoV infection and little is known about their role in the recovery process. However, recent studies in mice suggest the importance of T cells in viral clearance during SARS-CoV infection. Moreover, a growing number of studies have investigated the memory T cell responses in recovered SARS patients. This review covers the available literature on the emerging importance of T cell responses in SARS-CoV infection, particularly on the mapping of cytotoxic T lymphocyte (CTL) epitopes, longevity, polyfunctionality and human leukocyte antigen (HLA) association as well as their potential implications on treatment and vaccine development.
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Amini M, Poustchi H. Hepatitis C virus spontaneous clearance: immunology and genetic variance. Viral Immunol 2012; 25:241-8. [PMID: 22823386 DOI: 10.1089/vim.2011.0052] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis C virus (HCV) infection is one of the most common chronic viral infections in the world. Approximately 80-90% of acutely infected individuals develop persistent infection, which is a major risk for liver cirrhosis and liver cancer. However, a small portion of patients (10-20%) clear the virus. Clinical outcomes of HCV infection are determined by the interplay between the host immune response, and viral and environmental factors. In regulating immune responses, cytokines play an indispensable role that controls the underlying pathogenesis and the resulting outcome of HCV infection. Cytokines themselves are manipulated by polymorphisms in their genes. In fact, the majority of genetic variants that apparently confer a significant risk for chronic HCV infection have been localized in genes involved in cytokine synthesis and the ultimate immune response. So far, treatment strategies for HCV infection have remained controversial. Genotyping of different polymorphisms will aid clinical decision making for both current standard and personalized care. Genotyping can potentially be useful for future integration of other agents, which provides an opportunity for clinicians to personalize treatment regimens for HCV patients. This review summarizes findings of different studies on host immune responses after HCV infection and the association between cytokine gene polymorphisms and the likelihood of HCV clearance.
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Affiliation(s)
- Marzyeh Amini
- Digestive Disease Research Centre, Shariati Hospital, Tehran University of Medical science, Tehran, Iran
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Rodríguez-Torres M, Hallman D. Impact of Ethnicity and Race on Treatment Response: Past, Present and Future. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s11901-012-0134-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Shah DP, Grimes CZ, Brown E, Hwang LY. Demographics, socio-behavioral factors, and drug use patterns: what matters in spontaneous HCV clearance? J Med Virol 2012; 84:235-41. [PMID: 22170543 DOI: 10.1002/jmv.22271] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV), an emerging bloodborne pathogen, causes chronic liver disease frequently except in about 10-20% of infections which undergo spontaneous resolution. Investigating factors that influence viral clearance is essential to understand the natural history of this infection and establishing novel strategies for prevention and treatment. HCV clearance was estimated in a unique cohort of 1,260 HIV and HBV negative current drug users enrolled for a hepatitis B vaccination study. It was defined as the inability to detect viral RNA using a PCR method in presence of serum anti-HCV antibody EIA. Associated demographic and socio-behavioral factors including drug use patterns were identified from the enrolled subjects using multivariate regression analysis. 33.3% (420/1260) of drug users were found positive for anti-HCV antibodies and 14.8% (62/420) of these individuals achieved viral clearance (negative PCR test). Race or ethnicity of the participants was the only significant factor associated with HCV clearance. Hispanics (OR = 3.4, 95% CI: 1.3-8.5, P = 0.01) and Caucasians (OR = 3.1, 95% CI: 1.5-6.6, P = 0.003) had significantly higher odds of clearing the virus compared to African Americans when adjusted for age and gender. None of the socio-behavioral factors including alcohol intake and drug use patterns were significant determinants of HCV clearance. Racial or ethnic differences in HCV clearance were observed in this study suggesting an important role of host genetic susceptibility factors in determining the clinical course of this disease. Further research is needed to examine these genetic associations of host-virus relationships.
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Affiliation(s)
- Dimpy P Shah
- Center for Infectious Diseases, Division of Epidemiology and Disease Control, School of Public Health, University of Texas Health Science Center, Houston, Texas 77030, USA
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Kahraman A, Fingas CD, Syn WK, Gerken G, Canbay A. Role of stress-induced NKG2D ligands in liver diseases. Liver Int 2012; 32:370-82. [PMID: 22097967 DOI: 10.1111/j.1478-3231.2011.02608.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 06/15/2011] [Indexed: 12/24/2022]
Abstract
Cell death by apoptosis is a prominent feature in a variety of liver diseases. It is likely that apoptosis is the initial cellular response to hepatocyte and biliary injury, which then leads to the initiation of cellular and cytokine cascades culminating in hepatocyte death with subsequent fibrosis and cirrhosis. This sequence of events is of paramount clinical importance. Recently, soluble forms of the major histocompatibility complex class I-related chains A and closely related B (MIC A and B) were reported to be increased in patients with a variety of liver diseases. MIC A and B are cell surface glycoproteins that function as indicators for cellular stress and thus activate circulating cytotoxic natural killer (NK) cells. The interaction between MIC A and B with their cognate receptor natural killer group 2 member D (NKG2D) culminates in enhanced liver cell death, which is mediated in part by apoptotic mechanisms. The present overview focuses on the role of the stress-induced NKG2D ligands MIC A and B in diverse liver diseases. Critical insights into these complex relations may help to promote rationally based therapies in liver diseases. Importantly, we hope that this overview will help to stimulate further studies into mechanisms by which stress ligands mediate cell death and its sequale.
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Affiliation(s)
- Alisan Kahraman
- University Clinic Essen, University of Duisburg-Essen, Essen, Germany
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Marangon AV, Moliterno RA, Sell AM, de Moraes CFV, Grotto RMT, Pardini MC, De Pauli DS, Visentainer JEL, Silva GF. Influence of HLA alleles in response to treatment with pegylated interferon-alpha and ribavirin in patients with chronic hepatitis C. Int J Immunogenet 2012; 39:296-302. [PMID: 22284614 DOI: 10.1111/j.1744-313x.2012.01088.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The objective of this study was to analyse the possible role of HLA polymorphism of chronically infected hepatitis C virus patients in the response outcome to treatment with pegylated interferon-alpha plus ribavirin. To that end, 144 Brazilian patients infected only with genotype 1 of the virus were treated with pegylated interferon-alpha at 1.5 μg kg(-1) in conjunction with ribavirin (1000 mg if patient weight was <75 kg and 1250 mg if >75 kg) for 48 weeks. The patients did not have concomitant HBV or HIV infections or liver disease, did not undergo previous antiviral treatment, and were followed up for 24 weeks after the end of treatment to assure they presented a sustained virological response. Patients were classified according to response to treatment in responsive (SVR), nonresponsive (NRS) and relapsers (REL). HLA class I and class II typing were carried out through PCR-SSO using Luminex technology. A statistically higher frequency of DRB1*11 patients was observed in the SVR group (39.6% vs. 14.3%P = 0.0012; Pc = 0.0156; OR = 3.94; 95% CI = 1.8-8.8). HLA-DQB1*03 patients were also more frequent in the SVR group, but the P value lost significance after Bonferroni correction (62.3% vs. 41.7%P = 0.024; Pc = 0.14, OR = 2.3; 95% CI = 1.14-4.60). HLA class II antigens can positively influence the response to treatment with pegylated interferon-alpha and ribavirin.
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Affiliation(s)
- A V Marangon
- Department of Basic Sciences, Immunogenetics Laboratory, Maringá State University, UEM, Maringá-PR, Brazil.
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Cangussu LOF, Teixeira R, Campos EF, Rampim GF, Mingoti SA, Martins-Filho OA, Gerbase-DeLima M. HLA class II alleles and chronic hepatitis C virus infection. Scand J Immunol 2011; 74:282-287. [PMID: 21535077 DOI: 10.1111/j.1365-3083.2011.02568.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The aim of this study was to investigate association of human leucocyte antigens (HLA)-DRB1 and DQB1 polymorphisms with hepatitis C virus (HCV) infection and with the occurrence of severe liver fibrosis/cirrhosis in chronically infected patients. Ninety-nine white patients, from southeast Brazil, with confirmed HCV chronic infection were included in the study. Severe fibrosis/cirrhosis (METAVIR scores F3-F4) was present in 49 patients. HLA-DRB1 specificities and DRB1*11 and DQB1* alleles were determined by PCR-SSP, and their frequencies were compared between patients and a control group of 103 healthy white Brazilian individuals. The results confirmed previous reports of the association of DRB1*11 and DQB1*03 with protection from chronic HCV infection, but did not confirm their association with protection from severe fibrosis/cirrhosis. Furthermore, the results suggested that the polymorphic sites on HLA molecules responsible for protection from chronic HCV infection are encoded not only by the DRB1*1101 and DQB1*0301, as suggested in the literature, but also by other DRB1*11 and DQB1*03 alleles. Thus, we hypothesized that the common polymorphic residues shared by different DRB1*11 and/or DQB1*03 alleles might be responsible for selection of viral epitopes for presentation to CD4(+) T cells, leading to an efficient immune response against the virus.
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Affiliation(s)
- L O F Cangussu
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - R Teixeira
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - E F Campos
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - G F Rampim
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - S A Mingoti
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - O A Martins-Filho
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - M Gerbase-DeLima
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
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de Almeida BS, Silva GMF, da Silva PM, Perez RDM, Figueiredo FAF, Porto LC. Ethnicity and route of HCV infection can influence the associations of HLA with viral clearance in an ethnically heterogeneous population. J Viral Hepat 2011; 18:692-9. [PMID: 21914086 DOI: 10.1111/j.1365-2893.2010.01429.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Approximately 20% of hepatitis C virus (HCV) infected individuals clear the virus. Host factors that influence the course of HCV infection are still under investigation, and the data on the association of human leukocyte antigen (HLA) alleles and HCV clearance are scarce and controversial. The aims of this study were to investigate whether HLA alleles are associated with clearance of HCV infection in a highly admixed Brazilian population and whether these associations could be influenced by ethnicity and route of infection. HLA-A, -B, -C, -DRB1 and -DQB1 genotyping were performed in 135 HCV-infected Brazilian patients among which 45 cleared HCV infection (cases) and 90 had persistent viral infection (controls). Controls were matched by sex, ethnicity (withes and non-whites) and route of infection (high infectious dose or low infectious dose). No significant association was identified between HLA alleles and the outcome of HCV infection when analyzing the sample as a single group. However, a new protective association of HLA-DQB1*04 (P = 0.006; P(c) = 0.030) and a rarely described association of HLA-DRB1*08 (P = 0.004; P(c) = 0.048) were found only among white patients. The DRB1*11 allele, previously reported in homogeneous population, was associated with HCV clearance (P = 0.020) only among patients with expected high-dose exposure. These findings confirm the influence of ethnicity on the associations of HLA with spontaneous viral clearance of HCV infection and emphasize the possible influence of route of infection in this process.
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Affiliation(s)
- B S de Almeida
- Department of Gastroenterology, Rio de Janeiro State University, Rio de Janeiro, Brazil.
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50
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Wang SF, Chen KH, Chen M, Li WY, Chen YJ, Tsao CH, Yen MY, Huang JC, Chen YMA. Human-leukocyte antigen class I Cw 1502 and class II DR 0301 genotypes are associated with resistance to severe acute respiratory syndrome (SARS) infection. Viral Immunol 2011; 24:421-6. [PMID: 21958371 DOI: 10.1089/vim.2011.0024] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
One-hundred and thirty confirmed cases of severe acute respiratory syndrome (SARS) were recruited to evaluate their anti-SARS-coronavirus (CoV) antibody status and human leukocyte antigen (HLA) types in September 2006, 3 y after the SARS outbreaks in Taiwan. Western blot assay showed that 6.9% of participants still had anti-spike and anti-nucleocapside antibodies. A case-control study of the association of HLA with SARS revealed that the HLA-Cw1502 and DR0301 alleles conferred resistance against SARS infection (p<0.05).
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Affiliation(s)
- Sheng-Fan Wang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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