DOCSLIB.ORG

Impact of Interferon Lambda 4 Genotype on Interferon‐

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Impact of Interferon Lambda 4 Genotype on Interferon‐ HEPATOLOGY, VOL. 68, NO. 3, 2018 VIRAL HEPATITIS Impact of Interferon Lambda 4 Genotype on Interferon-Stimulated Gene Expression During Direct-Acting Antiviral Therapy for Hepatitis C 1* 1* 1-3 2 4 1 Narayan Ramamurthy , Emanuele Marchi, M. Azim Ansari, Vincent Pedergnana, Angela Mclean, Emma Hudson, 2 2 1 1 STOP HCV consortium, Rory Bowden, Chris C.A. Spencer, Eleanor Barnes, and Paul Klenerman New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat, including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, patients with cirrhosis receiving a 16-week course of sofosbuvir and ribavirin had a sustained virological response (SVR) rate of around 50%. In patients with cirrhosis, interferon lambda 4 (IFNL4) CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon- stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, whereas the reverse was true for non-CC patients. Conclusion: These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. (Hepatology 2018; 68:859-871). epatitis C virus (HCV) infects approxi- Interferon (IFN) and ribavirin combination ther- mately 180 million people globally. An esti- apy was, for many years, the mainstay of treatment for (4) mated 20% of patients are able to control patients with chronic hepatitis C (CHC). However, Hthe infection spontaneously after exposure—that regimes using combined pegylated interferon (Peg-IFN) is, through a combination of innate and adaptive and ribavirin therapy result in only modest sustained (1,2) responses. In the remainder, chronic hepatitis virological response (SVR) rates and are associated with leads to HCV-related cirrhosis in around 15%-30% significant adverse effects. Recently, many new directly of patients and 1%-4% of patients with cirrhosis acting antiviral (DAA) therapies have been developed, (3) develop hepatocellular carcinoma. The develop- which provide significantly higher cure rates in different ment of treatments for HCV infection has therefore patient groups. Such drugs may be used in combination (5) been an important priority in recent years and huge with IFN (e.g., the protease inhibitor, telapravir) or, advances have been made. most recently, in IFN-free regimens, using combinations Abbreviations: DAA, direct-acting antiviral; GSEA, gene set enrichment analysis; HCV, hepatitis C virus; IFN, interferon; IFNL4, interferon lambda 4; ISG, interferon-stimulated gene; NS, nonstructural protein; OR, odds ratio; Peg-IFN, pegylated interferon; RNAseq, RNA sequencing; SNP, single-nucleotide polymorphism; SVR, sustained virological response. Received November 1, 2017; accepted March 8, 2018. Additional Supporting Information may be found at onlinelibrary.wiley.com/10.1002/hep.29877/suppinfo. This work was funded by a grant from the Medical Research Council (MRC) (MR/K01532X/1; to the STOP-HCV Consortium). The work was supported by the Wellcome Trust Fund WT109965MA, NIH (U19AI082630), and NIHR Senior Fellowship to P.K. and the NIHR Biomedical Research Centre, Oxford. *These authors contributed equally to the work. © 2018 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29877 Potential conflict of interest: Nothing to report. 859 RAMAMURTHY, MARCHI, ET AL. HEPATOLOGY, September 2018 of inhibitors of nonstructural protein (NS) 3, NS5A, a greater than 2-fold increase in the likelihood of (6) (12) and NS5B, with or without ribavirin. achieving SVR compared to the TT genotype. The HCV is genetically highly diverse and has evolved CC genotype was also associated with changes in the (12,16-19) into seven major genotypes and multiple subtypes. dynamics of viral control in genotypes 1 and 3. Response rates to both the IFN-based and, more The mechanism by which the IFNL4 locus affects recently, the DAA based regimes are genotype depen- hepatitis C outcomes has not been fully elucidated. dent. In particular, HCV genotype 3 (one of the most Although the CC genotype is associated with bet- common in the UK) has been associated with lower ter immune control and response to therapy, it has response rates to several DAA regimens, compared to also been associated with higher viral load than the (7-9) (13-16,18) genotype 1 infection. Defining optimal treatment non-CC genotypes. This elevated viral load for such patient groups is an issue that was addressed in is associated with a reduced host innate immune (10) the recent BOSON trial, which tested the efficacy response during chronic infection. Hepatic interfer- of the NS5B (polymerase) inhibitor, sofosbuvir, on 594 on-stimulated genes (ISGs) are also up-regulated in patients, mainly genotype 3, with a small subgroup of CHC patients resistant to antiviral therapy and higher (20) genotype 2 infections, and including patients with and in patients with the non-CC with IFNL4 genotype. without cirrhosis and with or without previous treat- These associations may be attributed to modulation of ment. Patients were divided into three groups, given 16 the IFNL4 gene itself or of linked genes. SNPs in the or 24 weeks of sofosbuvir with ribavirin or 12 weeks of IFNL4 region may influence expression, transcription sofosbuvir with Peg-IFN and ribavirin. A key result of factor binding, or mRNA stability, but overall appear (21) the study was that patients with cirrhosis who received to reduce IFNL3 gene expression. The C allele at 16 weeks of sofosbuvir and ribavirin had the lowest SNP rs12979860 tags a dinucleotide insertion poly- (22) rates of SVR—at 51%, compared to >80% attaining morphism (rs368234815-TT) that prevents IFNL4 (23) cure in other treatment groups. This prompted us to expression. Using human genotyping arrays com- ask: In such a setting (and in the absence of exoge- bined with whole-genome viral sequencing, we recently neous interferon), what is the role of the host immune reported viral “footprints” of host IFNL4 genotypes response and host genetics in defining outcome? (CC vs. non-CC at rs12979860). We identified the Host genetics play an important role in both the association of 11 sites in the HCV polyprotein with spontaneous control of HCV and response to therapy. IFNL4 genotypes, including one (serine vs. nonserine In particular, a single-nucleotide polymorphism (SNP; at position 2414 in NS5A) that was also associated (24) rs12979860) in the interferon lambda 4 (IFNL4) with viral load in vivo and viral fitness in vitro. (11-13) gene has been associated with higher probability of Based on these data, we hypothesized that host spontaneous clearance of the virus and of SVR follow- IFNL4 genotype might particularly affect viral outcome (12,14,15) ing Peg-IFN and ribavirin combination therapy. in patients with cirrhosis treated with the shortest proto- Those carrying the CC genotype at rs12979860 had col (16 weeks). We aimed to test whether transcriptional ARTICLE INFORMATION: 1 From the Peter Medawar Building for Pathogen Research and Translational Gastroeneterology Unit, Nuffield Department of 2 Medicine, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, 3 4 United Kingdom; Oxford Martin School, University of Oxford, Oxford, United Kingdom; Department of Zoology, University of Oxford, Oxford, United Kingdom. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Paul Klenerman, M.R.C.P., FRCPath Narayan Ramamurthy, Ph.D. Peter Medawar Building for Pathogen Research and Translational Peter Medawar Building for Pathogen Research Gastroeneterology Unit, Nuffield Department of Medicine Nuffield Department of Medicine University of Oxford University of Oxford South Parks Road South Parks Road Oxford, OX1 3SY, United Kingdom Oxford, OX1 3SY, United Kingdom E-mail: [email protected] E-mail: [email protected] Tel: +44 1865 281885 Tel: +44 1865 281885 or 860 HEPATOLOGY, Vol. 68, No. 3, 2018 RAMAMURTHY, MARCHI, ET AL. changes in the host response were detectable in blood BIOINFORMATIC ANALYSIS and linked to outcome. We therefore analyzed the host response to HCV by microarray analysis of gene expres- Illumina bead chip output files were processed and analyzed using the R package (http://www.r-project. sion in whole blood over time in a subset of patients from (25) the BOSON study. We make a report of a time-depen- org), wherein samples were normalized and gene dent molecular signature detectable in blood associated expression levels calculated to determine statistical sig- with IFNL4 genotypes, which, in itself, is associated with nificance. Differential gene expression between different SVR in patients with cirrhosis. We provide a model that groups was assessed by generating relevant contrasts cor- explains the paradoxical observations related to HCV responding to the possible comparisons. Statistical testing and its interaction with the IFNL4 region. was performed using the Linear Models for Microarray Analysis (LIMMA) package (http://bioconductor.org/ (26) packages/release/bioc/html/limma.html). Raw P val- Materials and Methods ues were corrected for multiple testing using the false discovery rate controlling procedure of Benjamini and (27) STUDY DESIGN, PATIENTS, AND Hochberg. Following this correction, adjusted P val- ETHICS ues <0.01 were considered significant. Pathway over-rep- resentation analysis and plotting was conducted using This study was part of the study described ear- (28) (10,22) Reactome PA. We also used the CAMERA pack- lier.
Load more

Recommended publications
  • Polymorphism Rs368234815 of Interferon Lambda 4 Gene and Spontaneous Clearance of Hepatitis C Virus in Haemodialysis Patients: a Case Control Study
    Polymorphism rs368234815 of Interferon Lambda 4 Gene and Spontaneous Clearance of Hepatitis C Virus in Haemodialysis Patients: A Case Control Study Alicja Grzegorzewska ( [email protected] ) Poznań University of Medical Sciences https://orcid.org/0000-0001-8087-4696 Adrianna Mostowska Uniwersytet Medyczny imienia Karola Marcinkowskiego w Poznaniu Monika Świderska Uniwersytet Medyczny imienia Karola Marcinkowskiego w Poznaniu Wojciech Marcinkowski Fresenius NephroCare Polska Sp zoo Ireneusz Stolarek Polska Akademia Nauk Marek Figlerowicz Polska Akademia Nauk Paweł P. Jagodziński Uniwersytet Medyczny imienia Karola Marcinkowskiego w Poznaniu Research article Keywords: haemodialysis, hepatitis C virus, interferon-λ4 gene, spontaneous viral clearance, transcription factors Posted Date: December 16th, 2019 DOI: https://doi.org/10.21203/rs.2.18966/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published on January 22nd, 2021. See the published version at https://doi.org/10.1186/s12879-021-05777-6. Page 1/16 Abstract Background In non-uremic subjects, IFNL4 rs368234815 predicts the HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in haemodialysis subjects. An association of rs368234815 with survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms were also evaluated. Methods Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917.
    [Show full text]
  • Health & Medicine Research
    WEDNESDAY, MARCH 30, 2016 HEALTH & MEDICINE RESEARCH DAY HEALTH & MEDICINE RESEARCH DAY WEDNESDAY, MARCH 30, 2016 MARVIN CENTER MARVIN CENTER 800 21ST STREET, NW, 3RD FLOOR 800 21ST STREET, NW, 3RD FLOOR 8:00–9:00 a.m. Posters Setup (Grand and Continental Ballrooms) 12:00–2:00 p.m. Distribution of Box Lunches (MC 310) 12:30–3:00 p.m. Poster Presentations and Judging JACK MORTON AUDITORIUM (Grand and Continental Ballrooms) 805 21ST STREET, NW 3:00–4:00 p.m. Awards Ceremony and Oral Presentations (includes 10-minute presentations by winners of oral 8:00–9:00 a.m. Registration and Breakfast competition awards) (MC 309) 9:00–9:05 a.m. Welcome to Research Days 2016 Jeffrey S. Akman, MD Vice President for Health Affairs and Dean, MILKEN INSTITUTE SCHOOL OF School of Medicine and Health Sciences PUBLIC HEALTH BUILDING 9:05–9:10 a.m. Introduction of Keynote Address 950 NEW HAMPSHIRE AVENUE, NW, 1ST FLOOR AUDITORIUM Catherine Bollard, MD, FRACP, FRCPA Professor of Pediatrics and Microbiology, Immunology 4:30–4:35 p.m. Welcome Video & Introduction of Keynote Address and Tropical Medicine, School of Medicine and Health Sciences; Director, Program for Cell Lynn R. Goldman, MD, MS, MPH Enhancement and Technologies for Immunotherapy Michael and Lori Milken Dean, Milken Institute School (CETI), Children’s National Health System of Public Health; Professor of Environmental and Occupational Health 9:10–10:00 a.m. Keynote Address Kimberly Horn, EdD, MSW Stanley R. Riddell, MD Associate Dean for Research, Milken Institute School Fred Hutchinson Cancer Research Center, Clinical of Public Health; Professor of Prevention and Research Division; Professor of Oncology, University of Community Health Washington School of Medicine 4:35–5:15 p.m.
    [Show full text]
  • When a Good Interferon Goes Bad
    JOURNAL OF INTERFERON & CYTOKINE RESEARCH Volume 00, Number 00, 2019 ª Mary Ann Liebert, Inc. DOI: 10.1089/jir.2019.0044 The IFN-l4 Conundrum: When a Good Interferon Goes Bad Olusegun O. Onabajo, Brian Muchmore, and Ludmila Prokunina-Olsson Since its discovery in 2013, interferon lambda 4 (IFN-l4) has received a reputation as a paradoxical type III IFN. Difficulties in detecting IFN-l4, especially in secreted form even led to questions about its existence. However, the genetic ability to generate IFN-l4, determined by the presence of the rs368234815-DG allele, is the strongest predictor of impaired clearance of hepatitis C virus (HCV) infection in humans. Significant modulation of IFN-l4 activity by a genetic variant (P70S) supports IFN-l4, and not other type III IFNs encoded in the same genomic locus, as the primary functional cause of the association with HCV clearance. Although the ability to produce IFN-l4 is associated with decreased HCV clearance, the recombinant IFN-l4 is active against HCV and other viruses. These observations present an apparent conundrum—when and how does a presumably good IFN, with anti-HCV activity, interfere with the ability to clear HCV? In this review, we discuss findings that suggest potential mechanisms for explaining this conundrum. Keywords: IFN-l4, type III interferon, SOCS1, USP18, regulation, HCV Introduction transiently overexpressed in vitro (Paquin and others 2016). The extent of conservation between these homologs suggests he family of class-2 cytokines includes type I in- an important functional role of IFN-l4 in evolution (Key and Tterferons (IFN-a, b, k, and o), type II IFN (IFN-g), type others 2014).
    [Show full text]
  • Interferon Lambda 3/4 Polymorphisms Are Associated with AIDS-Related
    CONCISE COMMUNICATION Interferon lambda 3/4 polymorphisms are associated with AIDS-related Kaposi’s sarcoma Stephanie Biberta, Agnieszka Wojtowicz a, Patrick Taffeb, Philip E. Tarrc, Enos Bernasconid, Hansjakob Furrere, f,g h i 11/22/2018 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3KirptPALrnDi+TL0TbiLtNhRYG30LMgOhEYax8qRJms= by https://journals.lww.com/aidsonline from Downloaded Downloaded Huldrych F. Gu¨nthard , Matthias Hoffmann , Laurent Kaiser , j k,l a from Michael Osthoff , Jacques Fellay , Matthias Cavassini , https://journals.lww.com/aidsonline M Pierre-Yves Bochuda, the Swiss HIV Cohort Study Background: Kaposi’s sarcoma, the most common AIDS-related cancer, represents a major public concern in resource-limited countries. Single nucleotide polymorphisms by within the Interferon lambda 3/4 region (IFNL3/4) determine the expression, function of BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3KirptPALrnDi+TL0TbiLtNhRYG30LMgOhEYax8qRJms= IFNL4, and influence the clinical course of an increasing number of viral infections. Objectives: To analyze whether IFNL3/4 variants are associated with susceptibility to AIDS-related Kaposi’s sarcoma among MSM enrolled in the Swiss HIV Cohort Study (SHCS). Methods: The risk of developing Kaposi’s sarcoma according to the carriage of IFNL3/4 SNPs rs8099917 and rs12980275 and their haplotypic combinations was assessed by using cumulative incidence curves and Cox regression models, accounting for relevant covariables. Results: Kaposi’s sarcoma was diagnosed in 221 of 2558 MSM Caucasian SHCS participants. Both rs12980275 and rs8099917 were associated with an increased risk of Kaposi’s sarcoma (cumulative incidence 15 versus 10%, P ¼ 0.01 and 16 versus 10%, P ¼ 0.009, respectively). Diplotypes predicted to produce the active P70 form (cumu- lative incidence 16 versus 10%, P ¼ 0.01) but not the less active S70 (cumulative incidence 11 versus 10%, P ¼ 0.7) form of IFNL4 were associated with an increased risk of Kaposi’s sarcoma, compared with those predicted not to produce IFNL4.
    [Show full text]
  • Interferon Lambda Polymorphisms Associate with Body Iron Indices and Hepatic Expression of Interferon-Responsive Long Non-Coding RNA in Chronic Hepatitis C
    Clin Exp Med DOI 10.1007/s10238-016-0423-4 ORIGINAL ARTICLE Interferon lambda polymorphisms associate with body iron indices and hepatic expression of interferon-responsive long non-coding RNA in chronic hepatitis C 1 1 1 2 Anna Wro´blewska • Agnieszka Bernat • Anna Woziwodzka • Joanna Markiewicz • 1 1 3 Tomasz Romanowski • Krzysztof P. Bielawski • Tomasz Smiatacz • Katarzyna Sikorska3,4 Received: 4 March 2016 / Accepted: 18 April 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Single nucleotide polymorphisms (SNPs) within markers of serum and hepatocyte iron overload associated DNA region containing interferon lambda 3 (IFNL3) and with higher activity of gamma-glutamyl transpeptidase and IFNL4 genes are prognostic factors of treatment response liver steatosis. The presence of two minor alleles in any of in chronic hepatitis C (CHC). Iron overload, frequently the tested SNPs predisposed to abnormally high serum iron diagnosed in CHC, is associated with unfavorable disease concentration and correlated with higher hepatic expres- course and a risk of carcinogenesis. Its etiology and rela- sion of lncRNA NRIR. On the other hand, homozygosity in tionship with the immune response in CHC are not fully any major allele associated with higher viral load. Patients explained. Our aim was to determine whether IFNL poly- bearing rs12979860 CC genotype had lower hepatic morphisms in CHC patients associate with body iron expression of hepcidin (HAMP; P = 0.03). HAMP mRNA indices, and whether they are linked with hepatic expres- level positively correlated with serum iron indices and sion of genes involved in iron homeostasis and IFN sig- degree of hepatocyte iron deposits.
    [Show full text]
  • IFNL4-ΔG Genotype Is Associated with Slower Viral Clearance In
    BRIEF REPORT IFNL4-ΔG Genotype Is Associated In treatment-naive hepatitis C virus (HCV) genotype-1 pa- tients, the current standard-of-care treatment, an NS3 prote- With Slower Viral Clearance in ase inhibitor with IFN-α/RBV, results in sustained virological Hepatitis C, Genotype-1 Patients response (SVR) rates of 63%–75% [1]. However, many pa- tients remain untreated due to relative or absolute contraindi- Treated With Sofosbuvir and cations, fear of adverse events, or pill burden. Treatment of Ribavirin chronic HCV infection is evolving towards IFN-α–free, direct-acting antiviral (DAA) regimens that specifically target Eric G. Meissner,1,a Dimitra Bon,2,a Ludmila Prokunina-Olsson,3 the HCV protease (NS3/4A), RNA polymerase (NS5B), or 3 4 ’ 5 2 Wei Tang, Henry Masur, Thomas R. O Brien, Eva Herrmann, nonstructural protein NS5A. While phase 2 and 3 studies of Shyamasundaran Kottilil,1 and Anuoluwapo Osinusi1,6,7 DAA therapies demonstrate promising efficacy and tolerabili- 1Laboratory of Immunoregulation/National Institute of Allergy and Infectious Diseases/National Institutes of Health, Bethesda, Maryland; 2Institute of ty [2], issues of cost and access to treatment will remain rele- Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, vant. Identification of host factors that affect differential 3 Frankfurt, Germany; Laboratory of Translational Genomics, Division of Cancer response to DAA therapies could permit personalization of Epidemiology and Genetics/National Cancer Institute/National Institutes of Health, HCV
    [Show full text]
  • IFNL4-ΔG Allele Is Associated with an Interferon Signature in Tumors And
    Author Manuscript Published OnlineFirst on July 16, 2018; DOI: 10.1158/1078-0432.CCR-18-1060 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. IFNL4-G allele is associated with an interferon signature in tumors and survival of African-American men with prostate cancer Wei Tang1, Tiffany A. Wallace1, Ming Yi2, Cristina Magi-Galluzzi3, Tiffany H. Dorsey1, Olusegun O. Onabajo4, Adeola Obajemu4, Symone V. Jordan1, Christopher A. Loffredo5, Robert M. Stephens2, Robert H. Silverman6, George R. Stark6, Eric A. Klein7, Ludmila Prokunina-Olsson4, and Stefan Ambs1 1 Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA 2 Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA 3 Department of Pathology, Cleveland Clinic, Cleveland, OH, USA 4 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, MD, USA 5 Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 6 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA 7 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA Running title: Interferon signature and African-American prostate cancer patients Key words: Prostate cancer, IFNL4, interferon signature, African-American, gene expression, disease recurrence, immune therapy, IDO1 Abbreviations: AA, African-American; EA, European-American; IFNL4, interferon-4; IRDS, interferon-related DNA damage resistance signature; IRG, interferon response genes; ISG, interferon-stimulated gene; IDO1, indoleamine-2,3-dioxygenase-1 Address all correspondence to: Stefan Ambs, PhD, Laboratory of Human Carcinogenesis, NCI, NIH, Bldg.37/Room 3050B, Bethesda, MD 20892-4258.
    [Show full text]
  • Interferon Lambda 4 Gene (IFNL4)
    The Egyptian Journal of Hospital Medicine (Apr. 2017) Vol.67 (2), Page 635- 644 Interferon Lambda 4 Gene (IFNL4) Linked to Hepatitis C virus clearance, treatment 1Saadia Farid, 2Laila Rashed and 3Samya Sweilam Department of Tropical Medicine, Biochemistry, and Medical Biochemistry National Hepatology and Tropical Medicine Research Institute and Faculty of Medicine, Cairo University ABSTRACT Background: A designated IFNL4 gene, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3, is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Aim of the work: The study was attempted for the identification of interferon Lambda 4 (IFNL4) gene expression in the liver biopsy and the recombinant IFNL4 protein in the serum of CHCV patients. Patients and methods: Eighty five patients with chronic hepatitis C virus infection (CHCV), whose age ranged between 19 and 57 years, were selected from the National Hepatology and Tropical Medicine Research Institute were included in this study, before chronic HCV therapy, during the preparation of patients, and ten healthy individuals were included to serve as controls. All the patients and controls were subjected to the following: history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigations, CBCs. Liver biopsy was done to all patients and controls. Patients revealed mild fibrosis (Metavir fibrosis from F1 to F3). Using freshly frozen liver biopsies to identify gene (IFNL4) by real time-PCR and the detection of its serum protein levels by ELISA. Results: Patients with CHCV have higher hepatic expression of IFNL4 before treatment and also recombinant IFNL4 protein expression was detectable in serum with high levels.
    [Show full text]
  • Annual Conference 2017
    Annual Conference 2017 3–6 APRIL, EICC, EDINBURGH, UK POSTER ABSTRACT BOOK @MicrobioSoc #Microbio17 Annual Conference 2017 EICC, Edinburgh 3-6 April Posters displayed Monday to Thursday Virus Workshop: Antivirals and Vaccines Virus Workshop: Clinical Virology Network Virus Workshop: Evolution and Virus Populations Virus Workshop: Gene expression and replication Virus Workshop: Innate Immunity Virus Workshop: Morphogenesis, egress and entry Virus Workshop: Pathogenesis Annual Meeting of Protistology-UK society: Intracellular infection and endosymbiosis within protists Aquatic Microbiology Cell biology of pathogen entry into host cells Circadian Rhythms Critical health challenges in medical mycology Epigenetic and Non Coding RNAs in Eukaryotes Synthetic and Systems Biology Approaches to Microbiology Posters displayed on Monday and Tuesday Geomicrobiology Macromolecular Machines Microbial Mechanisms of Plant pathology Prokaryotic Genetics and Genomics Forum Prokaryotic Microbial Infection Forum Posters displayed on Wednesday and Thursday Anaerobes in infection Environmental and Applied Microbiology Forum Heterogeneity and Polymicrobial Interactions in Biofilms Microbial Cell Surfaces Microbial Genomics: Whole Population to Single Cell Microbial Physiology, Metabolism and Molecular Mechanisms Forum Please note: Abstracts are published as received from the authors and are not subject to editing Annual Conference 2017 EICC, Edinburgh 3-6 April Virus Workshop: Antivirals and Vaccines 1 Investigating membrane viral bending proteins in coronavirus replication. Entedar Alsaadi1, Benjamin W.Neuman1 1University of Reading, Reading, UK, 2University of Reading, Reading, UK The coronavirus envelope spike (S) glycoprotein, a class I viral fusion protein, is responsible for the fusion between the membranes of the virus and the host cell. The fusion peptide has yet to be definitively identified, but bioinformatics analysis suggests that at least part of the fusion peptide is located near the amino terminus of the S2 region of S.
    [Show full text]
  • Negative Regulation of ACE2 by Interferons in Vivo and Its Genetic Control
    medRxiv preprint doi: https://doi.org/10.1101/2020.04.26.20080408; this version posted June 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Negative regulation of ACE2 by interferons in vivo and its genetic control M. Azim Ansari1,2,3,4*, Emanuele Marchi1,2,3*, Narayan Ramamurthy1,2,3*, Dominik Aschenbrenner1,3, Carl-Philipp Hackstein2, STOP-HCV consortium, ISARIC-4C Investigators, Shang-Kuan Lin4, Rory Bowden4, Eshita Sharma4, Vincent Pedergnana5, Suresh Venkateswaran6, Subra Kugathasan6, Angela Mo7, Greg Gibson7, Graham Cooke8, John McLauchlan9, Eleanor Barnes1,2,3, John Kenneth Baillie10,11, Sarah Teichmann12, Alex Mentzer4, 4 4 1,3,13 1,2,3 John Todd , Julian Knight , Holm Uhlig , Paul Klenerman * 1. Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK 2. Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK 3. NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU 4. Wellcome Centre for Human Genetics, Roosevelt Dr, Headington, Oxford OX3 7BN 5. French National Centre for Scientific Research (CNRS), Laboratory MIVEGEC (CNRS, IRD, UM), Montpellier, France 6. Department of Pediatrics, Emory University School of Medicine and Children’s health care of Atlanta, Atlanta, USA 7. Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, USA 8. Department of Infectious Disease, Faculty of Medicine, Imperial College London, London W2 1PG, UK 9.
    [Show full text]
  • Interferon Lambda 4 Expression Is Suppressed by the Host During Viral Infection
    Published October 31, 2016 Brief Definitive Report Interferon lambda 4 expression is suppressed by the host during viral infection MeeAe Hong,1* Johannes Schwerk,1* Chrissie Lim,1* Alison Kell,1 Abigail Jarret,1 Joseph Pangallo,1 Yueh-Ming Loo,1 Shuanghu Liu,2 Curt H. Hagedorn,3,4 Michael Gale Jr.,1 and Ram Savan1 1Department of Immunology, University of Washington, Seattle, WA 98109 2Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84112 3Department of Medicine and 4Genetics Program, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205 Interferon (IFN) lambdas are critical antiviral effectors in hepatic and mucosal infections. Although IFNλ1, IFNλ2, and IFNλ3 act antiviral, genetic association studies have shown that expression of the recently discovered IFNL4 is detrimental to hepa- titis C virus (HCV) infection through a yet unknown mechanism. Intriguingly, human IFNL4 harbors a genetic variant that in- troduces a premature stop codon. We performed a molecular and biochemical characterization of IFNλ4 to determine its role and regulation of expression. We found that IFNλ4 exhibits similar antiviral activity to IFNλ3 without negatively affecting antiviral IFN activity or cell survival. We show that humans deploy several mechanisms to limit expression of functional IFNλ4 Downloaded from through noncoding splice variants and nonfunctional protein isoforms. Furthermore, protein-coding IFNL4 mRNA are not loaded onto polyribosomes and lack a strong polyadenylation signal, resulting in poor translation efficiency. This study provides mechanistic evidence that humans suppress IFNλ4 expression, suggesting that immune function is dependent on other IFNL family members.
    [Show full text]
  • Polymorphism Rs368234815 of Interferon Lambda 4 Gene and Spontaneous Clearance of Hepatitis C Virus in Haemodialysis Patients: a Case-Control Study Alicja E
    Grzegorzewska et al. BMC Infectious Diseases (2021) 21:102 https://doi.org/10.1186/s12879-021-05777-6 RESEARCH ARTICLE Open Access Polymorphism rs368234815 of interferon lambda 4 gene and spontaneous clearance of hepatitis C virus in haemodialysis patients: a case-control study Alicja E. Grzegorzewska1* , Adrianna Mostowska2, Monika K. Świderska1, Wojciech Marcinkowski3, Ireneusz Stolarek4, Marek Figlerowicz4 and Paweł P. Jagodziński2 Abstract Background: In non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms. Methods: Among 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software. Results: The probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38–5.04, 0.003).
    [Show full text]