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Immunogenetics of Viral Infections - Extending the Scope beyond IL28B SNPs and Hepatitis C

English title Immunogenetics of Viral Infections - Extending the Scope beyond IL28B SNPs and Hepatitis C
Applicant Bochud Pierre-Yves
Number 144054
Funding scheme Project funding (special)
Research institution Service des Maladies Infectieuses Département de Médecine Interne CHUV
Institution of higher education University of Lausanne - LA
Main discipline Clinical Immunology and Immunopathology
Start/End 01.10.2012 - 30.09.2015
Approved amount 390'000.00
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All Disciplines (3)

Discipline
Clinical Immunology and Immunopathology
Immunology, Immunopathology
Infectious Diseases

Keywords (2)

Innate Immunity; Swiss Hepatits C Cohort Study

Lay Summary (French)

Lead
Ce projet a pour but d'évaluer le rôle de polymorphismes dans des gènes du système immunitaire dans la susceptibilité à plusieurs types d'infections virales.
Lay summary

Environ 3% de la population mondiale est chroniquement infectée par le virus de l'hépatite C (HCV). De nombreux individus ignorent qu'ils sont porteurs de ce virus, et ne deviendront symptomatiques que lors de la découverte de complications sévères, comme la cirrhose ou le cancer du foie, à un stade avancé de la maladie. Malgré le développement de nouveaux médicaments, le traitement reste complexe, long, côuteux, et peut causer des effets indésirables et/ou aboutir à l'émergence de virus résistants.

Des études récentes ont montré que des polymorphismes d'un gène nommé IL28B expliquent en partie pourquoi certains individus répondent mieux que d'autres au traitement de l'hépatite C. Le rôle de ces polymorphismes dans des infections virales autres que l'hépatite C n'a pas été exploré.

Le but de ce projet est de mieux connaitre les mécanismes par lesquels le polymorphisms d'IL28B influence la réponse au virus et de déterminer dans quelle mesure ils influencent la susceptibilité à d'autres infections virales comme l'hépatite B, l'infection due au cytomegalovirus, au virus de la varicelle et de l'herpès.

Direct link to Lay Summary Last update: 24.01.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A systematic review and meta-analysis of HCV clearance.
Gauthiez Emeline, Habfast-Robertson Ines, Rüeger Sina, Kutalik Zoltan, Aubert Vincent, Berg Thomas, Cerny Andreas, Gorgievski Meri, George Jacob, Heim Markus H, Malinverni Raffaele, Moradpour Darius, Müllhaupt Beat, Negro Francesco, Semela David, Semmo Nasser, Villard Jean, Bibert Stéphanie, Bochud Pierre-Yves, Bochud Pierre-Yves (2017), A systematic review and meta-analysis of HCV clearance., in Liver international : official journal of the International Association for the Study of the Liver, 37(10), 1431-1445.
Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection.
Fischer Janett, Weber Alexander N R, Böhm Stephan, Dickhöfer Sabine, El Maadidi Souhayla, Deichsel Danilo, Knop Viola, Klinker Hartwig, Möller Bernd, Rasenack Jens, Wang Lisa, Sharma Manu, Hinrichsen Holger, Spengler Ulrich, Buggisch Peter, Sarrazin Christoph, Pawlita Michael, Waterboer Tim, Wiese Manfred, Probst-Müller Elsbeth, Malinverni Raffaele, Bochud Pierre-Yves, Gardiner Clair, O'Farrelly Cliona, Berg Thomas (2017), Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection., in Gut, 66(10), 1829-1837.
BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease.
Oussalah Abderrahim, Avogbe Patrice Hodonou, Guyot Erwan, Chery Céline, Guéant-Rodriguez Rosa-Maria, Ganne-Carrié Nathalie, Cobat Aurélie, Moradpour Darius, Nalpas Bertrand, Negro Francesco, Poynard Thierry, Pol Stanislas, Bochud Pierre-Yves, Abel Laurent, Jeulin Hélène, Schvoerer Evelyne, Chabi Nicodème, Amouzou Emile, Sanni Ambaliou, Barraud Hélène, Rouyer Pierre, Josse Thomas, Goffinet Laetitia, Jouve Jean-Louis, Minello Anne, Bonithon-Kopp Claire, Thiefin Gérard, Di Martino Vincent, Doffoël Michel, Richou Carine, Raab Jean-Jacques, Hillon Patrick, Bronowicki Jean-Pierre, Guéant Jean-Louis, Guéant Jean-Louis (2017), BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease., in Oncotarget, 8(38), 62842-62857.
A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected patients.
Ulveling Damien, Le Clerc Sigrid, Cobat Aurélie, Labib Taoufik, Noirel Josselin, Laville Vincent, Coulonges Cédric, Carpentier Wassila, Nalpas Bertrand, Heim Markus H, Poynard Thierry, Cerny Andreas, Pol Stanislas, Bochud Pierre-Yves, Dabis François, Theodorou Ioannis, Lévy Yves, Salmon Dominique, Abel Laurent, Dominguez Stéphanie, Zagury Jean-François, Zagury Jean-François, Zagury Jean-François, Zagury Jean-François (2016), A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected patients., in Hepatology (Baltimore, Md.), 64(5), 1462-1472.
Host - hepatitis C viral interactions: The role of genetics.
Heim Markus H, Bochud Pierre-Yves, George Jacob (2016), Host - hepatitis C viral interactions: The role of genetics., in Journal of hepatology, 65(1 Suppl), 22-32.
A significant effect of the killer cell immunoglobulin-like receptor ligand human leucocyte antigen-C on fibrosis progression in chronic C hepatitis with or without liver transplantation.
Buhler Stéphane, Giostra Emiliano, Gbame Corinne, de Rham Casimir, Mullhaupt Beat, Dufour Jean-François, Majno Pietro, Negro Francesco, Bochud Pierre-Yves, Villard Jean, Villard Jean (2016), A significant effect of the killer cell immunoglobulin-like receptor ligand human leucocyte antigen-C on fibrosis progression in chronic C hepatitis with or without liver transplantation., in Liver international : official journal of the International Association for the Study of the Liver, 36(9), 1331-9.
A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance.
Wang H., El Maadidi S., Fischer J., Grabski E., Dickhöfer S., Klimosch S., Flannery SM., Filomena A., Wolz OO., Schneiderhan-Marra N., Löffler MW., Wiese M., Pichulik T., Müllhaupt B., Semela D., Dufour JF., Bochud PY., Bowie AG, Kalinke U, Berg T., Weber AN. (2015), A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance., in Hepatology, 1375.
Erratum: Reduced IFNI 4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes(Nature Communications (2014) 5 (5699) 10.1038/ncomms6699)
Terczyska-Dyla Ewa, Bibert Stephanie, Duong Francois H T, Krol Ilona, Jørgensen Sanne, Collinet Emilie, Kutalik Zoltán, Aubert Vincent, Cerny Andreas, Kaiser Laurent, Malinverni Raffaele, Mangia Alessandra, Moradpour Darius, Müllhaupt Beat, Negro Francesco, Santoro Rosanna, Semela David, Semmo Nasser, Heim Markus H., Bochud Pierre Yves, Hartmann Rune (2015), Erratum: Reduced IFNI 4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes(Nature Communications (2014) 5 (5699) 10.1038/ncomms6699), in Nature Communications, 6, 7280.
Impact of common risk factors of fibrosis progression in chronic hepatitis C
Rüeger S., Bochud P. Y., Dufour J. F., Müllhaupt B., Semela D., Heim M. H., Moradpour D., Cerny A., Malinverni R., Booth D. R., Suppiah V., George J., Argiro L., Halfon P., Bourlière M., Talal A. H., Jacobson I. M., Patin E., Nalpas B., Poynard T., Pol S., Abel L., Kutalik Z., Negro F. (2015), Impact of common risk factors of fibrosis progression in chronic hepatitis C, in Gut, 64(10), 1605-1615.
Birth year distribution in reported hepatitis C cases in Switzerland
Bruggmann Philip, Richard Jean Luc, Semela David, Negro Francesco, Müllhaupt Beat, Moradpour Darius, Malinverni Raffaele, Cerni Andreas, Gorgievski Meri, Heim Markus, Bochud Pierre Yves, Rickenbach Martin, Semo Nasser, Fabbro Thomas (2014), Birth year distribution in reported hepatitis C cases in Switzerland, in European Journal of Public Health, 25(1), 141-143.
Clinical significance of the CCR5delta32 allele in hepatitis C
Morard Isabelle, Clément Sophie, Calmy Alexandra, Mangia Alessandra, Cerny Andrea, De Gottardi Andrea, Gorgievski Meri, Heim Markus, Malinverni Raffaele, Moradpour Darius, MúLllhaupt Beat, Semela David, Pascarella Stéphanie, Bochud Pierre Yves, Negro Franco (2014), Clinical significance of the CCR5delta32 allele in hepatitis C, in PLoS ONE, 9(9), e106424.
Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation
Manuel Oriol, Wójtowicz Agnieszka, Bibert Stéphanie, Mueller Nicolas J., Van Delden Christian, Hirsch Hans H., Steiger Juerg, Stern Martin, Egli Adrian, Garzoni Christian, Binet Isabelle, Weisser Maja, Berger Christoph, Cusini Alexia, Meylan Pascal, Pascual Manuel, Bochud Pierre Yves (2014), Influence of IFNL3/4 polymorphisms on the incidence of cytomegalovirus infection after solid-organ transplantation, in Journal of Infectious Diseases, 211(6), 906-914.
Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes.
Terczyńska-Dyla E., Bibert S., Duong FH., Krol I., Jørgensen S., Collinet E., Kutalik Z., Aubert V., Cerny A., Kaiser L., Malinverni R., Mangia A., Moradpour D., Müllhaupt B., Negro F., Santoro R., Semela D., Semmo N., Heim MH., Bochud PY., Hartmann R. (2014), Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes., in Nat Commun, 5699.
The IFNL3/4 Δg variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients
Bibert Stéphanie, Wojtowicz Agnieszka, Taffé Patrick, Manuel Oriol, Bernasconi Enos, Furrer Hansjakob, Günthard Huldrych F., Hoffmann Matthias, Kaiser Laurent, Osthoff Michael, Cavassini Matthias, Bochud Pierre Yves (2014), The IFNL3/4 Δg variant increases susceptibility to cytomegalovirus retinitis among HIV-infected patients, in AIDS, 28(13), 1885-1889.
Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma
Lange Christian M., Bibert Stephanie, Dufour Jean-Francois, Cellerai Cristina, Cerny Andreas, Heim Markus H., Kaiser Laurent, Malinverni Raffaele, Muellhaupt Beat, Negro Francesco, Semela David, Moradpour Darius, Kutalik Zoltan, Bochud Pierre-Yves (2013), Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma, in JOURNAL OF HEPATOLOGY, 59(3), 504-509.
Genetic Analyses Reveal a Role for Vitamin D Insufficiency in HCV-Associated Hepatocellular Carcinoma Development
Lange Christian M., Miki Daiki, Ochi Hidenori, Nischalke Hans-Dieter, Bojunga Joerg, Bibert Stephanie, Morikawa Kenichi, Gouttenoire Jerome, Cerny Andreas, Dufour Jean-Francois, Gorgievski-Hrisoho Meri, Heim Markus H., Malinverni Raffaele, Muellhaupt Beat, Negro Francesco, Semela David, Kutalik Zoltan, Mueller Tobias, Spengler Ulrich, Berg Thomas, Chayama Kazuaki, Moradpour Darius, Bochud Pierre-Yves (2013), Genetic Analyses Reveal a Role for Vitamin D Insufficiency in HCV-Associated Hepatocellular Carcinoma Development, in PLOS ONE, 8(5), e64053.
IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction
Bibert Stéphanie, Roger Thierry, Calandra Thierry, Bochud Murielle, Cerny Andreas, Semmo Nasser, Duong François H T, Gerlach Tilman, Malinverni Raffaele, Moradpour Darius, Negro Francesco, Müllhaupt Beat, Bochud Pierre Yves (2013), IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction, in Journal of Experimental Medicine, 210(6), 1109-1116.
IL28B polymorphisms predict response to therapy among chronic hepatitis C patients with HCV genotype 4
Antaki N., Bibert S., Kebbewar K., Asaad F., Baroudi O., Alideeb S., Hadad M., Abboud D., Sabah H., Bochud P. -Y., Negro F. (2013), IL28B polymorphisms predict response to therapy among chronic hepatitis C patients with HCV genotype 4, in JOURNAL OF VIRAL HEPATITIS, 20(1), 59-64.
Impact of Soluble CD26 on Treatment Outcome and Hepatitis C Virus-Specific T Cells in Chronic Hepatitis C Virus Genotype 1 Infection
Soderholm Jonas, Waldenstrom Jesper, Askarieh Galia, Pilli Massimo, Bochud Pierre-Yves, Negro Francesco, Pawlotsky Jean-Michel, Zeuzem Stefan, Ferrari Carlo, Norkrans Gunnar, Wejstal Rune, Westin Johan, Neumann Avidan U., Haagmans Bart L., Lindh Magnus, Missale Gabriele, Hellstrand Kristoffer, Lagging Martin (2013), Impact of Soluble CD26 on Treatment Outcome and Hepatitis C Virus-Specific T Cells in Chronic Hepatitis C Virus Genotype 1 Infection, in PLOS ONE, 8(2), e56991.
The novel ss469415590 variant predicts virological response to therapy in patients with chronic hepatitis C virus type 1 infection
Covolo L., Bibert S., Donato F., Bochud P. Y., Lagging M., Negro F., Fattovich G. (2013), The novel ss469415590 variant predicts virological response to therapy in patients with chronic hepatitis C virus type 1 infection, in Alimentary Pharmacology and Therapeutics, 39(3), 322-330.
Genome-Wide Association Study Identifies Variants Associated With Progression of Liver Fibrosis From HCV Infection
Patin Etienne, Kutalik Zoltan, Guergnon Julien, Bibert Stephanie, Nalpas Bertrand, Jouanguy Emmanuelle, Munteanu Mona, Bousquet Laurence, Argiro Laurent, Halfon Philippe, Boland Anne, Muellhaupt Beat, Semela David, Dufour Jean-Francois, Heim Markus H., Moradpour Darius, Cerny Andreas, Malinverni Raffaele, Hirsch Hans, Booth David R., George Jacob, Casanova Jean-Laurent, Bochud PY., Abel L. (2012), Genome-Wide Association Study Identifies Variants Associated With Progression of Liver Fibrosis From HCV Infection, in GASTROENTEROLOGY, 143(5), 1244-1244.
Intrahepatic mRNA levels of SOCS1 and SOCS3 are associated with cirrhosis but do not predict virological response to therapy in chronic hepatitis C
Pascarella Stéphanie, Clément Sophie, Dill Michael T., Conzelmann Stéphanie, Lagging Martin, Missale Gabriele, Neumann Avidan U., Pawlotsky Jean Michel, Zeuzem Stefan, Rubbia-Brandt Laura, Bochud Pierre Yves, Negro Francesco (2012), Intrahepatic mRNA levels of SOCS1 and SOCS3 are associated with cirrhosis but do not predict virological response to therapy in chronic hepatitis C, in Liver International, 33(1), 94-103.

Collaboration

Group / person Country
Types of collaboration
Swiss HIV Cohort Study (SHCS) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Christian Lange/Christoph Sarrazin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Laurent Abel/Jean-Laurent Casanova France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Swiss HCV Cohort Study (SCCS) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Swiss Transplant Cohort Study (STCS) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Zoltan Kutalik Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
27th Challenge in Virology 2017 Talk given at a conference Immunogenetics of infectious diseases 26.01.2017 Grindelwald, Switzerland Bochud Pierre-Yves; Bibert Stéphanie;
ESCMID individualized medicine in infectious diseases 2016 Talk given at a conference Immunogenetics, from genomewide association studies to gene function 15.06.2016 Tübingen, Germany Bochud Pierre-Yves;
Swiss society for Immunology Annual Meeting 2016 Talk given at a conference Genetic testing: could it make a rapid diagnosis ? 02.06.2016 Montreux, Switzerland Bochud Pierre-Yves;
13th National Congress of the Italian Society of Infectious Diseases 2014 Talk given at a conference Immunogenetics of Infectious Diseases 26.10.2014 Genova, Italy Bochud Pierre-Yves;
Mérieux Research Grant Meeting Talk given at a conference Host genetics in the Swiss Transplantation Cohort Study 2014 23.10.2014 Annecy, France Bochud Pierre-Yves;
Swiss Society for Infectious Diseases 2014 Talk given at a conference The IFNL3/4 DG variant increases susceptibility to CMV retinitis among HIV-infected patients. 28.08.2014 Aarau, Switzerland Bochud Pierre-Yves; Bibert Stéphanie;
Antimicrobial Therapy in Immunocompromised and Critically Ill Patients: Management and Perspectives 2014 Talk given at a conference Immunogenetic of Viral Infections 29.05.2014 Lugano, Switzerland Bochud Pierre-Yves;
14th International Symposium Current Topics in Infectious Diseases 2014 Talk given at a conference Human Genetics of Viral and Bacterial Infections 26.01.2014 Grindelwald, Switzerland Bochud Pierre-Yves;
3ème Journée Janssen en Hépatologie 2013 Talk given at a conference Human Genetics of Hepatitis C Infection 21.11.2013 Institut Pasteur, Paris, France Bochud Pierre-Yves;
Swiss Society for Infectious Diseases 2013 Talk given at a conference IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction 30.05.2013 Lugano, Switzerland Bibert Stéphanie; Bochud Pierre-Yves;
48th meeting of the European Association for the Study of the Liver 2013 Poster IL28B RNA expression depends on a novel TT/-G polymorphism associated with improved HCV clearance prediction. 24.04.2013 Amsterdam, Netherlands Bibert Stéphanie;


Awards

Title Year
1st prize Swiss Transplant Society to Dr Oriol Manuel and Dr Pierre-Yves Bochud 2014

Associated projects

Number Title Start Funding scheme
127613 Innate Immunogenetic Study of Invasive Aspergillosis in Hematopoietic Cells Transplant Recipients 01.11.2009 Project funding
165954 Immunogenetics of Viral Infections - Focus on human herpesviruses (HHVs) 01.06.2016 Project funding (special)

Abstract

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV). Many infected individuals are not aware of the diagnosis and will become symptomatic with the advent of complications such as cirrhosis and hepatocarcinoma. Despite the availability of new drugs, treatment remains challenging due to its complexity, duration, cost, toxicities and potential emergence of drug resistance.Recent genome-wide association studies (GWAs) identified polymorphisms in IL28B, a gene encoding type III interferon (IFN), as important predictors of spontaneous and treatment induced clearance of HCV, but the functional mechanisms underlying this association are still elusive and their discovery remains an exciting challenge. Furthermore, the role of such polymorphisms for infections due to viruses other than HCV has been poorly explored. Altogether, functional immunogenetics may improve our knowledge of the pathogenesis of viral infections.The project will investigate the contribution of genetics and epigenetics on HCV clearance and on other infections, including those due to the hepatitis B virus (HBV) and herpesviruses. Specifically, the project will be divided in 3 specific aims.Aim 1We will identify and characterise IL28B polymorphism(s) associated with HCV clearance as follows1.1 To identify new IL28B variants, including• Variable nucleotide tandem repeats (VNTRs)• Epigenetic variations• Large DNA deletions/insertions1.2 To determine whether these IL28B markers are better predictors of spontaneous or treatment induced HCV clearance than previously identified IL28B markers in patients from the Swiss HCV Cohort study.1.3 To determine the mechanisms by which these IL28B markers influence IL28B function, by analysing• Their quantitative impact on IL28B and IFN-stimulated genes (ISGs) expression.• Their interaction with potential transcriptional/regulatory factors.Aim 2Polymorphisms nearby IL28B can only explain a fraction of individual variability in HCV clearance. To complete our understanding of the immunopathogenesis of hepatitis C, we will look for polymorphisms in genes other than IL28B that further influence this phenotype as follows:2.1 To identify rare variants by full exome sequencing of extreme HCV phenotypes, selected based on unusual response patterns. Those new variants will be functionally characterised in in vitro models.2.2 To find frequent variants by using a previous GWA dataset. Candidate genes will be selected from genes identified in full exome data as well as a systematic review of the literature (previous associations and genes known to be involved in HCV immunity).Aim 3Since polymorphisms in IL28B have a strong influence on HCV clearance, we will determine whether they also influence the natural history or clinical course of infections due to other viruses including HBV, herpes simplex virus (HSV), varicella-zoster virus (VZV) and cytomegalovirus (CMV) in patients from the Swiss HIV and Transplant Cohort Studies. Polymorphisms in genes discovered in aim 2 will also be analysed.Preliminary resultsOur preliminary observations from HCV infected patients identified a TT/-G substitution in the CpG region of IL28B as a better predictor of spontaneous HCV clearance and response to treatment than rs8099917 and rs12979860. The polymorphism induced the methylation of the adjacent cytosine residue and is a promising target for functional investigations. RelevanceImmunogenetic studies can contribute to a better understanding of antiviral immune mechanisms and improve the prevention and treatment of severe viral infections.
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