Reduced IFNλ4 Activity is Associated with Improved HCV Clearance and Reduced Expression of Interferon-stimulated Genes

Overview

Journal Nat Commun

Specialty Biology

Date 2014 Dec 24

PMID 25534433

Citations 71

Authors

Ewa Terczynska-Dyla

Stephanie Bibert

Francois H T Duong

Ilona Krol

Sanne Jorgensen

Emilie Collinet

Zoltan Kutalik

Vincent Aubert

Andreas Cerny

Laurent Kaiser

Raffaele Malinverni

Alessandra Mangia

Darius Moradpour

Beat Mullhaupt

Francesco Negro

Rosanna Santoro

David Semela

Nasser Semmo

Markus H Heim

Pierre-Yves Bochud

Rune Hartmann

Affiliations

Soon will be listed here.

Abstract

Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNλ4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNλ4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNλ4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNλ4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

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References

Dellgren C, Gad H, Hamming O, Melchjorsen J, Hartmann R . Human interferon-lambda3 is a potent member of the type III interferon family. Genes Immun. 2008; 10(2):125-31. DOI: 10.1038/gene.2008.87. View

Muir A . IL28B in the era of direct-acting antivirals for hepatitis C. J Clin Gastroenterol. 2013; 47(3):222-7. DOI: 10.1097/MCG.0b013e3182680221. View

Francois-Newton V, Magno de Freitas Almeida G, Payelle-Brogard B, Monneron D, Pichard-Garcia L, Piehler J . USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response. PLoS One. 2011; 6(7):e22200. PMC: 3136508. DOI: 10.1371/journal.pone.0022200. View

Thomas D, Thio C, Martin M, Qi Y, Ge D, OhUigin C . Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009; 461(7265):798-801. PMC: 3172006. DOI: 10.1038/nature08463. View

Heim M . 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nat Rev Immunol. 2013; 13(7):535-42. DOI: 10.1038/nri3463. View

Honda M, Sakai A, Yamashita T, Nakamoto Y, Mizukoshi E, Sakai Y . Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology. 2010; 139(2):499-509. DOI: 10.1053/j.gastro.2010.04.049. View

Sarasin-Filipowicz M, Wang X, Yan M, Duong F, Poli V, Hilton D . Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43. Mol Cell Biol. 2009; 29(17):4841-51. PMC: 2725724. DOI: 10.1128/MCB.00224-09. View

Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate M . IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009; 41(10):1100-4. DOI: 10.1038/ng.447. View

Santantonio T, Wiegand J, Gerlach J . Acute hepatitis C: current status and remaining challenges. J Hepatol. 2008; 49(4):625-33. DOI: 10.1016/j.jhep.2008.07.005. View

10.

Asselah T, Bieche I, Narguet S, Sabbagh A, Laurendeau I, Ripault M . Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut. 2007; 57(4):516-24. DOI: 10.1136/gut.2007.128611. View

11.

Prasad L, Masserey Spicher V, Zwahlen M, Rickenbach M, Helbling B, Negro F . Cohort Profile: the Swiss Hepatitis C Cohort Study (SCCS). Int J Epidemiol. 2007; 36(4):731-7. DOI: 10.1093/ije/dym096. View

12.

Dill M, Duong F, Vogt J, Bibert S, Bochud P, Terracciano L . Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C. Gastroenterology. 2010; 140(3):1021-31. DOI: 10.1053/j.gastro.2010.11.039. View

13.

Zeuzem S, Soriano V, Asselah T, Bronowicki J, Lohse A, Mullhaupt B . Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013; 369(7):630-9. DOI: 10.1056/NEJMoa1213557. View

14.

Meissner E, Bon D, Prokunina-Olsson L, Tang W, Masur H, OBrien T . IFNL4-ΔG genotype is associated with slower viral clearance in hepatitis C, genotype-1 patients treated with sofosbuvir and ribavirin. J Infect Dis. 2013; 209(11):1700-4. PMC: 4017364. DOI: 10.1093/infdis/jit827. View

15.

Urban T, Thompson A, Bradrick S, Fellay J, Schuppan D, Cronin K . IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology. 2010; 52(6):1888-96. PMC: 3653303. DOI: 10.1002/hep.23912. View

16.

Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N . Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009; 41(10):1105-9. DOI: 10.1038/ng.449. View

17.

Shepard C, Finelli L, Alter M . Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005; 5(9):558-67. DOI: 10.1016/S1473-3099(05)70216-4. View

18.

Aka P, Kuniholm M, Pfeiffer R, Wang A, Tang W, Chen S . Association of the IFNL4-ΔG Allele With Impaired Spontaneous Clearance of Hepatitis C Virus. J Infect Dis. 2013; 209(3):350-4. PMC: 3883162. DOI: 10.1093/infdis/jit433. View

19.

Gad H, Dellgren C, Hamming O, Vends S, Paludan S, Hartmann R . Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family. J Biol Chem. 2009; 284(31):20869-75. PMC: 2742852. DOI: 10.1074/jbc.M109.002923. View

20.

Bibert S, Roger T, Calandra T, Bochud M, Cerny A, Semmo N . IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction. J Exp Med. 2013; 210(6):1109-16. PMC: 3674704. DOI: 10.1084/jem.20130012. View