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RNAi: a powerful tool to unravel hepatitis C virus-host interactions within the infectious life cycle.
Lupberger J., Brino L., Baumert T. F.
Journal of Hepatology 48, 3 (2008) 523-5 - http://www.hal.inserm.fr/inserm-00741249
(18192054)
RNAi: a powerful tool to unravel hepatitis C virus-host interactions within the infectious life cycle.
Joachim Lupberger1, Laurent Brino2, Thomas Baumert () 1, 3
1 :  Interaction virus-hôte et maladies du foie
INSERM : U748 – Université de Strasbourg
Faculte de Medecine 3 Rue Koeberle 67000 STRASBOURG
France
2 :  PCT - Plate-forme de R&D - Puces à Cellules Transfectées
Cancéropôle du Grand-Est (CGE) – Centre Européen de Biologie et de Génomique Structurale (CEBGS) – Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
1 rue Laurent Fries 67404 Illkirch cedex
France
3 :  Service d'Hépato-gastroentérologie
Nouvel Hôpital Civil – Hôpitaux Universitaires de Strasbourg
1 Place de l'Hôpital, F-67000 Strasbourg
France
Cellular cofactors affecting hepatitis C virus infection and replication. Randall G, Panis M, Cooper JD, Tellinghuisen TL, Sukhodolets KE, Pfeffer S, Landthaler M, Landgraf P, Kan S, Lindenbach BD, Chien M, Weir DB, Russo JJ, Ju J, Brownstein MJ, Sheridan R, Sander C, Zavolan M, Tuschl T, Rice CM. Recently identified hepatitis C virus (HCV) isolates that are infectious in cell culture provide a genetic system to evaluate the significance of virus-host interactions for HCV replication. We have completed a systematic RNAi screen wherein siRNAs were designed that target 62 host genes encoding proteins that physically interact with HCV RNA or proteins or belong to cellular pathways thought to modulate HCV infection. This includes 10 host proteins that we identify in this study to bind HCV NS5A. siRNAs that target 26 of these host genes alter infectious HCV production >3-fold. Included in this set of 26 were siRNAs that target DICER, a principal component of the RNAi silencing pathway. Contrary to the hypothesis that RNAi is an antiviral pathway in mammals, as has been reported for subgenomic HCV replicons, siRNAs that target DICER inhibited HCV replication. Furthermore, siRNAs that target several other components of the RNAi pathway also inhibit HCV replication. MicroRNA profiling of human liver, human hepatoma Huh7.5 cells, and Huh7.5 cells that harbor replicating HCV demonstrated that miR-122 is the predominant microRNA in each environment. miR-122 has been previously implicated in positively regulating the replication of HCV genotype 1 replicons. We find that 2'-O-methyl antisense oligonucleotide depletion of miR-122 also inhibits HCV genotype 2a replication and infectious virus production. Our data define 26 host genes that modulate HCV infection and indicate that the requirement for functional RNAi for HCV replication is dominant over any antiviral activity this pathway may exert against HCV. [Abstract reproduced by permission of Proc Natl Acad Sci USA 2007;104:12884-12889]
Sciences du Vivant/Médecine humaine et pathologie/Hépatologie et Gastroentérologie
Anglais
0168-8278

Articles dans des revues avec comité de lecture
10.1016/j.jhep.2007.12.007
Journal of Hepatology (J Hepatol)
Publisher Elsevier
ISSN 0168-8278 (eISSN : 0168-8278)
internationale
03/2008
31/12/2007
48
3
523-5

The authors acknowledge financial support from the European Union (LSHM-CT-2004- 503359), Inserm, the Agence Nationale de la Recherche (ANR-05-CEXC-008), the Agence Nationale de la Recherche sur le SIDA et les Hépatites Virales (ANRS-06221), France and the Deutsche Forschungsgemeinschaft (Ba1417/11-2), Germany (T. F. B). J. L. was supported by the exchange fellowship program of the Embassy of France, Berlin in the frame work of Inserm European Associated Laboratory University of Freiburg-Inserm UMR748 Strasbourg. L. B. thanks the Région Alsace, the Conseil Général du Bas Rhin, the Communité Urbaine de Strasbourg and the Cancéropôle du Grand Est, France for financial support.
Référence du projet ANR-05-CEXC-008
Année 2005
Acronyme du projet HCV-HOST-INTERACTION
Titre du projet Infection par le virus de l'hépatite C : Etude des interactions virus-cellule cible et des mécanismes impliqués dans la pathogénie de l'infection
Intitulé Programme "Chaires d'excellence": aide à l'accueil de chercheurs et d'enseignants chercheurs de haut niveau venant de l'étranger
Acronyme de l'appel CEXC
Acronyme LSHM-CT-2004- 503359
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