Sequential biogenesis of host cell membrane rearrangements induced by hepatitis C virus infection
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Cellular and Molecular Life Sciences
RESEARCH ARTICLE
Sequential biogenesis of host cell membrane rearrangements induced by hepatitis C virus infection Pauline Ferraris • Elodie Beaumont • Rustem Uzbekov • Denys Brand • Julien Gaillard Emmanuelle Blanchard • Philippe Roingeard
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Received: 30 June 2012 / Revised: 13 October 2012 / Accepted: 7 November 2012 Ó Springer Basel 2012
Abstract Like most positive-strand RNA viruses, hepatitis C virus (HCV) forms a membrane-associated replication complex consisting of replicating RNA, viral and host proteins anchored to altered cell membranes. We used a combination of qualitative and quantitative electron microscopy (EM), immuno-EM, and the 3D reconstruction of serial EM sections to analyze the host cell membrane alterations induced by HCV. Three different types of membrane alteration were observed: vesicles in clusters (ViCs), contiguous vesicles (CVs), and double-membrane vesicles (DMVs). The main ultrastructural change observed early in infection was the formation of a network of CVs surrounding the lipid droplets. Later stages in the infectious cycle were characterized by a large increase in the number of DMVs, which may be derived from the CVs. These DMVs are thought to constitute the membranous structures harboring the viral replication complexes in which viral replication is firmly and permanently established and to protect the virus against double-stranded RNA-triggered host antiviral responses.
Keywords HCV Host cell membranes Membranous web Electron microscopy 3D reconstruction Abbreviations BSA Bovine serum albumin CM Convoluted membranes CV Contiguous vesicles DENV Dengue virus DMEM Dulbecco’s modified Eagle medium DMV Double-membrane vesicle EM Electron microscopy FFU Focus forming unit HCV Hepatitis C virus KUNV Kunjin virus LD Lipid droplet MAbs Mouse monoclonal antibody MMV Multimembrane vesicles MVB Multivesicular bodies ViC Vesicles in cluster VP Vesicle packets WNV West Nile virus
E. Blanchard and P. Roingeard are co-last authors.
Electronic supplementary material The online version of this article (doi:10.1007/s00018-012-1213-0) contains supplementary material, which is available to authorized users. P. Ferraris E. Beaumont D. Brand E. Blanchard P. Roingeard (&) INSERM U966, Faculte´ de Me´decine, Universite´ Franc¸ois Rabelais de Tours, CHRU de Tours, 10 boulevard Tonnelle´, 37032 Tours Cedex, France e-mail: [email protected] R. Uzbekov J. Gaillard E. Blanchard P. Roingeard Plate-Forme des Microscopies, PPF ASB, Universite´ Franc¸ois Rabelais & CHRU de Tours, Tours Cedex, France
Introduction Hepatitis C virus (HCV), a member of the Flaviviridae family, is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide [1]. It has a single positive-strand RNA genome encoding a large polyprotein precursor that is processed co- and post-translationally, by cellular and viral proteases, to yield 10 different proteins [2, 3]. The structural proteins core, E1, and E2 are the main constituents
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