Hepatitis C virus ultrastructure and morphogenesis

Roingeard, Philippe; Hourioux, Christophe; Blanchard, Emmanuelle; Brand, Denys; Ait-Goughoulte, Malika

doi:10.1016/j.biolcel.2003.11.006

Cited by 37 publications

(36 citation statements)

References 58 publications

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“…None of these particles has been shown to be infectious, even when full-length genomes are used for protein expression (2,21,37). The current model for HCV morphogenesis proposes that core particles containing the genome acquire the viral envelope by budding through the endoplasmic reticulum (ER) membrane (44), where viral glycoproteins are inserted as a complex (14,15,45).…”

mentioning

confidence: 99%

Differential Biophysical Properties of Infectious Intracellular and Secreted Hepatitis C Virus Particles

Gastaminza

Kapadia

Chisari

2006

J Virol

215

232

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The recent development of a cell culture infection model for hepatitis C virus (HCV) permits the production of infectious particles in vitro. In this report, we demonstrate that infectious particles are present both within the infected cells and in the supernatant. Kinetic analysis indicates that intracellular particles constitute precursors of the secreted infectious virus. Ultracentrifugation analyses indicate that intracellular infectious viral particles are similar in size (ϳ65 to 70 nm) but different in buoyant density (ϳ1.15 to 1.20 g/ml) from extracellular particles (ϳ1.03 to 1.16 g/ml). These results indicate that infectious HCV particles are assembled intracellularly and that their biochemical composition is altered during viral egress.Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Approximately 3% of the human population is infected, and more than 80% of all HCV infections progress to chronicity, ultimately leading to fibrosis, cirrhosis, and hepatocellular carcinoma (24). There is no vaccine against HCV, and the most widely used therapy involves the administration of type I interferon (␣2A) combined with ribavirin. However, this treatment strategy is toxic and has been shown to be ineffective in a significant proportion of the cases (41).HCV is a member of the Flaviviridae family and the sole member of the genus Hepacivirus (34). HCV is an enveloped virus with a single-strand positive RNA genome that codes for a unique polyprotein of approximatively 3,000 amino acids (11,12). A single open reading frame is flanked by 5Ј and 3Ј untranslated regions that contain RNA sequences essential for RNA translation and replication, respectively (17,18,23). The translation of the single open reading frame is driven by an internal ribosomal entry site sequence present within the 5Ј untranslated region (23), and the resulting polyprotein is processed by cellular and viral proteases into its individual components (reviewed in reference 42). The E1, E2, and core structural proteins are assembled into particles (3, 4), but are not essential for viral RNA replication or translation. The NS2, NS3, NS4A, NS4B, NS5A, and NS5B nonstructural proteins constitute the viral components necessary for efficient viral RNA replication, although NS2 is dispensable for this function (5, 33). In the linear sequence of the polyprotein, the structural proteins are separated from the nonstructural proteins by a small hydrophobic protein, p7 (29), whose function remains unknown but that has the potential to form ion channels (19). Viral proteins are localized in the cytoplasm, and it is assumed, by analogy with other members of the Flaviviridae family, that the entire life cycle of the virus is exclusively cytoplasmic (32).

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mentioning

confidence: 99%

Differential Biophysical Properties of Infectious Intracellular and Secreted Hepatitis C Virus Particles

Gastaminza

Kapadia

Chisari

2006

J Virol

215

232

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“…The structural proteins, the core (C) and envelope glycoproteins E1 and E2, are present in the N-terminal part of the polyprotein and presumably self-assemble to form the virion. The nonstructural (NS) proteins have various functions and form the replication complex (5).…”

mentioning

confidence: 99%

Coordinated evolution of the hepatitis C virus

Campo

Dimitrova

Mitchell

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Hepatitis C virus is a genetically heterogeneous RNA virus that is a major cause of liver disease worldwide. Here, we show that, despite its extensive heterogeneity, the evolution of hepatitis C virus is primarily shaped by negative selection and that numerous coordinated substitutions in the polyprotein can be organized into a scale-free network whose degree of connections between sites follows a power-law distribution. This network shares all major properties with many complex biological and technological networks. The topological structure and hierarchical organization of this network suggest that a small number of amino acid sites exert extensive impact on hepatitis C virus evolution. Nonstructural proteins are enriched for negatively selected sites of high centrality, whereas structural proteins are enriched for positively selected sites located in the periphery of the network. The complex network of coordinated substitutions is an emergent property of genetic systems with implications for evolution, vaccine research, and drug development. In addition to such properties as polymorphism or strength of selection, the epistatic connectivity mapped in the network is important for typing individual sites, proteins, or entire genetic systems. The network topology may help devise molecular intervention strategies for disrupting viral functions or impeding compensatory changes for vaccine escape or drug resistance mutations. Also, it may be used to find new therapeutic targets, as suggested in this study for the NS4A protein, which plays an important role in the network.complex systems ͉ scale-free network ͉ covariation ͉ natural selection ͉ epistasis H epatitis C virus (HCV) is a major cause of liver disease worldwide. The global prevalence of HCV infection is estimated to be 2.2%, representing 130 million people (1). HCV causes chronic infection in 70-85% of infected adults (2). There is no vaccine against HCV and current antiviral therapy is relatively toxic, being effective in 50-60% of patients treated (3). HCV is a single-stranded RNA virus of Ϸ9.4 kb belonging to the Flaviviridae family (4). The positive-sense genome of HCV contains one large ORF that encodes a polyprotein that can undergo proteolytic cleavage into 10 mature proteins (C-E1-E2-P7-NS2-NS3-NS4A-NS4B-NS5A-NS5B). The structural proteins, the core (C) and envelope glycoproteins E1 and E2, are present in the N-terminal part of the polyprotein and presumably self-assemble to form the virion. The nonstructural (NS) proteins have various functions and form the replication complex (5).The HCV genome continually mutates during virus replication. Although a high rate of mutation significantly contributes to the enormous adaptability of RNA viruses, it also limits the size of viral genomes by causing error catastrophe (6). The small size of viral genomes imposes strong evolutionary constraints on their organization, as a result of which each genomic region may encode multiple and often conflicting functions. Such genomic organization requires a tight coor...

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“…Malheureusement, ces réplicons ne permettaient pas de produire du virus complet et d'étudier la morphogenèse virale. Cette étape du cycle infectieux n'a pu être abordée que grâce à des modèles de surexpression des protéines structurales du VHC, montrant notamment le rôle majeur de la protéine de core dans la morphogenèse de pseudovirions [3,4]. Finalement, l'année 2005 aura été un tournant dans la recherche sur le VHC, avec la mise au point d'un système cellulaire permettant de reproduire un cycle infectieux complet du VHC in vitro [5].…”

Section: > Le Virus De L'hépatite C (Vhc)unclassified

“…Elle est caractérisée par l'activation d'un système moléculaire complexe, la NADPH oxydase, qui induit une réduction de l'oxygène moléculaire en anion superoxyde (O 2 -. ) à l'origine d'autres formes réactives de l'oxygène telles que le peroxyde d'hydrogène (H 2 O 2 ), le radical hydroxyle (OH°) et l'acide hypochloreux (HOCl) [3,4].…”

unclassified