Core protein domains involved in hepatitis C virus-like particle assembly and budding at the endoplasmic reticulum membrane.

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HAL Id: inserm-00137282

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Submitted on 6 Dec 2007

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Core protein domains involved in hepatitis C virus-like particle assembly and budding at the endoplasmic

reticulum membrane.

Christophe Hourioux, Malika Ait-Goughoulte, Romuald Patient, Delphine Fouquenet, Fabienne Arcanger-Doudet, Denys Brand, Annette Martin,

Philippe Roingeard

To cite this version:

Christophe Hourioux, Malika Ait-Goughoulte, Romuald Patient, Delphine Fouquenet, Fabienne Arcanger-Doudet, et al.. Core protein domains involved in hepatitis C virus-like particle assembly and budding at the endoplasmic reticulum membrane.: HCV core protein domain involved in viral morpho- genesis. Cellular Microbiology, Wiley, 2007, 9 (4), pp.1014-27. �10.1111/j.1462-5822.2006.00848.x�.

�inserm-00137282�

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HAL author manuscript inserm-00137282, version 1

HAL author manuscript

Cell microbiol 06/12/2006; epub ahead of print

HAL author manuscript inserm-00137282, version 1

HAL author manuscript

Cell Microbiol 2007;9(4):1014-1027

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HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1

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HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1

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HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1

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HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1

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HAL author manuscript inserm-00137282, version 1HAL author manuscript inserm-00137282, version 1

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References