The hepatitis c virus ns4b protein can trans-complement viral rna replication and modulates production of infectious virus

Jones, D. M., Patel, A. H., Targett-Adams, P. and McLauchlan, J. (2009) The hepatitis c virus ns4b protein can trans-complement viral rna replication and modulates production of infectious virus. Journal of Virology, 83(5), pp. 2163-2177. (doi:10.1128/JVI.01885-08) (PMID:19073716) (PMCID:PMC2643717)

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Abstract

Studies on the hepatitis C virus (HCV) life cycle have been aided by development of in vitro systems that enable replication of viral RNA and production of infectious virus. However, the functions of the individual proteins, especially those engaged in RNA replication, remain poorly understood. It is considered that NS4B, one of the replicase components, creates sites for genome synthesis, which appear as punctuate foci at the ER membrane. In this study, a panel of mutations in NS4B was generated to gain deeper insight into its functions. Our analysis identified 5 mutants that were incapable of supporting RNA replication, 3 of which had defects in production of foci at the ER membrane. These mutants also influenced post-translational modification and intracellular mobility of another replicase protein, NS5A, suggesting that such characteristics are linked to foci formation by NS4B. From previous studies, NS4B could not be trans-complemented in replication assays. Using the mutants that blocked RNA synthesis, defective NS4B expressed from 2 mutants could be rescued in trans-complementation replication assays by wild-type protein produced by a functional HCV replicon. Moreover, active replication could be reconstituted by combining replicons that were defective in NS4B and NS5A. The ability to restore replication from inactive replicons has implications for our understanding of the mechanisms that direct viral RNA synthesis. Finally, 1 of the NS4B mutations increased yield of infectious virus by 5-6 fold. Hence, NS4B functions not only in RNA replication but also contributes to the processes engaged in virus assembly and release

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jones, Dr Daniel and Patel, Professor Arvind and McLauchlan, Professor John
Authors: Jones, D. M., Patel, A. H., Targett-Adams, P., and McLauchlan, J.
Subjects:Q Science > QR Microbiology > QR355 Virology
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Virology
Journal Abbr.:J. Virol.
Publisher:American Society for Microbiology
ISSN:0022-538X
ISSN (Online):1098-5514
Published Online:10 December 2008

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656341Virus-host interactions in hepatitis C virus infectionJohn MclauchlanMedical Research Council (MRC)MC_UU_12014/1MVLS III - CENTRE FOR VIRUS RESEARCH