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Journal of Virology, May 2004, p. 4617-4627, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4617-4627.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Quasispecies Variability Modulates Nonstructural Protein 5A Transcriptional Activation, Pointing to Cellular Compartmentalization of Virus-Host Interactions

Muriel Pellerin,1 Yolanda Lopez-Aguirre,1 François Penin,2 Daniel Dhumeaux,1,3 and Jean-Michel Pawlotsky1*

Department of Virology INSERM U635,1 Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris XII, 94010 Créteil,3 Institut de Biologie et Chimie des Protéines, CNRS-UMR 5086, 69367 Lyon, France2

Received 4 November 2003/ Accepted 7 January 2004

Hepatitis C virus (HCV) behaves in infected patients as a complex mixture of genetically distinct but closely related variants referred to as a "quasispecies." By using quasispecies analysis strategies, we showed that HCV nonstructural protein 5A (NS5A) has a quasispecies distribution in infected humans and that NS5A quasispecies undergo significant genetic evolution over time, as a result of random accumulation of nucleotide mutations during replication. Genetic evolution of the NS5A quasispecies results in sporadic amino acid changes in the protein sequence. By using the functional in vitro model of HCV NS5A transcriptional activation in Saccharomyces cerevisiae, we showed that natural NS5A quasispecies variants induce different levels of transcriptional activation, according to the charge of the residues (and possibly minor conformational changes) in the quasispecies variant sequence. These findings show that the accumulation of mutations on HCV genomes during replication randomly generates variant proteins with quantitatively different functional properties. The fact that each new variant protein is initially produced in a single infected hepatocyte and may or may not subsequently spread throughout the liver (depending on the replication capacities of the variant virus) points to cellular compartmentalization of virus-host interactions during chronic infection. This feature of quasispecies-distributed viruses could play an important role in various aspects of the viral life cycle and related disease.

* Corresponding author. Mailing address: Service de Virologie, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. Phone: 33-1-4981-2827. Fax: 33-1-4981-4831. E-mail: jean-michel.pawlotsky{at}hmn.ap-hop-paris.fr.

Journal of Virology, May 2004, p. 4617-4627, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4617-4627.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kalliampakou, K. I., Kalamvoki, M., Mavromara, P. (2005). Hepatitis C virus (HCV) NS5A protein downregulates HCV IRES-dependent translation. J. Gen. Virol. 86: 1015-1025 [Abstract] [Full Text]  


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