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Journal of Virology, June 2006, p. 5599-5610, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.01773-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Silencing of Hepatitis A Virus Infection by Small Interfering RNAs

Yuri Kusov,1* Tatsuo Kanda,2 Ann Palmenberg,3 Jean-Yves Sgro,3 and Verena Gauss-Müller1

Department of Medical Molecular Biology, University of Lübeck, Lübeck, Germany,1 Health Science Center and Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan,2 Institute for Molecular Virology, University of Wisconsin, Madison, Wisconsin3

Received 23 August 2005/ Accepted 14 March 2006

Infection by hepatitis A virus (HAV) can cause acute hepatitis and, rarely, fulminant liver failure, in particular in patients chronically infected with hepatitis C virus. Based on our previous observation that small interfering RNAs (siRNAs) can silence translation and replication of the firefly luciferase-encoding HAV replicon, we now exploited this technology to demonstrate the effect of siRNAs on viral infection in Huh-7 cells. Freshly and persistently infected cells were transfected with siRNAs targeting various sites in the HAV nonstructural genes. Compared to a single application, consecutive siRNA transfections targeting multiple sequences in the viral genome resulted in a more efficient and sustained silencing effect than a single transfection. In most instances, multiple applications of a single siRNA led to the emergence of viral escape mutants with mutated target sites that rendered these genomes resistant to RNA interference (RNAi). Efficient and sustained suppression of the viral infectivity was achieved after consecutive applications of an siRNA targeting a computer-predicted hairpin structure. This siRNA holds promise as a therapeutic tool for severe courses of HAV infection. In addition, the results provide new insight into the structural bases for sequence-specific RNAi.

* Corresponding author. Mailing address: Institute of Medical Molecular Biology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany. Phone: 49-451-5004085. Fax: 49-451-5003637. E-mail: koussov{at}molbio.uni-luebeck.de.

Journal of Virology, June 2006, p. 5599-5610, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.01773-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • von Eije, K. J., Brake, O. t., Berkhout, B. (2008). Human Immunodeficiency Virus Type 1 Escape Is Restricted When Conserved Genome Sequences Are Targeted by RNA Interference. J. Virol. 82: 2895-2903 [Abstract] [Full Text]  


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