Inhibition of hepatitis B virus in mice by RNA interference

Anton P. McCaffrey; Hiroyuki Nakai; Kusum Pandey; Zan Huang; Felix H. Salazar; Hui Xu; Stefan F. Wieland; Patricia L. Marion; Mark A. Kay

doi:10.1038/nbt824

Inhibition of hepatitis B virus in mice by RNA interference

Anton P. McCaffrey, Hiroyuki Nakai, Kusum Pandey, Zan Huang, Felix H. Salazar, Hui Xu, Stefan F. Wieland, Patricia L. Marion, Mark A. Kay

Research output: Contribution to journal › Article › peer-review

594 Scopus citations

Abstract

Hepatitis B virus (HBV) infection substantially increases the risk of chronic liver disease and hepatocellular carcinoma in humans. RNA interference (RNAi) of virus-specific genes has emerged as a potential antiviral mechanism. Here we show that RNAi can be applied to inhibit production of HBV replicative intermediates in cell culture and in immunocompetent and immunodeficient mice transfected with an HBV plasmid. Cotransfection with plasmids expressing short hairpin RNAs (shRNAs) homologous to HBV mRNAs induced an RNAi response. Northern and Southern analyses of mouse liver RNA and DNA showed substantially reduced levels of HBV RNAs and replicated HBV genomes upon RNAi treatment. Secreted HBV surface antigen (HBsAg) was reduced by 94.2% in cell culture and 84.5% in mouse serum, whereas immunohistochemical detection of HBV core antigen (HBcAg) revealed >99% reduction in stained hepatocytes upon RNAi treatment. Thus, RNAi effectively inhibited replication initiation in cultured cells and mammalian liver, showing that such an approach could be useful in the treatment of viral diseases.

Original language	English (US)
Pages (from-to)	639-644
Number of pages	6
Journal	Nature biotechnology
Volume	21
Issue number	6
DOIs	https://doi.org/10.1038/nbt824
State	Published - Jun 1 2003
Externally published	Yes

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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title = "Inhibition of hepatitis B virus in mice by RNA interference",

abstract = "Hepatitis B virus (HBV) infection substantially increases the risk of chronic liver disease and hepatocellular carcinoma in humans. RNA interference (RNAi) of virus-specific genes has emerged as a potential antiviral mechanism. Here we show that RNAi can be applied to inhibit production of HBV replicative intermediates in cell culture and in immunocompetent and immunodeficient mice transfected with an HBV plasmid. Cotransfection with plasmids expressing short hairpin RNAs (shRNAs) homologous to HBV mRNAs induced an RNAi response. Northern and Southern analyses of mouse liver RNA and DNA showed substantially reduced levels of HBV RNAs and replicated HBV genomes upon RNAi treatment. Secreted HBV surface antigen (HBsAg) was reduced by 94.2% in cell culture and 84.5% in mouse serum, whereas immunohistochemical detection of HBV core antigen (HBcAg) revealed >99% reduction in stained hepatocytes upon RNAi treatment. Thus, RNAi effectively inhibited replication initiation in cultured cells and mammalian liver, showing that such an approach could be useful in the treatment of viral diseases.",

author = "McCaffrey, {Anton P.} and Hiroyuki Nakai and Kusum Pandey and Zan Huang and Salazar, {Felix H.} and Hui Xu and Wieland, {Stefan F.} and Marion, {Patricia L.} and Kay, {Mark A.}",

note = "Funding Information: Thanks to Ramona Gonzales for critical review of the manuscript and to Mark Winters, Greg Hannon and Patrick Paddison for providing plasmids, and special thanks to Peter Bradley, Bruno B. Bordier, Francis Chisari and Stephen Yant for technical advice and helpful suggestions. This work was supported by the US National Institutes of Health grant no. AI40034 and the Anna Ng Charitable Foundation.",

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AU - McCaffrey, Anton P.

AU - Nakai, Hiroyuki

AU - Pandey, Kusum

AU - Huang, Zan

AU - Salazar, Felix H.

AU - Xu, Hui

AU - Wieland, Stefan F.

AU - Marion, Patricia L.

AU - Kay, Mark A.

N1 - Funding Information: Thanks to Ramona Gonzales for critical review of the manuscript and to Mark Winters, Greg Hannon and Patrick Paddison for providing plasmids, and special thanks to Peter Bradley, Bruno B. Bordier, Francis Chisari and Stephen Yant for technical advice and helpful suggestions. This work was supported by the US National Institutes of Health grant no. AI40034 and the Anna Ng Charitable Foundation.

PY - 2003/6/1

Y1 - 2003/6/1

N2 - Hepatitis B virus (HBV) infection substantially increases the risk of chronic liver disease and hepatocellular carcinoma in humans. RNA interference (RNAi) of virus-specific genes has emerged as a potential antiviral mechanism. Here we show that RNAi can be applied to inhibit production of HBV replicative intermediates in cell culture and in immunocompetent and immunodeficient mice transfected with an HBV plasmid. Cotransfection with plasmids expressing short hairpin RNAs (shRNAs) homologous to HBV mRNAs induced an RNAi response. Northern and Southern analyses of mouse liver RNA and DNA showed substantially reduced levels of HBV RNAs and replicated HBV genomes upon RNAi treatment. Secreted HBV surface antigen (HBsAg) was reduced by 94.2% in cell culture and 84.5% in mouse serum, whereas immunohistochemical detection of HBV core antigen (HBcAg) revealed >99% reduction in stained hepatocytes upon RNAi treatment. Thus, RNAi effectively inhibited replication initiation in cultured cells and mammalian liver, showing that such an approach could be useful in the treatment of viral diseases.

AB - Hepatitis B virus (HBV) infection substantially increases the risk of chronic liver disease and hepatocellular carcinoma in humans. RNA interference (RNAi) of virus-specific genes has emerged as a potential antiviral mechanism. Here we show that RNAi can be applied to inhibit production of HBV replicative intermediates in cell culture and in immunocompetent and immunodeficient mice transfected with an HBV plasmid. Cotransfection with plasmids expressing short hairpin RNAs (shRNAs) homologous to HBV mRNAs induced an RNAi response. Northern and Southern analyses of mouse liver RNA and DNA showed substantially reduced levels of HBV RNAs and replicated HBV genomes upon RNAi treatment. Secreted HBV surface antigen (HBsAg) was reduced by 94.2% in cell culture and 84.5% in mouse serum, whereas immunohistochemical detection of HBV core antigen (HBcAg) revealed >99% reduction in stained hepatocytes upon RNAi treatment. Thus, RNAi effectively inhibited replication initiation in cultured cells and mammalian liver, showing that such an approach could be useful in the treatment of viral diseases.

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Inhibition of hepatitis B virus in mice by RNA interference

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