Nature Biotechnology
21, 639 - 644 (2003)
Published online: 12 May 2003; | doi:10.1038/nbt824
Inhibition of hepatitis B virus in mice by RNA interferenceAnton P McCaffrey1, Hiroyuki Nakai1, 4, Kusum Pandey1, 4, Zan Huang1, 4, Felix H Salazar2, Hui Xu1, Stefan F Wieland3, Patricia L Marion2
& Mark A Kay11
Departments of Pediatrics and Genetics, Stanford
University School of Medicine, 300 Pasteur Drive, Room G305,
Stanford, California, USA. 2
Hepadnavirus Testing, Inc., 831H Sierra Vista
Ave., Mountain View, California, USA. 3
Department of Molecular and Experimental Medicine,
The Scripps Research Institute, La Jolla, California,
USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to Mark A Kay markay@stanford.eduHepatitis 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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