Silencing Viral Infection

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Abstract

The authors describe recent progress and obstacles to harnessing RNA interference to prevent or treat viral infection.

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Most cited references 13

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Inhibition of respiratory viruses by nasally administered siRNA.

Vira Bitko, Alla Musiyenko, Olena Shulyayeva … (2005)

Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are two respiratory pathogens of paramount medical significance that exert high mortality. At present, there is no reliable vaccine or antiviral drug against either virus. Using an RNA interference (RNAi) approach, we show that individual as well as joint infection by RSV and PIV can be specifically prevented and inhibited by short interfering RNAs (siRNAs), instilled intranasally in the mouse, with or without transfection reagents. The degree of protection matched the antiviral activity of the siRNA in cell culture, allowing an avenue for quick screening of an efficacious siRNA. When targeting both viruses in a joint infection, excess of one siRNA moderated the inhibitory effect of the other, suggesting competition for the RNAi machinery. Our results suggest that, if properly designed, low dosages of inhaled siRNA might offer a fast, potent and easily administrable antiviral regimen against respiratory viral diseases in humans.

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RNA interference targeting Fas protects mice from fulminant hepatitis.

Erwei Song, Sang-Kyung Lee, Jie Wang … (2003)

RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving. We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.

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SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells.

Christopher S Sullivan, Adam Grundhoff, Satvir Tevethia … (2005)

MicroRNAs (miRNAs) are small (approximately 22-nucleotide) RNAs that in lower organisms serve important regulatory roles in development and gene expression, typically by forming imperfect duplexes with target messenger RNAs. miRNAs have also been described in mammalian cells and in infections with Epstein-Barr virus (EBV), but the function of most of them is unknown. Although one EBV miRNA probably altered the processing of a viral mRNA, the regulatory significance of this event is uncertain, because other transcripts exist that can supply the targeted function. Here we report the identification of miRNAs encoded by simian virus 40 (SV40) and define their functional significance for viral infection. SVmiRNAs accumulate at late times in infection, are perfectly complementary to early viral mRNAs, and target those mRNAs for cleavage. This reduces the expression of viral T antigens but does not reduce the yield of infectious virus relative to that generated by a mutant lacking SVmiRNAs. However, wild-type SV40-infected cells are less sensitive than the mutant to lysis by cytotoxic T cells, and trigger less cytokine production by such cells. Thus, viral evolution has taken advantage of the miRNA pathway to generate effectors that enhance the probability of successful infection.

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Author and article information

Journal

Journal ID (nlm-ta): PLoS Med

Journal ID (publisher-id): pmed

Title: PLoS Medicine

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1549-1277

ISSN (Electronic): 1549-1676

Publication date (Print): July 2006

Publication date (Electronic): 25 July 2006

Volume: 3

Issue: 7

Electronic Location Identifier: e242

Author notes

Competing Interests: The National Institutes of Health played no role in the preparation of this essay. JL declares that she has pending patent applications on the use of RNA interference to target HIV infection or fas and other apoptotic or proinflammatory genes activated in response to infection; on the topical application of small interfering RNAs for use as a microbicide or for other antiviral prevention or treatment indications; and on cell-type-specific small interfering RNA delivery using an antibody fragment–protamine fusion protein.

Derek M. Dykxhoorn and Judy Lieberman are at the CBR Institute for Biomedical Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America.

* To whom correspondence should be addressed. E-mail: lieberman@ 123456cbr.med.harvard.edu

Article

DOI: 10.1371/journal.pmed.0030242

PMC ID: 1518680

PubMed ID: 16848617

SO-VID: 89856bcb-e7d8-4630-be44-9564ed17d53f

Copyright statement: Copyright: © 2006 Dykxhoorn and Lieberman. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Silencing Viral Infection

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Abstract

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Most cited references 13

Inhibition of respiratory viruses by nasally administered siRNA.

RNA interference targeting Fas protects mice from fulminant hepatitis.

SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells.

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