Herpes simplex virus 2 (HSV-2) infection causes significant morbidity¹ and is an important cofactor for the transmission of HIV infection². A microbicide to prevent sexual transmission of HSV-2 would contribute substantially to controlling the spread of HIV and other infections^{3, 4}. Because RNA interference (RNAi) provides effective antiviral defence in plants and other organisms, several studies have focused on harnessing RNAi to inhibit viral infection⁵. Here we show that vaginal instillation of small interfering RNAs (siRNAs) targeting HSV-2 protects mice from lethal infection. siRNAs mixed with lipid are efficiently taken up by epithelial and lamina propria cells and silence gene expression in the mouse vagina and ectocervix for at least nine days. Intravaginal application of siRNAs targeting the HSV-2 UL27 and UL29 genes (which encode an envelope glycoprotein and a DNA binding protein⁶, respectively) was well tolerated, did not induce interferon-responsive genes or cause inflammation, and protected mice when administered before and/or after lethal HSV-2 challenge. These results suggest that siRNAs are attractive candidates for the active component of a microbicide designed to prevent viral infection or transmission.

1. CBR Institute for Biomedical Research,
2. Department of Pediatrics,
3. Department of Microbiology and Molecular Genetics,
4. Dana Farber Cancer Institute and
5. Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Judy Lieberman^1,2 Correspondence and requests for materials should be addressed to J.L. (Email: lieberman@cbr.med.harvard.edu).

Received 12 July 2005 | Accepted 26 September 2005 |

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