An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection

Deborah Palliser; Dipanjan Chowdhury; Qing Yin Wang; Sandra J. Lee; Roderick T. Bronson; David M. Knipe; Judy Lieberman

doi:10.1038/nature04263

An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection

Deborah Palliser, Dipanjan Chowdhury, Qing Yin Wang, Sandra J. Lee, Roderick T. Bronson, David M. Knipe, Judy Lieberman

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

376 Scopus citations

Abstract

Herpes simplex virus 2 (HSV-2) infection causes significant morbidity ¹ 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 UL27and 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.

Original language	English (US)
Pages (from-to)	89-94
Number of pages	6
Journal	Nature
Volume	439
Issue number	7072
DOIs	https://doi.org/10.1038/nature04263
State	Published - Jan 5 2006
Externally published	Yes

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title = "An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection",

abstract = "Herpes simplex virus 2 (HSV-2) infection causes significant morbidity 1 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 infections3,4. 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 UL27and 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.",

author = "Deborah Palliser and Dipanjan Chowdhury and Wang, {Qing Yin} and Lee, {Sandra J.} and Bronson, {Roderick T.} and Knipe, {David M.} and Judy Lieberman",

note = "Funding Information: Acknowledgements We thank R. Colgrove, T. Taylor, E. Torres-Lopez, D. Brown and S. White for advice. This work was supported by grants from the NIH to D.M.K. and J.L., and by postdoctoral fellowships from the Harvard Center for AIDS Research and amfAR to D.P. and the Leukemia and Lymphoma Society to D.C.",

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AU - Chowdhury, Dipanjan

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AU - Knipe, David M.

AU - Lieberman, Judy

N1 - Funding Information: Acknowledgements We thank R. Colgrove, T. Taylor, E. Torres-Lopez, D. Brown and S. White for advice. This work was supported by grants from the NIH to D.M.K. and J.L., and by postdoctoral fellowships from the Harvard Center for AIDS Research and amfAR to D.P. and the Leukemia and Lymphoma Society to D.C.

PY - 2006/1/5

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N2 - Herpes simplex virus 2 (HSV-2) infection causes significant morbidity 1 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 infections3,4. 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 UL27and 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.

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An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection

Abstract

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