Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene

Yichao Wu; Francisco Navarro; Ashish Lal; Emre Basar; Rajendra K. Pandey; Muthiah Manoharan; Yang Feng; Sandra J. Lee; Judy Lieberman; Deborah Palliser

doi:10.1016/j.chom.2008.12.003

Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene

Yichao Wu
, Francisco Navarro
, Ashish Lal
, Emre Basar
, Rajendra K. Pandey
, Muthiah Manoharan
, Yang Feng
, Sandra J. Lee
, Judy Lieberman
, Deborah Palliser

Microbiology & Immunology

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

88 Scopus citations

Abstract

A vaginal microbicide should prevent pathogen transmission without disrupting tissue barriers to infection. Ideally, it would not need to be applied immediately before sexual intercourse, when compliance is a problem. Intravaginal administration of small interfering RNA (siRNA) lipoplexes targeting Herpes Simplex Virus Type 2 (HSV-2) genes protects mice from HSV-2. However, protection is short-lived, and the transfection lipid on its own unacceptably enhances transmission. Here, we show that cholesterol-conjugated (chol)-siRNAs without lipid silence gene expression in the vagina without causing inflammation or inducing interferons. A viral siRNA prevents transmission within a day of challenge, whereas an siRNA targeting the HSV-2 receptor nectin-1 protects for a week, but protection is delayed for a few days until the receptor is downmodulated. Combining siRNAs targeting a viral and host gene protects mice from HSV-2 for a week, irrespective of the time of challenge. Therefore, intravaginal siRNAs could provide sustained protection against viral transmission.

Original language	English (US)
Pages (from-to)	84-94
Number of pages	11
Journal	Cell Host and Microbe
Volume	5
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2008.12.003
State	Published - Jan 22 2009

Keywords

MICROBIO
RNA

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2008.12.003

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title = "Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene",

abstract = "A vaginal microbicide should prevent pathogen transmission without disrupting tissue barriers to infection. Ideally, it would not need to be applied immediately before sexual intercourse, when compliance is a problem. Intravaginal administration of small interfering RNA (siRNA) lipoplexes targeting Herpes Simplex Virus Type 2 (HSV-2) genes protects mice from HSV-2. However, protection is short-lived, and the transfection lipid on its own unacceptably enhances transmission. Here, we show that cholesterol-conjugated (chol)-siRNAs without lipid silence gene expression in the vagina without causing inflammation or inducing interferons. A viral siRNA prevents transmission within a day of challenge, whereas an siRNA targeting the HSV-2 receptor nectin-1 protects for a week, but protection is delayed for a few days until the receptor is downmodulated. Combining siRNAs targeting a viral and host gene protects mice from HSV-2 for a week, irrespective of the time of challenge. Therefore, intravaginal siRNAs could provide sustained protection against viral transmission.",

keywords = "MICROBIO, RNA",

author = "Yichao Wu and Francisco Navarro and Ashish Lal and Emre Basar and Pandey, \{Rajendra K.\} and Muthiah Manoharan and Yang Feng and Lee, \{Sandra J.\} and Judy Lieberman and Deborah Palliser",

note = "Funding Information: This work was supported by NIH grant AI070302 (J.L.), an amfAR Scholar Award (D.P.), and a CFAR pilot project grant AECOM/MMC 2P30AI051519 (D.P.).",

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doi = "10.1016/j.chom.2008.12.003",

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AU - Wu, Yichao

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AU - Lal, Ashish

AU - Basar, Emre

AU - Pandey, Rajendra K.

AU - Manoharan, Muthiah

AU - Feng, Yang

AU - Lee, Sandra J.

AU - Lieberman, Judy

AU - Palliser, Deborah

N1 - Funding Information: This work was supported by NIH grant AI070302 (J.L.), an amfAR Scholar Award (D.P.), and a CFAR pilot project grant AECOM/MMC 2P30AI051519 (D.P.).

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N2 - A vaginal microbicide should prevent pathogen transmission without disrupting tissue barriers to infection. Ideally, it would not need to be applied immediately before sexual intercourse, when compliance is a problem. Intravaginal administration of small interfering RNA (siRNA) lipoplexes targeting Herpes Simplex Virus Type 2 (HSV-2) genes protects mice from HSV-2. However, protection is short-lived, and the transfection lipid on its own unacceptably enhances transmission. Here, we show that cholesterol-conjugated (chol)-siRNAs without lipid silence gene expression in the vagina without causing inflammation or inducing interferons. A viral siRNA prevents transmission within a day of challenge, whereas an siRNA targeting the HSV-2 receptor nectin-1 protects for a week, but protection is delayed for a few days until the receptor is downmodulated. Combining siRNAs targeting a viral and host gene protects mice from HSV-2 for a week, irrespective of the time of challenge. Therefore, intravaginal siRNAs could provide sustained protection against viral transmission.

AB - A vaginal microbicide should prevent pathogen transmission without disrupting tissue barriers to infection. Ideally, it would not need to be applied immediately before sexual intercourse, when compliance is a problem. Intravaginal administration of small interfering RNA (siRNA) lipoplexes targeting Herpes Simplex Virus Type 2 (HSV-2) genes protects mice from HSV-2. However, protection is short-lived, and the transfection lipid on its own unacceptably enhances transmission. Here, we show that cholesterol-conjugated (chol)-siRNAs without lipid silence gene expression in the vagina without causing inflammation or inducing interferons. A viral siRNA prevents transmission within a day of challenge, whereas an siRNA targeting the HSV-2 receptor nectin-1 protects for a week, but protection is delayed for a few days until the receptor is downmodulated. Combining siRNAs targeting a viral and host gene protects mice from HSV-2 for a week, irrespective of the time of challenge. Therefore, intravaginal siRNAs could provide sustained protection against viral transmission.

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Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene

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Keywords

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