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

Research output: Contribution to journalArticle

69 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)84-94
Number of pages11
JournalCell Host and Microbe
Volume5
Issue number1
DOIs
StatePublished - Jan 22 2009

Fingerprint

Human Herpesvirus 2
Viral Genes
Small Interfering RNA
Intravaginal Administration
Lipids
Infectious Disease Transmission
Coitus
Viral RNA
Vagina
Anti-Infective Agents
Interferons
Compliance
Transfection
Cholesterol
Inflammation
Gene Expression
Infection
Genes

Keywords

  • MICROBIO
  • RNA

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Cancer Research
  • Molecular Biology

Cite this

Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene. / Wu, Yichao; Navarro, Francisco; Lal, Ashish; Basar, Emre; Pandey, Rajendra K.; Manoharan, Muthiah; Feng, Yang; Lee, Sandra J.; Lieberman, Judy; Palliser, Deborah.

In: Cell Host and Microbe, Vol. 5, No. 1, 22.01.2009, p. 84-94.

Research output: Contribution to journalArticle

Wu, Y, Navarro, F, Lal, A, Basar, E, Pandey, RK, Manoharan, M, Feng, Y, Lee, SJ, Lieberman, J & Palliser, D 2009, 'Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene', Cell Host and Microbe, vol. 5, no. 1, pp. 84-94. https://doi.org/10.1016/j.chom.2008.12.003
Wu, Yichao ; Navarro, Francisco ; Lal, Ashish ; Basar, Emre ; Pandey, Rajendra K. ; Manoharan, Muthiah ; Feng, Yang ; Lee, Sandra J. ; Lieberman, Judy ; Palliser, Deborah. / Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene. In: Cell Host and Microbe. 2009 ; Vol. 5, No. 1. pp. 84-94.
@article{c9e36bfe153b4a0987af85dd3ba0012d,
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",
year = "2009",
month = "1",
day = "22",
doi = "10.1016/j.chom.2008.12.003",
language = "English (US)",
volume = "5",
pages = "84--94",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene

AU - Wu, Yichao

AU - Navarro, Francisco

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

PY - 2009/1/22

Y1 - 2009/1/22

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.

KW - MICROBIO

KW - RNA

UR - http://www.scopus.com/inward/record.url?scp=58249094519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58249094519&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2008.12.003

DO - 10.1016/j.chom.2008.12.003

M3 - Article

VL - 5

SP - 84

EP - 94

JO - Cell Host and Microbe

JF - Cell Host and Microbe

SN - 1931-3128

IS - 1

ER -