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

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

Keywords

  • MICROBIO
  • RNA

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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    Wu, Y., Navarro, F., Lal, A., Basar, E., Pandey, R. K., Manoharan, M., Feng, Y., Lee, S. J., 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, 5(1), 84-94. https://doi.org/10.1016/j.chom.2008.12.003