[PDF][PDF] Durable protection from Herpes Simplex Virus-2 transmission following intravaginal application of siRNAs targeting both a viral and host gene

Y Wu, F Navarro, A Lal, E Basar, RK Pandey… - Cell host & …, 2009 - cell.com
Y Wu, F Navarro, A Lal, E Basar, RK Pandey, M Manoharan, Y Feng, SJ Lee, J Lieberman
Cell host & microbe, 2009cell.com
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) …
Summary
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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