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.
authors.affiliation: The Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Wu
authors.forename: Francisco
authors.initials: F
authors.lastname: Navarro
authors.forename: Ashish
authors.initials: A
authors.lastname: Lal
authors.forename: Emre
authors.initials: E
authors.lastname: Basar
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Pandey
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Deborah
authors.initials: D
authors.lastname: Palliser
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D005260:Female; D020868:Gene Silencing; D006558:Herpes Genitalis / Q000517:prevention & control* / Q000635:transmission*; D018258:Herpesvirus 2, Human / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D000075983:Nectins; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics*; D016019:Survival Analysis; D014621:Vagina / Q000473:pathology / Q000821:virology
chemical_list: D000998:Antiviral Agents; D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619015:Nectin1 protein, mouse; D000075983:Nectins; D034741:RNA, Small Interfering