title: Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model.
abstract: Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1% [n = 4], 0.5% [n = 6], and 1% [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 10(5) 50% tissue culture infectious doses). Rx mice were challenged at 4 h (0.1%), 24 h (0.5%), and 7 days (1%) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100% protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality.
authors.affiliation: Creighton University School of Pharmacy & Health Professions, Omaha, Nebraska, USA destache@creighton.edu.
authors.forename: Christopher J
authors.identifier: 0000-0001-7923-3939
authors.initials: CJ
authors.lastname: Destache
authors.affiliation: Creighton University School of Pharmacy & Health Professions, Omaha, Nebraska, USA.
authors.forename: Subhra
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Guobin
authors.initials: G
authors.lastname: Kang
authors.affiliation: Creighton University School of Pharmacy & Health Professions, Omaha, Nebraska, USA.
authors.forename: Abhijit A
authors.initials: AA
authors.lastname: Date
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Wuxun
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Biology, Creighton University, Omaha, Nebraska, USA.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Department of Biology, Creighton University, Omaha, Nebraska, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Pham
authors.affiliation: Department of Biology, Creighton University, Omaha, Nebraska, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruck
authors.affiliation: Department of Biology, Creighton University, Omaha, Nebraska, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rezich
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Creighton University School of Medicine, Omaha, Nebraska, USA.
authors.forename: Renuga
authors.initials: R
authors.lastname: Vivekanandan
authors.affiliation: University of Nebraska Medical Center College of Pharmacy, Omaha, Nebraska, USA.
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D045703:Emulsifying Agents / Q000737:chemistry; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011322:Primary Prevention / Q000379:methods*; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000235:genetics; D013696:Temperature; D000068698:Tenofovir / Q000008:administration & dosage*; D013997:Time Factors; D014621:Vagina / Q000187:drug effects / Q000821:virology; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage* / Q000737:chemistry; D019562:Viral Load / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D045703:Emulsifying Agents; D012367:RNA, Viral; D014622:Vaginal Creams, Foams, and Jellies; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000068698:Tenofovir