title: MIV-150-containing intravaginal rings protect macaque vaginal explants against SHIV-RT infection.
abstract: Recent studies demonstrated that intravaginal rings (IVRs) containing 100 mg of the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 significantly protect macaques against a chimeric simian-human immunodeficiency virus that expresses the HIV-1 HxB2 reverse transcriptase (SHIV-RT) when present before and after vaginal challenge. The objectives of this study were to (i) evaluate the pharmacodynamics (PD) of MIV-150 in vaginal fluids (VF) and in ectocervical and vaginal tissues following 100-mg MIV-150 IVR exposure and to (ii) gain more insight whether pharmacokinetics (PK) of MIV-150 can predict PD. MIV-150 in VF collected at 1 day and 14 days post-MIV-150 IVR insertion inhibited ex vivo SHIV-RT infection in vaginal biopsy specimens from untreated animals (not carrying IVRs) in a dose-dependent manner. Previous PK studies demonstrated a significant increase of ectocervical and vaginal tissue MIV-150 concentrations 14 days versus 1 day post-IVR insertion, with the highest increase in vaginal tissue. Therefore, we tested PD of MIV-150 in tissues 14 days post-MIV-150 IVR insertion. Ex vivo SHIV-RT infection of vaginal, but not ectocervical, tissues collected 14 days post-MIV-150 IVR insertion was significantly inhibited compared to infection at the baseline (prior to MIV-150 IVR exposure). No changes in vaginal and ectocervical tissue infection were observed after placebo IVR exposure. Overall, these data underscore the use of the ex vivo macaque explant challenge models to evaluate tissue and VF PK/PD of candidate microbicides before in vivo animal efficacy studies. The data support further development of MIV-150-containing IVRs.
authors.affiliation: HIV/AIDS Program, Population Council, Center for Biomedical Research, New York, New York, USA.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Ouattara
authors.forename: Patrick
authors.initials: P
authors.lastname: Barnable
authors.forename: Paul
authors.initials: P
authors.lastname: Mawson
authors.forename: Samantha
authors.initials: S
authors.lastname: Seidor
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Zydowsky
authors.forename: Larisa
authors.initials: L
authors.lastname: Kizima
authors.forename: Aixa
authors.initials: A
authors.lastname: Rodriguez
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cooney
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Roberts
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbiani
authors.forename: Natalia
authors.initials: N
authors.lastname: Teleshova
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D005260:Female; D008251:Macaca; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C510296:MIV 150; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D014508:Urea