title: A Novel Microbicide/Contraceptive Intravaginal Ring Protects Macaque Genital Mucosa against SHIV-RT Infection Ex Vivo.
abstract: Women need multipurpose prevention products (MPTs) that protect against sexually transmitted infections (STIs) and provide contraception. The Population Council has developed a prototype intravaginal ring (IVR) releasing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (M), zinc acetate (ZA), carrageenan (CG) and levonorgestrel (LNG) (MZCL IVR) to protect against HIV, HSV-2, HPV and unintended pregnancy. Our objective was to evaluate the anti-SHIV-RT activity of MZCL IVR in genital mucosa. First, macaque vaginal tissues were challenged with SHIV-RT in the presence of (i) MIV-150 ± LNG or (ii) vaginal fluids (VF); available from studies completed earlier) collected at various time points post insertion of MZCL and MZC IVRs. Then, (iii) MZCL IVRs (vs. LNG IVRs) were inserted in non-Depo Provera-treated macaques for 24h and VF, genital biopsies, and blood were collected and tissues were challenged with SHIV-RT. Infection was monitored with one step SIV gag qRT-PCR or p27 ELISA. MIV-150 (LCMS/MS, RIA), LNG (RIA) and CG (ELISA) were measured in different compartments. Log-normal generalized mixed linear models were used for analysis. LNG did not affect the anti-SHIV-RT activity of MIV-150 in vitro. MIV-150 in VF from MZC/MZCL IVR-treated macaques inhibited SHIV-RT in vaginal mucosa in a dose-dependent manner (p<0.05). MIV-150 in vaginal tissue from MZCL IVR-treated animals inhibited ex vivo infection relative to baseline (96%; p<0.0001) and post LNG IVR group (90%, p<0.001). No MIV-150 dose-dependent protection was observed, likely because of high MIV-150 concentrations in all vaginal tissue samples. In cervical tissue, MIV-150 inhibited infection vs. baseline (99%; p<0.05). No cervical tissue was available for MIV-150 measurement. Exposure to LNG IVR did not change tissue infection level. These observations support further development of MZCL IVR as a multipurpose prevention technology to improve women's sexual and reproductive health.
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Villegas
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Giulia
authors.initials: G
authors.lastname: Calenda
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Shweta
authors.initials: S
authors.lastname: Ugaonkar
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Shimin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Larisa
authors.initials: L
authors.lastname: Kizima
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Mizenina
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, United States of America.
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.affiliation: Tulane National Primate Research Center, Tulane University, Covington, Louisiana, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cooney
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Robbiani
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández-Romero
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Zydowsky
authors.affiliation: Population Council, New York, New York, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Teleshova
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002351:Carrageenan / Q000494:pharmacology; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D003274:Contraceptive Devices, Female; D004338:Drug Combinations; D005260:Female; D006678:HIV / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D016912:Levonorgestrel / Q000494:pharmacology*; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000187:drug effects / Q000821:virology; D011725:Pyridines / Q000494:pharmacology*; D016865:Reassortant Viruses / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D016896:Treatment Outcome; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014621:Vagina / Q000187:drug effects* / Q000821:virology; D019345:Zinc Acetate / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D003271:Contraceptive Agents, Female; D004338:Drug Combinations; C510296:MIV 150; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D016912:Levonorgestrel; D014508:Urea; D002351:Carrageenan; D019345:Zinc Acetate