The nonnucleoside reverse transcription inhibitor MIV-160 delivered from an intravaginal ring, but not from a carrageenan gel, protects against simian/human immunodeficiency virus-RT infection
Document Type
Article (peer-reviewed)
Publication Date
2012
Abstract
We previously showed that a carrageenan (CG) gel containing 50 μM MIV-150 (MIV-150/CG) reduced vaginal simian/human immunodeficiency virus (SHIV)-RT infection of macaques (56%, p > 0.05) when administered daily for 2 weeks with the last dose given 8 h before challenge. Additionally, when 100 mg of MIV-150 was loaded into an intravaginal ring (IVR) inserted 24 h before challenge and removed 2 weeks after challenge, > 80% protection was observed (p < 0.03). MIV-160 is a related NNRTI with a similar IC, greater aqueous solubility, and a shorter synthesis. To objectively compare MIV-160 with MIV-150, herein we evaluated the antiviral effects of unformulated MIV-160 in vitro as well as the in vivo protection afforded by MIV-160 delivered in CG (MIV-160/CG gel) and in an IVR under regimens used with MIV-150 in earlier studies. Like MIV-150, MIV-160 exhibited potent antiviral activity against SHIV-RT in macaque vaginal explants. However, formulated MIV-160 exhibited divergent effects in vivo. The MIV-160/CG gel offered no protection compared to CG alone, whereas the MIV-160 IVRs protected significantly. Importantly, the results of in vitro release studies of the MIV-160/CG gel and the MIV-160 IVR suggested that in vivo efficacy paralleled the amount of MIV-160 released in vitro. Hundreds of micrograms of MIV-160 were released daily from IVRs while undetectable amounts of MIV-160 were released from the CG gel. Our findings highlight the importance of testing different modalities of microbicide delivery to identify the optimal formulation for efficacy in vivo.
Recommended Citation
Aravantinou, Meropi, Rachel Singer, Nina Derby, Giulia Calenda, Paul Mawson, Ciby J. Abraham, Radhika Menon, Samantha Seidor, Daniel Goldman, Jessica Kenney, Guillermo Villegas, Agegnehu Gettie, James Blanchard, Jeffrey D. Lifson, Michael Piatak Jr., José Fernández-Romero, Thomas Zydowsky, Natalia Teleshova, and Melissa Robbiani. 2012. "The nonnucleoside reverse transcription inhibitor MIV-160 delivered from an intravaginal ring, but not from a carrageenan gel, protects against simian/human immunodeficiency virus-RT infection," AIDS Research and Human Retroviruses 28(11): 1467–1475.
DOI
10.1089/aid.2012.0080
Language
English
Project
Developing ARV-Based Microbicide and Microbicide/Contraceptive Vaginal Rings; Developing an ARV-Based Microbicide Gel