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

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(50), 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.

MIV-150-Containing Intravaginal Rings Protect Macaque Vaginal Explants against SHIV-RT Infection

“…The biopsy specimens were processed as described previously (22). Briefly, ϳ3-by 3-mm explants were stimulated with 5 g/ml phytohemagglutinin (PHA) (Sigma-Aldrich, St. Louis, MO) and 100 U/ml interleukin-2 (IL-2) (Roche Applied Science, Indianapolis, IN, or NCI BRB Preclinical Repository, Frederick, MD) for 2 days.…”

“…Tissue viability in the presence of VF was tested by thiazolyl blue tetrazolium bromide (MTT) assay (22). Briefly, ϳ3-by 3-mm explants were immersed for ϳ18 h in pooled diluted VF alone or spiked with MIV-150.…”

MIV-150/Zinc Acetate Gel Inhibits Cell-Associated Simian-Human Immunodeficiency Virus Reverse Transcriptase Infection in a Macaque Vaginal Explant Model

“…Macaque vaginal mucosa (n ϭ 2 biopsy specimens collected using 3-by 5-mm forceps or necropsy tissues) was transported overnight as previously described (24,33,34). The amount of recovered biopsy tissue allowed us to prepare 6 to 17 3-by 3-mm explants.…”

Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

“…SIV is not susceptible to NNRTIs due to sequence differences within the RT coding region, but NNRTI sensitivity is established by swapping the SIV and HIV-1 RT coding regions (31,32). RT-SHIV macaque models have been used to study HIV-1 ART, drug resistance, PrEP, and persistence (30,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). In this study, we treated RT-SHIV-infected macaques with RPV LA and measured plasma viremia, drug concentrations, and drug-resistant isolates over 35 weeks.…”