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. 2015 Nov 23;60(2):1141-4.
doi: 10.1128/AAC.02468-15. Print 2016 Feb.

Multipurpose Prevention Approaches with Antiretroviral-Based Formulations

Affiliations

Multipurpose Prevention Approaches with Antiretroviral-Based Formulations

Ninochka Jean-Pierre et al. Antimicrob Agents Chemother. .

Abstract

We compared the preclinical safety and efficacy of tenofovir (TFV) 1% gel with that of MZC gel [containing 50 μM MIV-150, 14 mM Zn(O2CCH3)2(H2O)2, and 3% carrageenan] through a series of in vitro, ex vivo, and in vivo assays. The two gels showed good antiviral therapeutic indexes (50% cytotoxic concentration/50% effective concentration ratios; range, >25 to 800). MZC showed greater anti-simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) activity than TFV 1% gel in rhesus macaque vaginal explants. MZC protected mice from vaginal herpes simplex virus 2 (HSV-2) challenge (P < 0.0001), but the TFV 1% gel did not.

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Figures

FIG 1
FIG 1
MZC and TFV gels have no apparent effect on tissue architecture and reduce cell-free and cell-associated SHIV-RT infection of macaque vaginal explants. (A) MZC and 1% TFV gels do not induce histopathological changes in macaque vaginal tissues using the previously described polarized macaque vaginal explant model (9). Results representative of 3 experiments are shown at 10× magnification. (B) Tissue challenge with cell-free SHIV-RT infection was performed as described in the study by Barnable et al. (9). Briefly, explants were immersed in diluted gels (1:30 or 1:100) (versus untreated controls) for 18 h in the presence of PHA/IL-2. Then tissues were washed and challenged with SHIV-RT (104 TCID50) 24 h or 4 days after exposure to the gels. The tissues were washed again 18 h after virus challenge and cultured for 14 days in the presence of IL-2. SIV p27 levels were measured over the culture period. (C) Tissue challenge with cell-associated SHIV-RT was performed as previously described (9). Briefly, explants were immersed in medium containing diluted gels (versus untreated controls) for 18 h in the presence of PHA/IL-2. Then tissues were washed and challenged (18 h) with mitomycin-C-treated, SHIV-RT-infected PBMCs (103 infected PBMCs/27 TCID50 per explant; 2 to 4 replicates) 24 h or 4 days after exposure to the gels. Then tissues were washed and cultured for 14 days in the presence of IL-2 (versus 10 μM 3TC control) and analyzed (results shown in panel B). No released p27 was detected in cultures of control mitomycin-C-treated, SHIV-RT-infected PBMCs cultured alone (not shown). The analysis was done using a log-normal generalized linear mixed model with the individual replicate data. (B, C) Shown are results from SOFT analyses (mean ± standard error of the mean [SEM]) of n = 5 to 9 (24 h) and n = 3 to 9 (4 days) experiments. SHIV-RT p27 concentrations of individual replicate values more than or equal to the lower limit of quantification (LLOQ) were assumed to be log-normal. Type 3 F tests were used to determine the overall effect of treatment. Tukey's adjusted t tests were used for pairwise comparisons of treatments. The analysis was performed with SAS v9.4 and SAS/STAT v13.1 with α = 0.05. *, P values < 0.05; **, P values < 0.01; and ***, P values < 0.001 for relevant comparisons. MZC gel was tested only at 1:100 dilution in the cell-free model due to tissue availability.
FIG 2
FIG 2
MZC, but not 1% TFV gel, protects mice from HSV-2 vaginal challenge. Depo-Provera-treated BALB/c mice were treated intravaginally with 10 μl of the indicated formulations 1 h before and after HSV-2 challenge with 5 × 103 PFU (n = 20/formulation). The percentages of uninfected animals are shown for each treatment group. Fisher's exact test was used for statistical comparison, and P values of <0.05 were taken as statistically significant.

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