| Autor: |
Mizenina O; Center for Biomedical Research, Population Council, New York, NY, USA., Hsu M; Center for Biomedical Research, Population Council, New York, NY, USA., Jean-Pierre N; Center for Biomedical Research, Population Council, New York, NY, USA., Aravantinou M; Center for Biomedical Research, Population Council, New York, NY, USA., Levendosky K; Center for Biomedical Research, Population Council, New York, NY, USA., Paglini G; Instituto de Virología J.M.Vanella-Facultad de Ciencias Médicas-Universidad Nacional de Córdoba, Córdoba, Argentina., Zydowsky TM; Center for Biomedical Research, Population Council, New York, NY, USA., Robbiani M; Center for Biomedical Research, Population Council, New York, NY, USA., Fernández-Romero JA; Center for Biomedical Research, Population Council, New York, NY, USA. jfernandezromero@bmcc.cuny.edu.; Science Department, Borough of Manhattan Community College, The City University of New York, 199 Chambers Street, New York, NY, 10007, USA. jfernandezromero@bmcc.cuny.edu. |
| Abstrakt: |
We previously showed that the combination of the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 with zinc acetate (ZA) formulated in a carrageenan (CG; MZC) gel provided macaques significant protection against vaginal simian-human immunodeficiency virus-RT (SHIV-RT) challenge, better than either MIV-150/CG or ZA/CG. The MZC gel was shown to be safe in a phase 1 clinical trial. Herein, we used in vitro approaches to study the antiviral properties of ZA and the MIV-150/ZA combination, compared to other NNRTIs. Like other NNRTIs, MIV-150 has EC 50 values in the subnanomolar to nanomolar range against wild type and NNRTI or RT-resistant HIVs. While less potent than NNRTIs, ZA was shown to be active in primary cells against laboratory-adapted and primary HIV-1 isolates and HIV-1 isolates/clones with NNRTI and RT resistance mutations, with EC 50 values between 20 and 110 μM. The MIV-150/ZA combination had a potent and broad antiviral activity in primary cells. In vitro resistance selection studies revealed that previously described NNRTI-resistant mutations were selected by MIV-150. ZA-resistant virus retained susceptibility to MIV-150 (and other RTIs) and MIV-150-selected virus remained sensitive to ZA. Notably, resistant virus was not selected when cultured in the presence of both ZA and MIV-150. This underscores the potency and breadth of the MIV-150/ZA combination, supporting preclinical macaque studies and the advancement of MZC microbicides into clinical testing. |
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