MIV-150 and zinc acetate combination provides potent and broad activity against HIV-1
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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 EC50 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 EC50 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.
KeywordsHIV-1 Zinc Antiviral NNRTIs Microbicides
We thank Dr. Jeffrey D. Lifson and Julian Bess at Leidos Biomedical Research, Inc. for providing the HIV-1BaL, as well as Samantha Seidor and Ciby Abraham for preparation of ZA and control buffer solutions. This work was funded with the support of the United States Agency for International Development (USAID) Cooperative Agreement GPO-A-00-04-00019-00. This research is made possible by the generous support of the American people through the USAID. The contents of this manuscript are the sole responsibility of the Population Council and do not necessarily reflect the views or policies of USAID or of the U.S. government. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the material in this article has been published or is under consideration elsewhere. MR is a 2002 Elizabeth Glaser Scientist.
Compliance with ethical standards
All the experiments published in this manuscript comply with the current laws of the country in which they were performed. All institutional and national guidelines for the care and use of laboratory animals were followed.
O. Mizenina, M. Hsu, N. Jean-Pierre, M. Aravantinou, K. Levendosky, G. Paglini, T.M. Zydowsky, M. Robbiani, and J. A. Fernández-Romero declare that they have no conflict of interest.
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