MIV-150 and zinc acetate combination provides potent and broad activity against HIV-1

OLGA MIZENINA; MAYLA HSU; NINOCHKA JEAN-PIERRE; MEROPI ARAVANTINOU; KEITH LEVENDOSKY; MARÍA GABRIELA PAGLINI; THOMAS M. ZYDOWSKY; MELISSA ROBBIANI; JOSE FERNANDEZ-ROMERO

Drug delivery and translational research

Springer

Lugar: New York; Año: 2017

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. 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 sub-nM to nM 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 lab-adapted and primary HIV-1 isolates and HIV-1 isolates/clones with NNRTI and RT resistance mutations, with EC50 values between 20-110 µM. The MIV-150/ZA combination had additive antiviral effects 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.