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Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments

Tibotec, Mechelen, Belgium.
Journal of Virology (Impact Factor: 4.65). 11/2005; 79(20):12773-82. DOI: 10.1128/JVI.79.20.12773-12782.2005
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ABSTRACT TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is active against human immunodeficiency virus type 1 (HIV-1) with resistance to currently licensed NNRTIs. Sequential passage experiments with both wild-type virus and NNRTI-resistant virus were performed to identify mutations selected by TMC125 in vitro. In addition to "classic" selection experiments at a low multiplicity of infection (MOI) with increasing concentrations of inhibitors, experiments at a high MOI with fixed concentrations of inhibitors were performed to ensure a standardized comparison between TMC125 and current NNRTIs. Both low- and high-MOI experiments demonstrated that the development of resistance to TMC125 required multiple mutations which frequently conferred cross-resistance to efavirenz and nevirapine. In high-MOI experiments, 1 muM TMC125 completely inhibited the breakthrough of resistant virus from wild-type and NNRTI-resistant HIV-1, in contrast to efavirenz and nevirapine. Furthermore, breakthrough of virus from site-directed mutant (SDM) SDM-K103N/Y181C occurred at the same time or later with TMC125 as breakthrough from wild-type HIV-1 with efavirenz or nevirapine. The selection experiments identified mutations selected by TMC125 that included known NNRTI-associated mutations L100I, Y181C, G190E, M230L, and Y318F and the novel mutations V179I and V179F. Testing the antiviral activity of TMC125 against a panel of SDMs indicated that the impact of these individual mutations on resistance was highly dependent upon the presence and identity of coexisting mutations. These results demonstrate that TMC125 has a unique profile of activity against NNRTI-resistant virus and possesses a high genetic barrier to the development of resistance in vitro.

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Available from: Dirk Jochmans, Aug 17, 2015
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    • "However, based on the weighted mutation score algorithm for the prediction of ETR susceptibility [Vingerhoets et al., 2010b], some of the HIV-1 isolated strains (23.6%) had mutations or combinations of mutations associated with intermediate resistance to ETR. Furthermore, L100I was the most prevalent ETR RAM found (16.4%) and in combination with K103N, a first-generation NNRTIs RAM widely present in EFV resistant viruses [Tambuyzer et al., 2009], was described to be associated in vitro with intermediate resistance to ETR [Vingerhoets et al., 2005]. Therefore, careful genotypic analysis is necessary when the use of ETR is considered. "
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    • "4-[6-Amino-5-bromo-2-[(4-cyanophenyl)amino] pyrimidin-4-yl]oxy-3,5- dimethylbenzonitrile (etravirine; ETR) is a second-generation NNRTI that, like other NNRTIs, functions by binding noncompetitively to HIV reverse transcriptase, thereby preventing synthesis of DNA from the RNA genome of the virus. As a diarylpyrimidine, ETR has a high capacity for isomerization, which allows it to effectively bind to and inhibit common mutated forms of the viral enzyme (Andries et al., 2004; Vingerhoets et al., 2005; Gupta et al., This work was supported by the PhRMA Foundation (Research Starter Grant in Pharmacology/Toxicology; to N.N.B.). The AB SCIEX QTRAP 5500 mass spectrometer was purchased using a grant from the National Institutes of Health National Center for Research Resources [Grant 1S10-RR27733]; the Waters Acquity ultraperformance liquid chromatograph interfaced with the AB SCIEX QTRAP 5500 mass spectrometer was purchased with funds provided by the Pendleton Foundation Trust. "
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