title: TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments.
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.
authors.affiliation: Tibotec, Mechelen, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vingerhoets
authors.forename: Hilde
authors.initials: H
authors.lastname: Azijn
authors.forename: Els
authors.initials: E
authors.lastname: Fransen
authors.forename: Inky
authors.initials: I
authors.lastname: De Baere
authors.forename: Liesbet
authors.initials: L
authors.lastname: Smeulders
authors.forename: Dirk
authors.initials: D
authors.lastname: Jochmans
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Rudi
authors.initials: R
authors.lastname: Pauwels
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: de Béthune
mesh_terms: D000595:Amino Acid Sequence; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D016679:Genome, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests / Q000379:methods*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009570:Nitriles; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012641:Selection, Genetic
chemical_list: D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D054303:HIV Reverse Transcriptase