TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments.
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.
Vingerhoets
Johan
J
Tibotec, Mechelen, Belgium.
Azijn
Hilde
H
Fransen
Els
E
De Baere
Inky
I
Smeulders
Liesbet
L
Jochmans
Dirk
D
Andries
Koen
K
Pauwels
Rudi
R
de Béthune
Marie-Pierre
MP
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
D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D054303:HIV Reverse Transcriptase