Author:

Keywords:

Amino Acid Sequence, Dose-Response Relationship, Drug, Drug Resistance, Viral, Genome, Viral, HIV Reverse Transcriptase, HIV-1, Microbial Sensitivity Tests, Molecular Sequence Data, Mutagenesis, Site-Directed, Pyridazines, Reverse Transcriptase Inhibitors, Selection, Genetic, Science & Technology, Life Sciences & Biomedicine, Virology, IMMUNODEFICIENCY-VIRUS TYPE-1, REVERSE-TRANSCRIPTASE INHIBITORS, ANTIRETROVIRAL DRUG-RESISTANCE, TREATMENT-EXPERIENCED PATIENTS, PHENOTYPIC RESISTANCE, CROSS-RESISTANCE, CONTROLLED TRIAL, HIV-1 INFECTION, INITIAL THERAPY, PLUS ZIDOVUDINE, In Vitro Techniques, Nitriles, Pyrimidines, 06 Biological Sciences, 07 Agricultural and Veterinary Sciences, 11 Medical and Health Sciences, 30 Agricultural, veterinary and food sciences, 31 Biological sciences, 32 Biomedical and clinical sciences

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.