title: A combined sequence-structure approach for predicting resistance to the non-nucleoside HIV-1 reverse transcriptase inhibitor Nevirapine.
abstract: The development of drug resistance to antiretroviral medications used to treat infection with HIV-1 is a major concern. Given the cost and time constraints associated with phenotypic resistance testing, computational approaches leading to accurate predictive models of resistance based on a patient's mutational patterns in the target protein would provide a welcome alternative. A combined sequence-structure computational mutagenesis procedure is used to generate attribute vectors for each of 222 mutational patterns of HIV-1 reverse transcriptase that were isolated and sequenced from patients. Phenotypic fold-levels of resistance to the non-nucleoside inhibitor Nevirapine are known for over 25% of these mutants, whose values are used to assign each assayed mutant to a drug susceptibility class, either sensitive or resistant. Support vector machine and random forest supervised learning algorithms applied to this subset respectively classify mutants based on drug susceptibility with 85% and 92% cross-validation accuracy. The trained models are used to predict susceptibility to Nevirapine for all remaining mutant isolates, and predictions are in agreement for 90% of the test cases.
authors.affiliation: Laboratory for Structural Bioinformatics, Department of Bioinformatics and Computational Biology, George Mason University, 10900 University Blvd., MSN 5B3, Manassas, VA 20110, USA.
authors.forename: Vadim L
authors.initials: VL
authors.lastname: Ravich
authors.forename: Majid
authors.initials: M
authors.lastname: Masso
authors.forename: Iosif I
authors.initials: II
authors.lastname: Vaisman
mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D005822:Genetic Vectors; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D019829:Nevirapine / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase