Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis
| Autor: | Blanca Miriam Torres-Mendoza, Francisco Javier Gálvez-Gastélum, M.E. Flores-Soto, Marcelo Castillero-Manzano, Carlos Mata-Munguía, Mildred Vázquez-Torres, Eduardo Vázquez-Valls, Arturo Viniegra-Osorio, Martha Escoto-Delgadillo |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Pyridines Bioinformatics medicine.medical_treatment In silico Atazanavir Sulfate Molecular Sequence Data HIV Infections Drug resistance Biology medicine.disease_cause Biochemistry HIV-1 protease HIV Protease Structural Biology Genotype Drug Resistance Viral medicine HIV Protease Inhibitor Humans Molecular docking simulation Polymorphism Molecular Biology Darunavir Genetics Mutation Sulfonamides Protease Polymorphism Genetic Base Sequence Applied Mathematics virus diseases HIV Protease Inhibitors Virology Antiretroviral agents Computer Science Applications Phenotype Pyrones biology.protein HIV-1 Female Oligopeptides Mutations medicine.drug Research Article |
| Zdroj: | BMC Bioinformatics |
| ISSN: | 1471-2105 |
| Popis: | Background The correlations of genotypic and phenotypic tests with treatment, clinical history and the significance of mutations in viruses of HIV-infected patients are used to establish resistance mutations to protease inhibitors (PIs). Emerging mutations in human immunodeficiency virus type 1 (HIV-1) protease confer resistance to PIs by inducing structural changes at the ligand interaction site. The aim of this study was to establish an in silico structural relationship between natural HIV-1 polymorphisms and unusual HIV-1 mutations that confer resistance to PIs. Results Protease sequences isolated from 151 Mexican HIV-1 patients that were naïve to, or subjected to antiretroviral therapy, were examined. We identified 41 unrelated resistance mutations with a prevalence greater than 1%. Among these mutations, nine exhibited positive selection, three were natural polymorphisms (L63S/V/H) in a codon associated with drug resistance, and six were unusual mutations (L5F, D29V, L63R/G, P79L and T91V). The D29V mutation, with a prevalence of 1.32% in the studied population, was only found in patients treated with antiretroviral drugs. Using in silico modelling, we observed that D29V formed unstable protease complexes when were docked with lopinavir, saquinavir, darunavir, tipranavir, indinavir and atazanavir. Conclusions The structural correlation of natural polymorphisms and unusual mutations with drug resistance is useful for the identification of HIV-1 variants with potential resistance to PIs. The D29V mutation likely confers a selection advantage in viruses; however, in silico, presence of this mutation results in unstable enzyme/PI complexes, that possibly induce resistance to PIs. |
| Databáze: | OpenAIRE |
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