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Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis

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 (HI...

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Autores principales: Mata-Munguía, Carlos, Escoto-Delgadillo, Martha, Torres-Mendoza, Blanca, Flores-Soto, Mario, Vázquez-Torres, Mildred, Gálvez-Gastelum, Francisco, Viniegra-Osorio, Arturo, Castillero-Manzano, Marcelo, Vázquez-Valls, Eduardo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003850/
https://www.ncbi.nlm.nih.gov/pubmed/24629078
http://dx.doi.org/10.1186/1471-2105-15-72
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author Mata-Munguía, Carlos
Escoto-Delgadillo, Martha
Torres-Mendoza, Blanca
Flores-Soto, Mario
Vázquez-Torres, Mildred
Gálvez-Gastelum, Francisco
Viniegra-Osorio, Arturo
Castillero-Manzano, Marcelo
Vázquez-Valls, Eduardo
author_facet Mata-Munguía, Carlos
Escoto-Delgadillo, Martha
Torres-Mendoza, Blanca
Flores-Soto, Mario
Vázquez-Torres, Mildred
Gálvez-Gastelum, Francisco
Viniegra-Osorio, Arturo
Castillero-Manzano, Marcelo
Vázquez-Valls, Eduardo
author_sort Mata-Munguía, Carlos
collection PubMed
description 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.
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spelling pubmed-40038502014-04-30 Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis Mata-Munguía, Carlos Escoto-Delgadillo, Martha Torres-Mendoza, Blanca Flores-Soto, Mario Vázquez-Torres, Mildred Gálvez-Gastelum, Francisco Viniegra-Osorio, Arturo Castillero-Manzano, Marcelo Vázquez-Valls, Eduardo BMC Bioinformatics Research Article 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. BioMed Central 2014-03-15 /pmc/articles/PMC4003850/ /pubmed/24629078 http://dx.doi.org/10.1186/1471-2105-15-72 Text en Copyright © 2014 Mata-Munguía et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
spellingShingle Research Article
Mata-Munguía, Carlos
Escoto-Delgadillo, Martha
Torres-Mendoza, Blanca
Flores-Soto, Mario
Vázquez-Torres, Mildred
Gálvez-Gastelum, Francisco
Viniegra-Osorio, Arturo
Castillero-Manzano, Marcelo
Vázquez-Valls, Eduardo
Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis
title Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis
title_full Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis
title_fullStr Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis
title_full_unstemmed Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis
title_short Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis
title_sort natural polymorphisms and unusual mutations in hiv-1 protease with potential antiretroviral resistance: a bioinformatic analysis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003850/
https://www.ncbi.nlm.nih.gov/pubmed/24629078
http://dx.doi.org/10.1186/1471-2105-15-72
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