title: Natural polymorphisms and unusual mutations in HIV-1 protease with potential antiretroviral resistance: a bioinformatic analysis.
abstract: 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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Mata-Munguía
authors.forename: Martha
authors.initials: M
authors.lastname: Escoto-Delgadillo
authors.forename: Blanca
authors.initials: B
authors.lastname: Torres-Mendoza
authors.forename: Mario
authors.initials: M
authors.lastname: Flores-Soto
authors.forename: Mildred
authors.initials: M
authors.lastname: Vázquez-Torres
authors.forename: Francisco
authors.initials: F
authors.lastname: Gálvez-Gastelum
authors.forename: Arturo
authors.initials: A
authors.lastname: Viniegra-Osorio
authors.forename: Marcelo
authors.initials: M
authors.lastname: Castillero-Manzano
authors.affiliation: Laboratorio de Inmunodeficiencias y Retrovirus Humanos, Centro de Investigación Biomédica de Occidente, CMNO, IMSS, Guadalajara 44340, México. eduardo.vazquez@imss.gob.mx.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vázquez-Valls
mesh_terms: D000069446:Atazanavir Sulfate; D001483:Base Sequence; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D010641:Phenotype; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011753:Pyrones / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir; C107201:tipranavir