title: Deep analysis of HIV-1 natural variability across HIV-1 variants at residues associated with integrase inhibitor (INI) resistance in INI-naive individuals.
abstract: OBJECTIVE
  We evaluated variant-associated variability at positions related to resistance to the integrase (IN) inhibitors (INIs) raltegravir, elvitegravir and dolutegravir using HIV-1 IN sequences from naive individuals retrieved from GenBank.
  
  
  METHODS
  We evaluated the frequency of major, secondary and rare amino acid changes associated with INI resistance (INI-R) in 6706 sequences from 3791 INI-naive individuals carrying a large panel of different HIV-1 variants retrieved from GenBank, including four groups: M (6663), O (24), N (15) and P (4). HIV-1 group M sequences included 4599 sequences from the nine group M subtypes and 2064 recombinants ascribed to 54 circulating recombinant forms (CRFs).
  
  
  RESULTS
  Primary INI-R mutations were rare in INI-naive participants and only present at a low rate in subtypes B, C and D and recombinants CRF01_AE and CRF14_BG, ranging from one to five per variant. Three secondary INI-R changes appeared with variable frequency in INI-naive individuals carrying specific HIV-1 variants: L74M in CRF43_02G (33.3%); T97A in group P (50%), J (33.3%), CRF18_cpx (20%) and F2 (11.5%); and G163RK in CRF44_BF (100%), CRF46_BF (66.7%), CRF17_BF (28.6%), F1 (21.7%), CRF12_BF (16.7%) and CRF29_BF (12.5%). Rare mutations were absent.
  
  
  CONCLUSIONS
  Natural variability in INI-R positions across HIV-1 variants should be studied as they may facilitate or delay the emergence of INI-R viruses.
authors.affiliation: HIV-1 Molecular Epidemiology Laboratory, Microbiology and Parasitology Department, Hospital Universitario Ramón y Cajal, Madrid, SpainInstituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainCIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Llácer Delicado
authors.affiliation: HIV-1 Molecular Epidemiology Laboratory, Microbiology and Parasitology Department, Hospital Universitario Ramón y Cajal, Madrid, SpainInstituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainCIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Torrecilla
authors.affiliation: HIV-1 Molecular Epidemiology Laboratory, Microbiology and Parasitology Department, Hospital Universitario Ramón y Cajal, Madrid, SpainInstituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, SpainCIBER en Epidemiología y Salud Pública (CIBERESP), Madrid, Spain africa.holguin@salud.madrid.org.
authors.forename: África
authors.initials: Á
authors.lastname: Holguín
mesh_terms: D019943:Amino Acid Substitution; D019295:Computational Biology; D024882:Drug Resistance, Viral; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics* / Q000302:isolation & purification; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones / Q000494:pharmacology; D000068898:Raltegravir Potassium / Q000494:pharmacology; D000099226:Dolutegravir
chemical_list: D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir