title: Specific HIV-1 integrase polymorphisms change their prevalence in untreated versus antiretroviral-treated HIV-1-infected patients, all naive to integrase inhibitors.
abstract: OBJECTIVE
  To define whether the prevalence of mutations associated with integrase inhibitor (INI) resistance is different in untreated versus antiretroviral-treated HIV-1-infected individuals (all INI naive).
  
  
  METHODS
  Gene sequences of the integrase (IN) and reverse transcriptase (RT) obtained from plasma samples of a well-defined cohort of 448 HIV-1-infected individuals (134 drug naive and 314 antiretroviral treated) were analysed. Docking simulations, using RT and IN models, were also performed.
  
  
  RESULTS
  Primary mutations and the majority of secondary mutations for raltegravir or elvitegravir were completely absent (or rarely found, <1%) in INI-naive patients, either drug naive or antiretroviral treated. Specific IN polymorphisms increased their frequency in antiretroviral-treated patients, and showed positive associations with specific RT resistance mutations. M154I and V165I IN polymorphisms occurred at a frequency of 6% in untreated patients, reaching 21.3% and 13.4%, respectively, in antiretroviral-treated patients. The mutation M154L, absent in drug-naive patients, was prevalent at 5.7% in antiretroviral-treated patients, and was positively associated with RT resistance mutations F227L and T215Y. Similarly, V165I and G163R mutations were associated with the RT resistance mutations F227L and M230L, respectively, and the T206S polymorphism was associated with the RT resistance mutation L210W. Docking simulations showed several favourable contacts between IN and RT residues.
  
  
  CONCLUSIONS
  Overall, results confirm that primary and secondary INI-associated mutations are absent or extremely rare in INI-naive patients. Conversely, a few specific IN polymorphisms found in INI-naive patients increased their frequency in antiretroviral-failing patients and/or are associated with RT resistance mutations. The potential contribution of such polymorphisms to the evolution of resistance under the pressure of INIs needs further investigation.
authors.affiliation: Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. ceccherini@med.uniroma2.it
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.forename: Lavinia
authors.initials: L
authors.lastname: Fabeni
authors.forename: Salvatore
authors.initials: S
authors.lastname: Dimonte
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Roberta
authors.initials: R
authors.lastname: D'Arrigo
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.forename: Giosuè
authors.initials: G
authors.lastname: Costa
authors.forename: Sara
authors.initials: S
authors.lastname: Bono
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Antonella d'Arminio
authors.initials: Ad
authors.lastname: Monforte
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Anne-Genevieve
authors.initials: AG
authors.lastname: Marcelin
authors.forename: Carlo-Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D019943:Amino Acid Substitution; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D015995:Prevalence; D017422:Sequence Analysis, DNA
chemical_list: D044966:Anti-Retroviral Agents; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1