title: Raltegravir susceptibility and fitness progression of HIV type-1 integrase in patients on long-term antiretroviral therapy.
abstract: BACKGROUND
  HIV type-1 (HIV-1) protease (PR), reverse transcriptase (RT) and integrase (IN) share the same precursor polyprotein and there is much evidence to suggest functional interactions between IN and RT. We aimed to elucidate whether long-term highly active antiretroviral therapy (HAART) targeting PR and RT could influence raltegravir susceptibility and the fitness of IN.
  
  
  METHODS
  HIV-1 IN sequences from 45 heavily antiretroviral-experienced patients with longitudinal samples separated by a median of 10 years were obtained to estimate the rate of nucleotide substitution. IN recombinant viruses were generated from five selected patients. Phenotypic susceptibility to raltegravir was tested in vitro. Changes in viral replication capacity were assayed by growth kinetics and competition of intrapatient IN recombinant viruses.
  
  
  RESULTS
  The amino acid substitution rate within IN was 0.06% per year during long-term antiretroviral treatment. Some substitutions had previously been associated with resistance to different IN inhibitors. Despite this, neither the early- nor late-derived IN recombinant viruses showed an increase in phenotypic susceptibility to raltegravir. Moreover, IN recombinant viruses corresponding to IN samples after 10 years of HAART had a replication capacity that was similar to or better than IN recombinant viruses from baseline samples.
  
  
  CONCLUSIONS
  HIV-1 IN from longitudinal samples taken from patients treated with IN inhibitor-sparing regimens showed no evidence of genotypic or phenotypic resistance to raltegravir. Additionally, long-term pressure with PR and RT inhibitors did not impair the fitness of HIV-1 IN. These data suggest that current antiretroviral regimens do not diminish the fitness of IN or influence raltegravir efficacy.
authors.affiliation: IrsiCaixa Foundation, Institut de Recerca en Ciències de la Salut Germans Trias i Pujol, Badalona, Spain.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Buzón
authors.forename: Silvia
authors.initials: S
authors.lastname: Marfil
authors.forename: Maria C
authors.initials: MC
authors.lastname: Puertas
authors.forename: Elisabet
authors.initials: E
authors.lastname: Garcia
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Lidia
authors.initials: L
authors.lastname: Ruiz
authors.forename: Julìa
authors.initials: J
authors.lastname: Blanco
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cabrera
mesh_terms: D019943:Amino Acid Substitution; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D011995:Recombination, Genetic; D013997:Time Factors; D014779:Virus Replication
chemical_list: D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase