title: Persistence of HIV-1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy can be explained by compensatory fixation.
abstract: OBJECTIVE
  To investigate the mechanism explaining the persistence of human immunodeficiency virus (HIV) type 1 variants with multiple protease inhibitor (PI)-resistance mutations in the absence of PI therapy.
  
  
  METHODS
  Longitudinal genotypic analyses were performed on sequential samples obtained from 2 HIV-1-infected patients who had stopped PI therapy for 4 years. Replication capacity (RC) was determined using recombinant viruses. Subsequently, the effect that changing individual protease mutations back to wild type has on RC was analyzed.
  
  
  RESULTS
  We observed prolonged persistence (up to 4 years) of viruses with multiple protease mutations after PI therapy was stopped, despite the fact that the RC of the viruses was severely reduced. Forcing the virus to evolve toward wild type by changing individual protease mutations to wild type was unsuccessful, because all variants displayed a decreased RC in comparison with that of their predecessors.
  
  
  CONCLUSIONS
  We propose compensatory fixation as a mechanism for the in vivo persistence of variants with multiple PI-resistance mutations in the absence of PI therapy. Viruses with multiple PI mutations have (partially) compensated for the initial loss in RC. Therefore, reversion of a single mutation causes a (further) reduction in RC and, as a consequence, the route to wild type is blocked.
authors.affiliation: Eijkman-Winkler Center, Department of Virology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Noortje M
authors.initials: NM
authors.lastname: van Maarseveen
authors.forename: Annemarie M J
authors.initials: AM
authors.lastname: Wensing
authors.forename: Dorien
authors.initials: D
authors.lastname: de Jong
authors.forename: Maaike
authors.initials: M
authors.lastname: Taconis
authors.forename: Jan C C
authors.initials: JC
authors.lastname: Borleffs
authors.forename: Charles A B
authors.initials: CA
authors.lastname: Boucher
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016415:Sequence Alignment; D014779:Virus Replication; D028761:Withholding Treatment
chemical_list: D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D016333:HIV Protease