title: The HIV-1 protease resistance mutation I50L is associated with resistance to atazanavir and susceptibility to other protease inhibitors in multiple mutational contexts.
abstract: BACKGROUND
  The HIV-1 protease mutation I50 L causes atazanavir resistance but increases susceptibility to other PIs. Predicted phenotypic FC values were obtained from viral genotypes, using the virtual Phenotype-LM bioinformatics tool (powering vircoTYPE).
  
  
  OBJECTIVE
  To evaluate I50 L's effect on susceptibility to 8 PIs, in a large genotype database.
  
  
  METHODS
  I50 L containing routine clinical isolate samples in Virco's genotype database were paired with samples having like patterns (or profiles) of IAS-USA-defined primary PI mutations, but lacking I50 L. Using vircoTYPE (version 4.1), the median predicted FC for each mutational profile was determined. I50 L-associated shifts in FC were evaluated using drug-specific CCOs.
  
  
  RESULTS
  We selected 307 and 37098 samples with and without I50 L. These corresponded to 31 mutation patterns of > or =3 samples each. I50 L caused resistance to atazanavir in all 31 mutation contexts, but was associated with higher susceptibility for other PIs. The largest I50 L-associated shifts in median predicted FC were: 1.2 to 42.4 (atazanavir), 10.2 to 3.2 (amprenavir), 3.3 to 0.5 (darunavir), 13 to 0.5 (indinavir), 34.9 to 1.3 (lopinavir), 22.3 to 1.3 (nelfinavir), 5.2 to 0.3 (saquinavir) and 29.9 to 5.2 (tipranavir).
  
  
  CONCLUSIONS
  The PI mutation I50 L causes clinically relevant resistance and increased susceptibility to atazanavir and other PIs respectively.
authors.affiliation: VircoLab Inc., Durham, NC 27713, USA. psista@vrcus.jnj.com
authors.forename: P
authors.initials: P
authors.lastname: Sista
authors.forename: B
authors.initials: B
authors.lastname: Wasikowski
authors.forename: P
authors.initials: P
authors.lastname: Lecocq
authors.forename: T
authors.initials: T
authors.lastname: Pattery
authors.forename: L
authors.initials: L
authors.lastname: Bacheler
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000069446:Atazanavir Sulfate; D030561:Databases, Nucleic Acid; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D009842:Oligopeptides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012984:Software
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1