title: Role of Gag mutations in PI resistance in the Swiss HIV cohort study: bystanders or contributors?
abstract: HIV Gag mutations have been reported to confer PI drug resistance. However, clinical implications are still controversial and most current genotyping algorithms consider solely the protease gene for assessing PI resistance.
  
  
  
  Our goal was to describe for HIV infections in Switzerland the potential role of the C-terminus of Gag (NC-p6) in PI resistance. We aimed to characterize resistance-relevant mutational patterns in Gag and protease and their possible interactions.
  
  
  
  Resistance information on plasma samples from 2004-12 was collected for patients treated by two diagnostic centres of the Swiss HIV Cohort Study. Sequence information on protease and the C-terminal Gag region was paired with the corresponding patient treatment history. The prevalence of Gag and protease mutations was analysed for PI treatment-experienced patients versus PI treatment-naive patients. In addition, we modelled multiple paths of an assumed ordered accumulation of genetic changes using random tree mixture models.
  
  
  
  More than half of all PI treatment-experienced patients in our sample set carried HIV variants with at least one of the known Gag mutations, and 17.9% (66/369) carried at least one Gag mutation for which a phenotypic proof of PI resistance by in vitro mutagenesis has been reported. We were able to identify several novel Gag mutations that are associated with PI exposure and therapy failure.
  
  
  
  Our analysis confirmed the association of Gag mutations, well known and new, with PI exposure. This could have clinical implications, since the level of potential PI drug resistance might be underestimated.
authors.affiliation: Molecular Virology, Department of Biomedicine - Petersplatz, University of Basel, Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Kletenkov
authors.affiliation: Bioinformatics and Computational Biophysics, Centre for Medical Biotechnology, University of Duisburg-Essen, Duisburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hoffmann
authors.affiliation: Institute of Medical Virology, National Reference Center for Retroviruses, University of Zurich, Zurich, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Böni
authors.affiliation: Laboratory of Virology, University Hospital Geneva, University of Geneva, Geneva, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Yerly
authors.affiliation: Division of Immunology and Allergy, University Hospital Lausanne, University of Lausanne, Lausanne, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Aubert
authors.affiliation: Swiss HIV Cohort Study, Data Centre, Institute for Social and Preventive Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Schöni-Affolter
authors.affiliation: Department of Population Health, Luxembourg Institute of Health, Luxembourg.
authors.forename: D
authors.initials: D
authors.lastname: Struck
authors.affiliation: Institute of Virology, University Hospital Essen, University Duisburg-Essen, Duisburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Verheyen
authors.affiliation: Molecular Virology, Department of Biomedicine - Petersplatz, University of Basel, Basel, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Klimkait
mesh_terms: D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics*; D015750:Genes, gag; D005838:Genotype; D015658:HIV Infections / Q000097:blood / 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 / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D015995:Prevalence; D012367:RNA, Viral / Q000097:blood; D017422:Sequence Analysis, DNA; D013557:Switzerland; D017211:Treatment Failure; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease