title: Compensatory mutations at the HIV cleavage sites p7/p1 and p1/p6-gag in therapy-naive and therapy-experienced patients.
abstract: BACKGROUND
  Mutations in the genome of HIV conferring drug resistance are a major reason for the failure of antiretroviral therapy, but they often compromise viral fitness. Protease (PR) cleavage site (CS) mutations could compensate for impaired replication capacity of drug-resistant viruses.
  
  
  METHODS
  We analysed the cleavage sites p1/p7 and p1/p6-gag of 500 HIV-1 subtype B infected patients. The collective consists of 275 therapy-naive and 225 therapy-experienced patients with at least one primary PR mutation, from whom eight underwent therapy-interruption in different clinical settings.
  
  
  RESULTS
  Multiple mutations within the CS p7/p1 and p1/p6-gag accumulated in therapy-experienced isolates (p7/p1: A431V-K436R-I437V and p1/p6-gag: L449F/V-P452S-P453L/A). Further rare CS mutations were totally absent in therapy-naive viruses. Sixty percent of all therapy-experienced viruses exhibited at least one therapy-associated CS mutation, but so did 10% of therapy-naive viruses. The analysis of CS and PR mutations in therapy-experienced viruses revealed several positive correlations--A431V with L24I-M46I/L-I54V-V82A; I437V with I54V-V82F/T/S; L449V with I54M/L/S/T/A; and L449F/R452S/P453L: with D30N-I84V--whereas P453L and V82A were negatively correlated. Mutagenetic trees constructed form this cross-sectional data showed an ordered accumulation of the most prominent CS mutations along two pathways L90M-I84V-P453L and I54-V82-A431V followed by either M46L or L24I. Furthermore, eight viruses with at least one therapy-associated mutation at each CS displayed an outstanding maintenance of major PR mutations during therapy interruption.
  
  
  CONCLUSIONS
  These findings emphasize the relevance of CS mutations in the evolution of HIV resistance to PR inhibitors. Therefore, therapy-associated CS mutations should be considered in HIV resistance tests to estimate viral fitness in different clinical settings.
authors.affiliation: Institute of Virology, University of Cologne, Cologne, Germany. jens.verheyen@uk-koeln.de
authors.forename: Jens
authors.initials: J
authors.lastname: Verheyen
authors.forename: Elena
authors.initials: E
authors.lastname: Litau
authors.forename: Tobias
authors.initials: T
authors.lastname: Sing
authors.forename: Martin
authors.initials: M
authors.lastname: Däumer
authors.forename: Melanie
authors.initials: M
authors.lastname: Balduin
authors.forename: Mark
authors.initials: M
authors.lastname: Oette
authors.forename: Gerd
authors.initials: G
authors.lastname: Fätkenheuer
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Rockstroh
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schuldenzucker
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoffmann
authors.forename: Herbert
authors.initials: H
authors.lastname: Pfister
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D001665:Binding Sites / Q000235:genetics; D036022:Capsid Proteins / Q000235:genetics*; D024882:Drug Resistance, Viral; D015683:Gene Products, gag / Q000235:genetics*; 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 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D013045:Species Specificity; D014764:Viral Proteins / Q000235:genetics*; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D019380:Anti-HIV Agents; D036022:Capsid Proteins; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; C071884:NCP7 protein, Human immunodeficiency virus 1; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C083868:gag protein p1, Human immunodeficiency virus; C083002:p6 gag protein, Human immunodeficiency virus 1; D016333:HIV Protease