title: Genetic evolution of gp41 reveals a highly exclusive relationship between codons 36, 38 and 43 in gp41 under long-term enfuvirtide-containing salvage regimen.
abstract: OBJECTIVE
  To analyse the genetic changes in the gp41 protein in HIV-infected patients with detectable plasma viraemia receiving a long-term salvage enfuvirtide regimen.
  
  
  METHODS
  We studied 13 heavily antiretroviral-experienced patients receiving a salvage regimen containing enfuvirtide. Substitutions in gp41 were analysed by population-based sequencing at baseline and longitudinally after the initiation of enfuvirtide treatment. To investigate sequence evolution we also analysed multiple gp41 clones from four selected patients. A Fisher's two-tailed test was used to assess the distribution of resistance-associated mutations in the clonal sequences.
  
  
  RESULTS
  Mutations at positions 36 and 38 in gp41 (HR1) emerged rapidly (median emerging time 10 weeks), but disappeared at subsequent timepoints in most of the patients. Amino acid changes did not accumulate over time, with no patient having more than two mutations in HR1 after 6 months of treatment. The mutation N43D was not observed together with changes at positions 36 or 38 in any patient. Clonal analysis showed that the three main gp41 resistance mutations were highly mutually exclusive (P < 0.001), being present in individual clones and constituting independent populations.
  
  
  CONCLUSIONS
  Substitutions at positions 36 and 38 are rapidly selected but disappear thereafter in HIV-1-infected patients failing an enfuvirtide-containing salvage therapy. We found a highly exclusive relationship between the three main enfuvirtide resistance-associated mutations (amino acids 36, 38 and 43), suggesting that the genetic evolution of HIV-1 gp41 protein is a dynamic and much more complex process than previously though.
authors.affiliation: IrsiCaixa Foundation and Lluita contra la SIDA Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. ccabrera@irsicaixa.es
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cabrera
authors.forename: Silvia
authors.initials: S
authors.lastname: Marfil
authors.forename: Elisabet
authors.initials: E
authors.lastname: García
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.forename: Anna
authors.initials: A
authors.lastname: Bonjoch
authors.forename: Margarita
authors.initials: M
authors.lastname: Bofill
authors.forename: Santiago
authors.initials: S
authors.lastname: Moreno
authors.forename: Esteban
authors.initials: E
authors.lastname: Ribera
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Lidia
authors.initials: L
authors.lastname: Ruiz
mesh_terms: D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral / Q000235:genetics; D000077560:Enfuvirtide; D019143:Evolution, Molecular; D005500:Follow-Up Studies; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000627:therapeutic use*; D016879:Salvage Therapy / Q000379:methods; D017211:Treatment Failure; D014766:Viremia / Q000188:drug therapy / Q000821:virology
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide