title: A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors.
abstract: OBJECTIVE
  We have shown that HIV-1 clade C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG<--ATG) after selection with efavirenz (EFV). This study evaluates the prevalence of V106 (GTG) and 106M (ATG) codons in clinical isolates as well as the effects of V106M on resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI).
  
  
  METHODS
  Genotypic analysis ascertained sequence diversity at codon 106, including both valine polymorphisms (GTA and GTG) and the V106A (GCA) and V106M (ATG) resistance-conferring mutations in B (n = 440) and non-B (n = 84) clinical isolates. Cell-based phenotypic assays were performed to determine the effects of V106M and V106A on levels of resistance to EFV, nevirapine and delavirdine.
  
  
  RESULTS
  Most subtype B isolates harbored GTA (valine) at codon 106 (97% of cases) while the GTG (valine) polymorphism was generally present in clade C viruses (94% of cases). Under conditions of EFV but not nevirapine or delavirdine pressure (n = 8) in tissue culture, clade C isolates developed the V106M mutation (GTG<--ATG), conferring high-level (100-1000-fold) cross-resistance to all NNRTI. Generation of V106M recombinant viruses by site-directed mutagenesis confirmed the ability of V106M to confer NNRTI cross-resistance. This mutation also developed in three of six EFV-treated patients harboring clade C infections. In current genotypic interpretative reports (including 15 algorithmic databases), V106A is listed as an nevirapine-specific mutation while V106M is not recognized.
  
  
  CONCLUSIONS
  V106M may be a signature mutation in clade C patients treated with EFV and may have the potential to confer high-level multi-NNRTI resistance.
authors.affiliation: McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Bluma
authors.initials: B
authors.lastname: Brenner
authors.forename: Dan
authors.initials: D
authors.lastname: Turner
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.forename: Daniela
authors.initials: D
authors.lastname: Moisi
authors.forename: Mervi
authors.initials: M
authors.lastname: Detorio
authors.forename: Mauricio
authors.initials: M
authors.lastname: Carobene
authors.forename: Richard G
authors.initials: RG
authors.lastname: Marlink
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schapiro
authors.forename: Michel
authors.initials: M
authors.lastname: Roger
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines; D046508:Culture Techniques; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010078:Oxazines / Q000494:pharmacology*; D010641:Phenotype; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz