title: Genetic barrier to the development of resistance to rilpivirine and etravirine between HIV-1 subtypes CRF02_AG and B.
abstract: OBJECTIVE
  It has been demonstrated for some drugs that the genetic barrier, defined as the number of genetic transitions and/or transversions needed to produce a resistance mutation, can differ between HIV-1 subtypes. We aimed to assess differences in the genetic barrier for the evolution of resistance to the second-generation non-nucleoside reverse transcriptase inhibitors etravirine and rilpivirine in subtypes B and CRF02_AG in antiretroviral-naive patients.
  
  
  METHODS
  An analysis was undertaken of 25 substitutions associated with etravirine and rilpivirine resistance at 12 amino acid positions in 267 nucleotide sequences (136 HIV-1 B and 131 HIV-1 CRF02_AG subtypes) of the reverse transcriptase gene.
  
  
  RESULTS
  The majority (7/12) of amino acid positions studied were conserved between the two HIV-1 subtypes, leading to a similar genetic barrier. Different predominant codons between the subtypes were observed in 5/12 positions (90, 98, 179, 181 and 227), with an effect on the calculated genetic barrier only at the V179D and V179F codons (2.5 versus 3.5 for V179D, and 2.5 versus 5 for V179F, respectively, for subtype B versus subtype CRF02_AG).
  
  
  CONCLUSIONS
  The majority of amino acids involved in etravirine and rilpivirine resistance showed a high degree of conservation of the predominant codon between the B and CRF02_AG subtypes. For rilpivirine, the genetic barrier was the same between the two subtypes. Nevertheless, subtype CRF02_AG showed a higher genetic barrier to acquiring mutations V179D and V179F (mutations associated with resistance to etravirine) compared with subtype B, suggesting that it would be more difficult to produce resistance to etravirine in the CRF02_AG subtype than the B subtype.
authors.affiliation: APHP, Hôpital Pitié-Salpêtrière, Laboratoire de Virologie, UPMC Univ Paris 06, INSERM U 943, F75013 Paris, France.
authors.forename: D B
authors.initials: DB
authors.lastname: Fofana
authors.forename: C
authors.initials: C
authors.lastname: Soulie
authors.forename: A I
authors.initials: AI
authors.lastname: Maiga
authors.forename: S
authors.initials: S
authors.lastname: Fourati
authors.forename: I
authors.initials: I
authors.lastname: Malet
authors.forename: M
authors.initials: M
authors.lastname: Wirden
authors.forename: A
authors.initials: A
authors.lastname: Tounkara
authors.forename: H A
authors.initials: HA
authors.lastname: Traore
authors.forename: V
authors.initials: V
authors.lastname: Calvez
authors.forename: A G
authors.initials: AG
authors.lastname: Marcelin
authors.forename: S
authors.initials: S
authors.lastname: Lambert-Niclot
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D017124:Conserved Sequence; D024882:Drug Resistance, Viral; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense; D009570:Nitriles / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000068696:Rilpivirine
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D000068696:Rilpivirine
keywords: genetic barrier; subtype B; subtype CRF02_AG