title: The HIV-1 integrase G118R mutation confers raltegravir resistance to the CRF02_AG HIV-1 subtype.
abstract: BACKGROUND
  Most of the previous studies that explored the molecular basis of raltegravir resistance were conducted studying the HIV-1 B subtype. It has been shown that the CRF02_AG subtype in relation to its natural integrase (IN) sequence could develop different genetic pathways associated with raltegravir resistance. The aim of this study was to explore resistance pathways preferably used by CRF02_AG viruses compared with subtype B.
  
  
  METHODS
  Twenty-five HIV-1 CRF02_AG-infected patients failing a raltegravir-containing regimen were studied. IN gene sequences were examined for the presence of previously described IN inhibitor (raltegravir, elvitegravir, dolutegravir and MK-2048) resistance mutations at 20 amino acid positions.
  
  
  RESULTS
  Among the 25 studied patients, 7 showed viruses harbouring major raltegravir resistance mutations mainly associated with the 155 genetic pathways and 18 showed viruses harbouring none of them; however, for 1 patient, we found a 118R mutation, associated with MK-2048 in vitro resistance, in a 74M background. For this patient, the phenotypic analysis showed that addition of only the G118R mutation conferred a high level of resistance to raltegravir (fold change = 25.5) and elvitegravir (fold change = 9.2).
  
  
  CONCLUSIONS
  This study confirmed that mutation pathways for raltegravir resistance could be different between the two subtypes CRF02_AG and B with a preferential use of the 155 mutation in non-B subtypes. A new genetic pathway associated with raltegravir resistance, including the 118R mutation, has also been identified. This new genetic pathway, never described in subtype B, should be further evaluated for phenotypic susceptibility to dolutegravir and MK-2048.
authors.affiliation: Laboratoire de Virologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UPMC Université Paris 06, INSERM U943, Paris, France. isabelle.malet@psl.aphp.fr
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.forename: Slim
authors.initials: S
authors.lastname: Fourati
authors.forename: Charlotte
authors.initials: C
authors.lastname: Charpentier
authors.forename: Laurence
authors.initials: L
authors.lastname: Morand-Joubert
authors.forename: Daniele
authors.initials: D
authors.lastname: Armenia
authors.forename: Marc
authors.initials: M
authors.lastname: Wirden
authors.forename: Sophie
authors.initials: S
authors.lastname: Sayon
authors.forename: Margriet
authors.initials: M
authors.lastname: Van Houtte
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Françoise
authors.initials: F
authors.lastname: Brun-Vézinet
authors.forename: Carlo-Federico
authors.initials: CF
authors.lastname: Perno
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
authors.forename: André
authors.initials: A
authors.lastname: Capt
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.forename: Anne-Geneviève
authors.initials: AG
authors.lastname: Marcelin
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D019427:HIV Integrase / Q000235:genetics*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D020125:Mutation, Missense; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D000068898:Raltegravir Potassium; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
chemical_list: D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1