title: Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors.
abstract: We used genotypic and phylogenetic analysis to determine integrase diversity among subtypes, and studied natural polymorphisms and mutations implicated in resistance to integrase inhibitors (INI) in treatment-naïve persons (n = 220) and -experienced individuals (n = 24). Phylogenetics revealed 7 and 10% inter-subtype diversity in the integrase and reverse transcriptase (RT)/protease regions, respectively. Integrase sequencing identified a novel A/B recombinant in which all viruses in a male-sex-male (MSM) transmission cluster (n = 12) appeared to possess subtype B in integrase and subtype A in the remainder of the pol region. Natural variations and signature polymorphisms were observed at codon positions 140, 148, 151, 157, and 160 among HIV subtypes. These variations predicted higher genetic barriers to G140S and G140C in subtypes C, CRF02_AG, and A/CRF01_AE, as well as higher genetic barriers toward acquisition of V151I in subtypes CRF02_AG and A/CRF01_AE. The E157Q and E160Q mutational motif was observed in 35% of INI-naïve patients harboring subtype C infections, indicating intra-subtype variations. Thirteen patients failed raltegravir (RAL)-containing regimens within 8 ± 1 months, in association with the major Q148K/R/H and G140A/S (n = 8/24) or N155H (n = 5/24) mutational pathways. Of note, the remaining patients on RAL regimens for 14 ± 3 months harbored no or only minor integrase mutations/polymorphisms (T66I, T97A, H114P, S119P, A124S, G163R, I203M, R263K). These results demonstrate the importance of understanding subtype variability in the development of resistance to INIs.
authors.affiliation: McGill AIDS Centre, Lady Davis Research Institute, Jewish General Hospital, Montreal, Canada.
authors.forename: Bluma G
authors.initials: BG
authors.lastname: Brenner
authors.forename: Matthew
authors.initials: M
authors.lastname: Lowe
authors.forename: Daniela
authors.initials: D
authors.lastname: Moisi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hardy
authors.forename: Simon
authors.initials: S
authors.lastname: Gagnon
authors.forename: Hugues
authors.initials: H
authors.lastname: Charest
authors.forename: Jean Guy
authors.initials: JG
authors.lastname: Baril
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.forename: Michel
authors.initials: M
authors.lastname: Roger
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D016000:Cluster Analysis; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D019428:HIV Integrase Inhibitors; D054302:pol Gene Products, Human Immunodeficiency Virus; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1