title: The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation.
abstract: Raltegravir (MK-0518) is the first integrase (IN) inhibitor to be approved by the US FDA and is currently used in clinical treatment of viruses resistant to other antiretroviral compounds. Virological failure of Raltegravir treatment is associated with mutations in the IN gene following two main distinct genetic pathways involving either the N155 or Q148 residue. Importantly, in most cases, an additional mutation at the position G140 is associated with the Q148 pathway. Here, we investigated the viral DNA kinetics for mutants identified in Raltegravir-resistant patients. We found that (i) integration is impaired for Q148H when compared with the wild-type, G140S and G140S/Q148H mutants; and (ii) the N155H and G140S mutations confer lower levels of resistance than the Q148H mutation. We also characterized the corresponding recombinant INs properties. Enzymatic performances closely parallel ex vivo studies. The Q148H mutation 'freezes' IN into a catalytically inactive state. By contrast, the conformational transition converting the inactive form into an active form is rescued by the G140S/Q148H double mutation. In conclusion, the Q148H mutation is responsible for resistance to Raltegravir whereas the G140S mutation increases viral fitness in the G140S/Q148H context. Altogether, these results account for the predominance of G140S/Q148H mutants in clinical trials using Raltegravir.
authors.affiliation: LBPA, CNRS, Ecole Normale Supérieure de Cachan, 94235 Cachan, France. delelis@lbpa.ens-cachan.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Delelis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Malet
authors.forename: Li
authors.initials: L
authors.lastname: Na
authors.forename: Luba
authors.initials: L
authors.lastname: Tchertanov
authors.forename: Vincent
authors.initials: V
authors.lastname: Calvez
authors.forename: Anne-Genevieve
authors.initials: AG
authors.lastname: Marcelin
authors.forename: Frederic
authors.initials: F
authors.lastname: Subra
authors.forename: Eric
authors.initials: E
authors.lastname: Deprez
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mouscadet
mesh_terms: D019943:Amino Acid Substitution; D002384:Catalysis; D002460:Cell Line; D004279:DNA, Viral / Q000096:biosynthesis; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D019427:HIV Integrase / Q000235:genetics* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D017354:Point Mutation; D011760:Pyrrolidinones / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1