title: Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor.
abstract: Raltegravir is the first integrase strand-transfer inhibitor (INSTI) approved for use in highly active antiretroviral therapy (HAART) for the management of HIV infection. Resistance to antiretrovirals can compromise the efficacy of HAART regimens. Therefore it is important to understand the emergence of resistance to RAL and cross-resistance to other INSTIs including potential second-generation INSTIs such as MK-2048. We have now studied the question of whether in vitro resistance selection (IVRS) with RAL initiated with viruses derived from clinical isolates would result in selection of resistance mutations consistent with those arising during treatment regimens with HAART containing RAL. Some correlation was observed between the primary mutations selected in vitro and during therapy, initiated with viruses with identical IN sequences. Additionally, phenotypic cross-resistance conferred by specific mutations to RAL and MK-2048 was quantified. N155H, a RAL-associated primary resistance mutation, was selected after IVRS with MK-2048, suggesting similar mechanisms of resistance to RAL and MK-2048. This was confirmed by phenotypic analysis of 766 clonal viruses harboring IN sequences isolated at the point of virological failure from 106 patients on HAART (including RAL), where mutation Q148H/K/R together with additional secondary mutations conferred reduced susceptibility to both RAL and MK-2048. A homology model of full length HIV-1 integrase complexed with viral DNA and RAL or MK-2048, based on an X-ray structure of the prototype foamy virus integrase-DNA complex, was used to explain resistance to RAL and cross-resistance to MK-2048. These findings will be important for the further discovery and profiling of next-generation INSTIs.
authors.affiliation: Tibotec Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Olivia
authors.initials: O
authors.lastname: Goethals
authors.forename: Marcia
authors.initials: M
authors.lastname: Van Ginderen
authors.forename: Ann
authors.initials: A
authors.lastname: Vos
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Koen
authors.initials: K
authors.lastname: Van Der Borght
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Van Wesenbeeck
authors.forename: Maxim
authors.initials: M
authors.lastname: Feyaerts
authors.forename: Ann
authors.initials: A
authors.lastname: Verheyen
authors.forename: Veerle
authors.initials: V
authors.lastname: Smits
authors.forename: Marnix
authors.initials: M
authors.lastname: Van Loock
authors.forename: Kurt
authors.initials: K
authors.lastname: Hertogs
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Clayton
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D002460:Cell Line; D003062:Codon / Q000235:genetics; D024882:Drug Resistance, Viral; D005838:Genotype; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity; D006801:Humans; D019426:Integrases / Q000235:genetics* / Q000378:metabolism; D008826:Microbial Sensitivity Tests / Q000379:methods; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010641:Phenotype; D010949:Plasma / Q000821:virology; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology; D000068898:Raltegravir Potassium; D014162:Transfection
chemical_list: D003062:Codon; D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D015363:Quinolones; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019426:Integrases