title: Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors.
abstract: Integration of viral DNA into the host chromosome is an essential step in the life cycle of retroviruses and is facilitated by the viral integrase enzyme. The first generation of integrase inhibitors recently approved or currently in late-stage clinical trials shows great promise for the treatment of human immunodeficiency virus (HIV) infection, but virus is expected to develop resistance to these drugs. Therefore, we used a novel resistance selection protocol to follow the emergence of resistant HIV in the presence of the integrase inhibitor elvitegravir (GS-9137). We find the primary resistance-conferring mutations to be Q148R, E92Q, and T66I and demonstrate that they confer a reduction in susceptibility not only to elvitegravir but also to raltegravir (MK-0518) and other integrase inhibitors. The locations of the mutations are highlighted in the catalytic sites of integrase, and we correlate the mutations with expected drug-protein contacts. In addition, mutations that do not confer reduced susceptibility when present alone (H114Y, L74M, R20K, A128T, E138K, and S230R) are also discussed in relation to their position in the catalytic core domain and their proximity to known structural features of integrase. These data broaden the understanding of antiviral resistance against integrase inhibitors and may give insight facilitating the discovery of second-generation compounds.
authors: Tibotec BVBA, Mechelen, Belgium. rclayton@its.jnj.com
authors: Olivia
authors: O
authors: Goethals
authors: Reginald
authors: R
authors: Clayton
authors: Marcia
authors: M
authors: Van Ginderen
authors: Inge
authors: I
authors: Vereycken
authors: Elisabeth
authors: E
authors: Wagemans
authors: Peggy
authors: P
authors: Geluykens
authors: Koen
authors: K
authors: Dockx
authors: Rudy
authors: R
authors: Strijbos
authors: Veerle
authors: V
authors: Smits
authors: Ann
authors: A
authors: Vos
authors: Geert
authors: G
authors: Meersseman
authors: Dirk
authors: D
authors: Jochmans
authors: Kurt
authors: K
authors: Vermeire
authors: Dominique
authors: D
authors: Schols
authors: Sabine
authors: S
authors: Hallenberger
authors: Kurt
authors: K
authors: Hertogs
mesh_terms: D020134:Catalytic Domain; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D019429:Integrase Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D020125:Mutation, Missense; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D019429:Integrase Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1