Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors
Goethals, Olivia × Clayton, Reginald Van Ginderen, Marcia Vereycken, Inge Wagemans, Elisabeth Geluykens, Peggy Dockx, Koen Strijbos, Rudy Smits, Veerle Vos, Ann Meersseman, Geert Jochmans, Dirk Vermeire, Kurt Schols, Dominique Hallenberger, Sabine Hertogs, Kurt #
American Society for Microbiology (ASM)
Journal of Virology vol:82 issue:21 pages:10366-10374
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, show great promise for the treatment of 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 Q148R, E92Q and T66I, and demonstrate that they not only confer a reduction in susceptibility to elvitegravir, but also to raltegravir (MK-0518) and other integrase inhibitors. The location of the mutations is highlighted in the catalytic site of integrase and we correlate them with expected drug-protein contacts. In addition, mutations which 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.