Resistance Mutations in Human Immunodeficiency Virus Type 1 Integrase Selected with Elvitegravir Confer Reduced Susceptibility to a Wide Range of Integrase Inhibitors

被引：143

作者：

Goethals, Olivia ^{[1
]}

Clayton, Reginald ^{[1
]}

Van Ginderen, Marcia ^{[1
]}

Vereycken, Inge ^{[1
]}

Wagemans, Elisabeth ^{[1
]}

Geluykens, Peggy ^{[1
]}

Dockx, Koen ^{[1
]}

Strijbos, Rudy ^{[1
]}

Smits, Veerle ^{[1
]}

Vos, Ann ^{[1
]}

Meersseman, Geert ^{[1
]}

Jochmans, Dirk ^{[1
]}

Vermeire, Kurt ^{[2
]}

Schols, Dominique ^{[2
]}

Hallenberger, Sabine ^{[1
]}

Hertogs, Kurt ^{[1
]}

机构：

[1] Tibotec BVBA, B-2800 Mechelen, Belgium

[2] Katholieke Univ Leuven, Rega Inst Med Res, Louvain, Belgium

来源：

JOURNAL OF VIROLOGY | 2008年 / 82卷 / 21期

关键词：

D O I：

10.1128/JVI.00470-08

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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.

引用

页码：10366 / 10374

页数：9

共 36 条

[1] Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection [J].