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Journal of Virology, November 2008, p. 10366-10374, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00470-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Olivia Goethals,1 Reginald Clayton,1* Marcia Van Ginderen,1 Inge Vereycken,1 Elisabeth Wagemans,1 Peggy Geluykens,1 Koen Dockx,1 Rudy Strijbos,1 Veerle Smits,1 Ann Vos,1 Geert Meersseman,1 Dirk Jochmans,1 Kurt Vermeire,2 Dominique Schols,2 Sabine Hallenberger,1 and Kurt Hertogs1

Tibotec BVBA, Mechelen, Belgium,1 Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium2

Received 4 March 2008/ Accepted 19 July 2008

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.

* Corresponding author. Mailing address: Tibotec BVBA, Gen De Wittelaan L 11B 3, 2800 Mechelen, Belgium. Phone: 32 15 461443. Fax: 32 15 286346. E-mail: rclayton{at}its.jnj.com

{triangledown} Published ahead of print on 20 August 2008.

Journal of Virology, November 2008, p. 10366-10374, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00470-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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