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Antimicrobial Agents and Chemotherapy, June 2008, p. 2069-2078, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.00911-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mutations in Human Immunodeficiency Virus Type 1 Integrase Confer Resistance to the Naphthyridine L-870,810 and Cross-Resistance to the Clinical Trial Drug GS-9137

Division of Molecular Medicine, Katholieke Universiteit Leuven, B-3000 Leuven,¹ IRC Katholieke Universiteit Leuven, Campus Kortrijk, Flanders,³ The Laboratory for Biomolecular Modelling, Katholieke Universiteit Leuven, Flanders, Belgium²

Received 11 July 2007/ Returned for modification 20 August 2007/ Accepted 21 March 2008

To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III_B) in cell culture in the presence of increasing concentrations of L-870,810 (III_B/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III_B/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III_B/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.

Published ahead of print on 31 March 2008.

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