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Journal of Virology, November 2003, p. 11459-11470, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11459-11470.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase Mutations

Valery Fikkert,1 Bénédicte Van Maele,1 Jo Vercammen,2 Anke Hantson,1 Barbara Van Remoortel,1 Martine Michiels,1 Cristina Gurnari,1,3 Christophe Pannecouque,1 Marc De Maeyer,4 Yves Engelborghs,2 Erik De Clercq,1 Zeger Debyser,1 and Myriam Witvrouw1*

Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven,1 Laboratory for Biomolecular Dynamics,2 Laboratory for Biomolecular Modeling, Katholieke Universiteit Leuven, B-3001 Leuven, Belgium,4 Dipartimento di Chimica Inorganica, Analitica e Struttura Molecolare, Università di Messina, Messina, Italy3

Received 30 January 2003/ Accepted 7 July 2003

The diketo acid L-708,906 has been reported to be a selective inhibitor of the strand transfer step of the human immunodeficiency virus type 1 (HIV-1) integration process (D. Hazuda, P. Felock, M. Witmer, A. Wolfe, K. Stillmock, J. A. Grobler, A. Espeseth, L. Gabryelski, W. Schleif, C. Blau, and M. D. Miller, Science 287:646-650, 2000). We have now studied the development of antiviral resistance to L-708,906 by growing HIV-1 strains in the presence of increasing concentrations of the compound. The mutations T66I, L74M, and S230R emerged successively in the integrase gene. The virus with three mutations (T66I L74M S230R) was 10-fold less susceptible to L-708,906, while displaying the sensitivity of the wild-type virus to inhibitors of the RT or PRO or viral entry process. Chimeric HIV-1 strains containing the mutant integrase genes displayed the same resistance profile as the in vitro-selected strains, corroborating the impact of the reported mutations on the resistance phenotype. Phenotypic cross-resistance to S-1360, a diketo analogue in clinical trials, was observed for all strains. Interestingly, the diketo acid-resistant strain remained fully sensitive to V-165, a novel integrase inhibitor (C. Pannecouque, W. Pluymers, B. Van Maele, V. Tetz, P. Cherepanov, E. De Clercq, M. Witvrouw, and Z. Debyser, Curr. Biol. 12:1169-1177, 2002). Antiviral resistance was also studied at the level of recombinant integrase. Single mutations did not appear to impair specific enzymatic activity. However, 3' processing and strand transfer activities of the recombinant integrases with two (T66I L74M) and three (T66I L74M S230R) mutations were notably lower than those of the wild-type integrase. Although the virus with three mutations was resistant to inhibition by diketo acids, the sensitivity of the corresponding enzyme to L-708,906 or S-1360 was reduced only two- to threefold. As to the replication kinetics of the selected strains, the replication fitness for all strains was lower than that of the wild-type HIV-1 strain.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: 32-16-33.21.70. Fax: 32-16-33.21.31. E-mail: Myriam.Witvrouw{at}uz.kuleuven.ac.be.

Journal of Virology, November 2003, p. 11459-11470, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11459-11470.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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