This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hombrouck, A.
Right arrow Articles by Witvrouw, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hombrouck, A.
Right arrow Articles by Witvrouw, M.

 Previous Article  |  Next Article 

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{triangledown}

Anneleen Hombrouck,1,3 Arnout Voet,2 Barbara Van Remoortel,1,3 Christel Desadeleer,1,3 Marc De Maeyer,2 Zeger Debyser,1,3* and Myriam Witvrouw1,3*

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(IIIB) in cell culture in the presence of increasing concentrations of L-870,810 (IIIB/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, IIIB/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 IIIB/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.

* Corresponding author. Mailing address for Myriam Witvrouw: Molecular Medicine, Kapucijnenvoer 33, 3000 Leuven, Belgium. Phone: 32-16-33.21.70. Fax: 32-16-33-63-36. E-mail: myriam.witvrouw{at}med.kuleuven.be. Mailing address for Zeger Debyser: Molecular Medicine, Kapucijnenvoer 33, 3000 Leuven, Belgium. Phone: 32-16-33.21.83. Fax: 32-16-33-63-36. E-mail: zeger.debyser{at}med.kuleuven.be

{triangledown} Published ahead of print on 31 March 2008.

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.



This article has been cited by other articles:

  • Low, A., Prada, N., Topper, M., Vaida, F., Castor, D., Mohri, H., Hazuda, D., Muesing, M., Markowitz, M. (2009). Natural Polymorphisms of Human Immunodeficiency Virus Type 1 Integrase and Inherent Susceptibilities to a Panel of Integrase Inhibitors. Antimicrob. Agents Chemother. 53: 4275-4282 [Abstract] [Full Text]  
  • Jones, G. S., Yu, F., Zeynalzadegan, A., Hesselgesser, J., Chen, X., Chen, J., Jin, H., Kim, C. U., Wright, M., Geleziunas, R., Tsiang, M. (2009). Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase. Antimicrob. Agents Chemother. 53: 1194-1203 [Abstract] [Full Text]  
  • Valkov, E., Gupta, S. S., Hare, S., Helander, A., Roversi, P., McClure, M., Cherepanov, P. (2009). Functional and structural characterization of the integrase from the prototype foamy virus. Nucleic Acids Res 37: 243-255 [Abstract] [Full Text]  
  • Hombrouck, A., Van Remoortel, B., Michiels, M., Noppe, W., Christ, F., Eneroth, A., Sahlberg, B. L., Benkestock, K., Vrang, L., Johansson, N. G., Barreca, M. L., De Luca, L., Ferro, S., Chimirri, A., Debyser, Z., Witvrouw, M. (2008). Preclinical Evaluation of 1H-Benzylindole Derivatives as Novel Human Immunodeficiency Virus Integrase Strand Transfer Inhibitors. Antimicrob. Agents Chemother. 52: 2861-2869 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»