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JAC Advance Access originally published online on April 30, 2007
Journal of Antimicrobial Chemotherapy 2007 59(6):1084-1095; doi:10.1093/jac/dkm101
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Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action

A. Hombrouck1,2, A. Hantson1,2, B. van Remoortel1, M. Michiels2, J. Vercammen3, D. Rhodes4, V. Tetz5, Y. Engelborghs3, F. Christ2, Z. Debyser2,6 and M. Witvrouw1,6,*

1 Laboratory for Molecular Virology and Drug Discovery, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium 2 Laboratory for Molecular Virology and Gene Therapy, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium 3 Laboratory for Biomolecular Dynamics, Katholieke Universiteit Leuven, Leuven, Flanders, Belgium 4 Avexa Limited, Richmond, Victoria, Australia 5 Department of Microbiology, Virology and Immunology, Saint-Petersburg Pavlov State Medical University, Saint-Petersburg, Russia 6 Interdisciplinary Research Center, Katholieke Universiteit Leuven Campus Kortrijk, Kortrijk, Flanders, Belgium

Received 2 January 2007; returned 15 January 2007; revised 12 March 2007; accepted 12 March 2007

* Correspondence address. Laboratory for Molecular Virology and Drug Discovery, Katholieke Universiteit Leuven, Kapucijnenvoer 35, B-3000 Leuven, Belgium. Tel: +32-16-33-21-70; Fax: +32-16-33-63-33; E-mail: myriam.witvrouw{at}med.kuleuven.be

Objectives: We have previously identified the pyranodipyrimidines (PDPs) as a new class of integrase (IN) inhibitors. The most potent congener V-165 inhibits HIV-1 integration at low micromolar concentrations by inhibiting the binding of IN to the DNA. As part of pre-clinical studies with PDP, we wanted to investigate HIV resistance development against V-165 and to further characterize the physicochemical properties of the compound.

Methods: We selected PDP-resistant HIV-1 strains by growing the virus in the presence of increasing concentrations of V-165. The selected strains were analysed genotypically and phenotypically. Mutant IN enzymes were generated and evaluated in an enzymatic oligonucleotide-based assay for their activity and sensitivity to the different IN inhibitors. In addition, the antiviral effect of the compound on viral entry and integration was measured using quantitative PCR.

Results: Numerous mutations were detected in the RT, IN and env genes of the virus selected in the presence of V-165. Although V-165 inhibited integration in vivo as indicated by a decrease in the number of integrated proviruses, the compound also inhibited viral entry at a concentration of 19 µM. V-165 was poorly recovered from human hepatic microsomal matrix and 1% BSA.

Conclusions: These data point to a multimodal mechanism of action. A quest for derivatives of V-165 that specifically target IN should be pursued.

Keywords: integrase inhibitors , antiviral resistance , HIV-1


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