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JVI Accepts, published online ahead of print on 7 February 2007
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J. Virol. doi:10.1128/JVI.02637-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Characterization of a replication-competent, integrase-defective human immunodeficiency virus (HIV)/simian virus 40 chimera as a powerful tool for the discovery and validation of HIV integrase inhibitors

Dirk Daelemans*, Richard Lu, Erik De Clercq, and Alan Engelman

Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA

* To whom correspondence should be addressed. Email: dirk.daelemans{at}rega.kuleuven.be.


  Abstract

Integrase is actively studied as an antiviral target, but many inhibitors selected from biochemical screens fail to inhibit human immunodeficiency virus (HIV) replication or primarily affect off-site targets. Here we develop and validate a replication-competent, simian virus 40 (SV40)-HIV integrase mutant chimera as a novel tool to classify the mechanism of action of potential integrase inhibitors. Whereas the mutant was more susceptible than wild-type to entry, reverse transcriptase, and protease inhibitors, it specifically resisted the action of integrase inhibitor L-870,810. We furthermore demonstrate inhibition of integration by GS-9137 and GS-9160, and off-site targeting by the 6-aminoquinolone antibiotic WM-5.






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