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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,^1* Richard Lu,^2, Erik De Clercq,¹ and Alan Engelman²

Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium,¹ Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115²

Received 29 November 2006/ Accepted 7 February 2007

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-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 the 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.

Published ahead of print on 7 February 2007.

Present address: Infectious Disease Division, Massachusetts General Hospital, 65 Landsdowne St., Cambridge, MA 02139.