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Antimicrob. Agents Chemother. doi:10.1128/AAC.00271-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mechanisms of Human Immunodeficiency Virus Type-1 Concerted Integration as related to Strand Transfer Inhibition and Drug Resistance

Institute for Molecular Virology, Saint Louis University Health Sciences Center, St. Louis, MO; and Department of Antiviral Research, Merck Research Laboratories, West Point, PA

^* To whom correspondence should be addressed. Email: Grandgdp{at}slu.edu.

	Abstract

The "strand transfer inhibitors" of human immunodeficiency virus type-1 (HIV-1) integrase (IN), so named because of their pronounced selectivity towards inhibiting strand transfer over 3'-OH processing, block virus replication in vivo and ex vivo and prevent concerted integration in vitro. We explored the kinetics of product formation and strand transfer inhibition within reconstituted synaptic complexes capable of concerted integration. Synaptic complexes were formed with viral DNA donors containing either two blunt ends, two 3' OH processed ends, or one of each. We determined that one blunt end within a synaptic complex is a sufficient condition for low nanomolar-range strand transfer inhibition with naphthyridine carboxamide inhibitors, L-870,810 and L-870,812. We further explored the catalytic properties and drug resistance profiles of a set of clinically relevant strand transfer inhibitor-resistant HIV-1 IN mutants. The diketo acids and naphthyridine carboxamides, mechanistically similar but structurally distinct strand transfer inhibitors, each selects for a distinct set of drug-resistance mutations ex vivo. The resistance IN mutants S153Y and N155S were selected with diketo acid L-841,411 and N155H was selected with L-810,812. Each mutant exhibited some degree of catalytic impairment as compared to wild type IN, although N155H displayed near wild type IN activities. The resistance profiles indicated that S153Y potentiates susceptibility to L-870,810 and L-870,812, while the N155S mutation confers resistance to L-870,810 and L-870,812. The N155H mutation confers resistance to L-870,810 and potentiates susceptibility to L-841,411. This study illuminates the interrelated mechanisms of concerted integration, strand transfer inhibition and resistance to strand transfer inhibitors.