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Antimicrobial Agents and Chemotherapy, September 2008, p. 3358-3368, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00271-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mechanisms of Human Immunodeficiency Virus Type 1 Concerted Integration Related to Strand Transfer Inhibition and Drug Resistance{triangledown}

Jacob A. Zahm,1 Sibes Bera,1,{dagger} Krishan K. Pandey,1,{dagger} Ajaykumar Vora,1 Kara Stillmock,2 Daria Hazuda,2 and Duane P. Grandgenett1*

Institute for Molecular Virology, Saint Louis University Health Sciences Center, St. Louis, Missouri,1 Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania2

Received 27 February 2008/ Returned for modification 16 April 2008/ Accepted 25 June 2008

The "strand transfer inhibitors" of human immunodeficiency virus type-1 (HIV-1) integrase (IN), so named because of their pronounced selectivity for 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 select for a distinct set of drug resistance mutations ex vivo. The S153Y and N155S IN resistance mutants were selected with the diketo acid L-841,411, and the N155H mutant was selected with L-810,812. Each mutant exhibited some degree of catalytic impairment relative to the activity of wild type IN, although the N155H mutant displayed near-wild-type IN activities. The resistance profiles indicated that the S153Y mutation 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.

* Corresponding author. Mailing address: Institute for Molecular Virology, Doisy Research Center, 1100 S. Grand Blvd., St. Louis, MO 63104. Phone: (314) 977-8784. Fax: (314) 977-8798. E-mail: Grandgdp{at}slu.edu

{triangledown} Published ahead of print on 30 June 2008.

{dagger} S.B. and K.K.P. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3358-3368, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00271-08
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]  


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