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Journal of Virology, November 2009, p. 11027-11042, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00628-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Protease-Correlated Cleavage Site Mutations Enhance Inhibitor Resistance ^,

Madhavi Kolli,^1, Eric Stawiski,^2, Colombe Chappey,^2, and Celia A. Schiffer^1*

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605,¹ Monogram Biosciences Inc., South San Francisco, California 94080²

Received 26 March 2009/ Accepted 5 August 2009

Drug resistance is an important cause of antiretroviral therapy failure in human immunodeficiency virus (HIV)-infected patients. Mutations in the protease render the virus resistant to protease inhibitors (PIs). Gag cleavage sites also mutate, sometimes correlating with resistance mutations in the protease, but their contribution to resistance has not been systematically analyzed. The present study examines mutations in Gag cleavage sites that associate with protease mutations and the impact of these associations on drug susceptibilities. Significant associations were observed between mutations in the nucleocapsid-p1 (NC-p1) and p1-p6 cleavage sites and various PI resistance-associated mutations in the protease. Several patterns were frequently observed, including mutations in the NC-p1 cleavage site in combination with I50L, V82A, and I84V within the protease and mutations within the p1-p6 cleavage site in combination with D30N, I50V, and I84V within the protease. For most patterns, viruses with mutations both in the protease and in either cleavage site were significantly less susceptible to specific PIs than viruses with mutations in the protease alone. Altered PI resistance in HIV-1 was found to be associated with the presence of Gag cleavage site mutations. These studies suggest that associated cleavage site mutations may contribute to PI susceptibility in highly specific ways depending on the particular combinations of mutations and inhibitors. Thus, cleavage site mutations should be considered when assessing the level of PI resistance.

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* Corresponding author. Mailing address: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Phone: (508) 856-8008. Fax: (508) 856-6464. E-mail: celia.schiffer{at}umassmed.edu

Published ahead of print on 12 August 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

These authors contributed equally to the manuscript and share first authorship.

Present address: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080.

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Journal of Virology, November 2009, p. 11027-11042, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00628-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.