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Journal of Virology, April 2009, p. 3826-3833, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01968-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutation I132M Confers Hypersensitivity to Nucleoside Analogs{triangledown}

Zandrea Ambrose,1* Brian D. Herman,1 Chih-Wei Sheen,1 Shannon Zelina,1 Katie L. Moore,4 Gilda Tachedjian,4,5 Dwight V. Nissley,2,3 and Nicolas Sluis-Cremer1

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,1 Basic Science Program, SAIC-Frederick, Frederick, Maryland 21702,2 Gene Regulation & Chromosome Biology Laboratory, NCI-Frederick, Frederick, Maryland 21702,3 Molecular Interactions Group, Centre for Virology, Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria 3004, Australia,4 Department of Microbiology, Monash University, Clayton, Victoria 3168, Australia5

Received 18 September 2008/ Accepted 25 January 2009

We previously identified a rare mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confers high-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In this study, we have further characterized the role of this mutation in viral replication capacity and in resistance to other RT inhibitors. Surprisingly, our data show that I132M confers marked hypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus and enzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RT was responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that this hypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate but increasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containing I132M is severely impaired. This decrease in viral replication capacity could be partially or completely compensated for by the A62V or L214I mutation, respectively. Taken together, these results help to explain the infrequent selection of I132M in patients for whom NNRTI regimens are failing and furthermore demonstrate that a single mutation outside of the polymerase active site and inside of the p51 subunit of RT can significantly influence nucleotide selectivity.

* Corresponding author. Mailing address: Division of Infectious Diseases, University of Pittsburgh School of Medicine, 817B Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Phone: (412) 624-0512. Fax: (412) 648-8521. E-mail: ambrosez{at}dom.pitt.edu

{triangledown} Published ahead of print on 4 February 2009.

Journal of Virology, April 2009, p. 3826-3833, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01968-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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