This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Parikh, U. M. Articles by Mellors, J. W. Search for Related Content PubMed PubMed Citation Articles by Parikh, U. M. Articles by Mellors, J. W.

In Vitro Activity of Structurally Diverse Nucleoside Analogs against Human Immunodeficiency Virus Type 1 with the K65R Mutation in Reverse Transcriptase

Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,¹ College of Pharmacy, University of Georgia, Athens,² Laboratory of Biochemical Pharmacology, Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine/Veterans Administration Medical Center, Decatur, Georgia³

Received 29 July 2004/ Returned for modification 13 September 2004/ Accepted 31 October 2004

Human immunodeficiency virus type 1 (HIV-1) with a lysine-to-arginine substitution at codon 65 (HIV-1_65R) of reverse transcriptase (RT) can rapidly emerge in patients being treated with specific combinations of nucleoside analog RT inhibitors (NRTIs). A better understanding of the activity of approved and investigational NRTIs against HIV-1_65R is needed to select optimal therapy for patients infected with this mutant and to devise strategies to prevent its emergence. Therefore, we tested a broad panel of NRTIs that differed by enantiomer, pseudosugar, and base component against HIV-1_65R to determine how NRTI structure affects activity. Drug susceptibilities of recombinant wild-type (HIV-1_65K) or mutant HIV-1_65R were determined using a single-replication-cycle susceptibility assay with P4/R5 cells and/or a multiple-replication-cycle susceptibility assay with MT-2 cells. All D, L, and acyclic NRTIs were significantly less active against HIV-1_65R than against HIV-1_65K except for analogs containing a 3'-azido moiety. Pseudosugar structure and base component but not enantiomer influenced NRTI activity against HIV-1_65R. These findings support the inclusion of 3'-azido-3'-deoxythymidine in drug combinations to treat patients having HIV-1_65R and to prevent its emergence.

This article has been cited by other articles:

• Brehm, J. H., Koontz, D., Meteer, J. D., Pathak, V., Sluis-Cremer, N., Mellors, J. W. (2007). Selection of Mutations in the Connection and RNase H Domains of Human Immunodeficiency Virus Type 1 Reverse Transcriptase That Increase Resistance to 3'-Azido-3'-Dideoxythymidine. J. Virol. 81: 7852-7859 [Abstract] [Full Text]  
• Lennerstrand, J., Chu, C. K., Schinazi, R. F. (2007). Biochemical Studies on the Mechanism of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistance to 1-({beta}-D-Dioxolane)Thymine Triphosphate. Antimicrob. Agents Chemother. 51: 2078-2084 [Abstract] [Full Text]  
• Rhee, S.-Y., Taylor, J., Wadhera, G., Ben-Hur, A., Brutlag, D. L., Shafer, R. W. (2006). Genotypic predictors of human immunodeficiency virus type 1 drug resistance. Proc. Natl. Acad. Sci. USA 103: 17355-17360 [Abstract] [Full Text]  
• Parikh, U. M., Bacheler, L., Koontz, D., Mellors, J. W. (2006). The K65R Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Exhibits Bidirectional Phenotypic Antagonism with Thymidine Analog Mutations.. J. Virol. 80: 4971-4977 [Abstract] [Full Text]  
• Hammond, J. L., Parikh, U. M., Koontz, D. L., Schlueter-Wirtz, S., Chu, C. K., Bazmi, H. Z., Schinazi, R. F., Mellors, J. W. (2005). In Vitro Selection and Analysis of Human Immunodeficiency Virus Type 1 Resistant to Derivatives of {beta}-2',3'-Didehydro-2',3'-Dideoxy-5-Fluorocytidine. Antimicrob. Agents Chemother. 49: 3930-3932 [Abstract] [Full Text]