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Antimicrobial Agents and Chemotherapy, March 2005, p. 1139-1144, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1139-1144.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Urvi M. Parikh,1 Dianna L. Koontz,1 Chung K. Chu,2 Raymond F. Schinazi,3 and John W. Mellors1*

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-165R) 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-165R 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-165R to determine how NRTI structure affects activity. Drug susceptibilities of recombinant wild-type (HIV-165K) or mutant HIV-165R 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-165R than against HIV-165K except for analogs containing a 3'-azido moiety. Pseudosugar structure and base component but not enantiomer influenced NRTI activity against HIV-165R. These findings support the inclusion of 3'-azido-3'-deoxythymidine in drug combinations to treat patients having HIV-165R and to prevent its emergence.

* Corresponding author. Mailing address: University of Pittsburgh School of Medicine, Scaife Hall, Suite 818, 3550 Terrace St., Pittsburgh, PA 15261. Phone: (412) 624-8512. Fax: (412) 383-7982. E-mail: mellors{at}msx.dept-med.pitt.edu.

Antimicrobial Agents and Chemotherapy, March 2005, p. 1139-1144, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.1139-1144.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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