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Antimicrobial Agents and Chemotherapy, June 2007, p. 2078-2084, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00119-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Biochemical Studies on the Mechanism of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistance to 1-(ß-D-Dioxolane)Thymine Triphosphate

Emory University School of Medicine/Veterans Affairs Medical Center, Atlanta, Georgia 30033,¹ College of Pharmacy, The University of Georgia, Athens, Georgia 30602²

Received 26 January 2007/ Returned for modification 2 March 2007/ Accepted 23 March 2007

A large panel of drug-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase (RT) was used to study the mechanisms of resistance to 1-(ß-D-dioxolane)thymine triphosphate (DOT-TP) and other nucleotide analogs. RT containing thymidine analog-associated mutations (TAM) or RT with a T69S-SG insertion in combination with TAM removed 3'-azido-3'-deoxythymidine-5'-monophosphate or tenofovir more efficiently than DOT-monophosphate from chain-terminated DNA primer/template through ATP-mediated pyrophosphorolysis. For non-ATP-dependent discrimination toward DOT-TP, high levels of resistance were found for RT bearing the Q151M mutation with family mutations, while RT bearing only the M184V or the Y115F mutation conferred no resistance to DOT-TP. A lower degree of resistance to DOT-TP than to tenofovir diphosphate or carbovir-TP was found for RT containing the K65R mutation. In the present studies, 1-(ß-D-dioxolane)guanine triphosphate, another nucleotide with a dioxolane sugar moiety, showed a resistance profile similar to that of DOT-TP. The results suggest that DOT, compared with other approved nucleoside analogs, is overall more resilient to mutations such as TAM, M184V, and K65R, which are commonly found in viruses derived from subjects failing multinucleoside therapy.

Published ahead of print on 2 April 2007.