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Antimicrobial Agents and Chemotherapy, Sep 1996, 1983-1987, Vol 40, No. 9
Copyright © 1996 by the American Society for Microbiology. All rights reserved.

Mutants of feline immunodeficiency virus resistant to 2',3'-dideoxy- 2',3'-didehydrothymidine

YQ Zhu, KM Remington and TW North
Division of Biological Sciences, University of Montana, Missoula 59812, USA.

We selected mutants of feline immunodeficiency virus (FIV) that are resistant to 2',3'-dideoxy-2',3'-didehydrothymidine (d4T). Two mutants were selected in cultured cells with a stepwise increase in d4T concentration, resulting in mutants able to replicate in 100 microM d4T. These mutants were three- to sixfold more resistant to d4T than wild-type FIV. They were also cross-resistant to 3'-azido-3'- deoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine, 2',3'- dideoxycytidine, 2',3'-dideoxyinosine, and 9-(2- phosphonylmethoxyethyl)adenine, and they were highly resistant to phosphonoformic acid (PFA). Plaque-purified mutants were isolated from each of the mutant populations. The mutant phenotype was stable, because both of the plaque-purified mutants remained d4T resistant even after three passages in the absence of d4T. One of the plaque-purified mutants, designated D4R-3c, was further characterized. Compared with wild-type reverse transcriptase (RT), RT purified from D4R-3c was 3- fold resistant to inhibition by the 5'-triphosphate of d4T, 10-fold resistant to inhibition by the 5'-triphosphate of AZT, and 6-fold resistant to PFA. D4R-3c had a single point mutation in the RT-encoding region of the pol gene at position 2474, resulting in a Val to Ile mutation at codon 47 of the FIV RT. The role of this mutation in d4T resistance was confirmed by site-directed mutagenesis.

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