Rapid phenotypic reversion of zidovudine-resistant feline immunodeficiency virus without loss of drug-resistant reverse transcriptase.
We have selected and plaque purified zidovudine (3'-azido-3'-deoxythymidine [AZT])-resistant mutants from an infectious molecular clone of feline immunodeficiency virus (FIV). The patterns of cross-resistance and drug susceptibilities of these mutants were similar to those of the AZT-resistant FIV that we previously selected in vitro from a wild-type FIV population and to those of the most common AZT-resistant clinical isolates of human immunodeficiency virus type 1. Two AZT-resistant mutants of FIV, one selected from a normal population and one selected from the molecular clone, each reverted rapidly to an AZT-sensitive phenotype when passaged in the absence of drug. Sequence analysis of the reverse transcriptase (RT)-encoding region from the plaque-purified AZT-resistant FIV revealed a single base change at position 2939, resulting in a Glu-to-Lys substitution at amino acid 202 of the RT. Similar analyses of plaque-purified revertants showed that the phenotypic reversion was not the result of a genotypic reversion at this position and that no additional mutations existed within the RT-encoding region of the revertants. Moreover, RTs purified from the mutant and revertant were both resistant to the 5'-triphosphate of AZT. These results indicate the complexity of AZT resistance and suggest the presence of additional factors, outside the RT-encoding region, which may contribute to AZT resistance.
Remington
K M
KM
Division of Biological Sciences, University of Montana, Missoula 59812.
Zhu
Y Q
YQ
Phillips
T R
TR
North
T W
TW
D000818:Animals; D001483:Base Sequence; D002415:Cats; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D012194:RNA-Directed DNA Polymerase / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D010948:Viral Plaque Assay; D015215:Zidovudine / Q000494:pharmacology*
D015215:Zidovudine; D012194:RNA-Directed DNA Polymerase