A novel Met-to-Thr mutation in the YMDD motif of reverse transcriptase from feline immunodeficiency virus confers resistance to oxathiolane nucleosides.
Variants of feline immunodeficiency virus (FIV) that possess a unique methionine-to-threonine mutation within the YMDD motif of reverse transcriptase (RT) were selected by culturing virus in the presence of inhibitory concentrations of (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC]. The mutants were resistant to (-)-FTC and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and additionally exhibited low-level resistance to 2',3'-dideoxycytidine (ddC). DNA sequence analysis of the RT-encoding region of the pol gene amplified from resistant viruses consistently identified a Met-to-Thr mutation in the YMDD motif. Purified RT from the mutants was also resistant to the 5'-triphosphate forms of 3TC, (-)-FTC, and ddC. Site-directed mutants of FIV were engineered which contain either the novel Met-to-Thr mutation or the Met-to-Val mutation seen in oxathiolane nucleoside-resistant HIV-1. Both site-directed mutants displayed resistance to 3TC, thus confirming the role of these mutations in the resistance of FIV to beta-L-3'-thianucleosides.
Smith
R A
RA
Division of Biological Sciences, University of Montana, Missoula 59812, USA.
Remington
K M
KM
Lloyd
R M
RM
Schinazi
R F
RF
North
T W
TW
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D002415:Cats; D002460:Cell Line; D004352:Drug Resistance, Microbial / Q000235:genetics*; D000068679:Emtricitabine / Q000031:analogs & derivatives; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects / Q000201:enzymology*; D019259:Lamivudine / Q000494:pharmacology*; D008715:Methionine; D016297:Mutagenesis, Site-Directed; D012194:RNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013912:Threonine; D010948:Viral Plaque Assay; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000998:Antiviral Agents; D019259:Lamivudine; D013912:Threonine; D016047:Zalcitabine; D008715:Methionine; D012194:RNA-Directed DNA Polymerase; D000068679:Emtricitabine; C075889:Racivir