The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine.
Variants of human immunodeficiency virus type 1 that display 500- to 1,000-fold resistance to the (-) enantiomer of 2'-deoxy-3'-thiacytidine and approximately 4- to 8-fold resistance to 2',3'-dideoxycytidine and 2',3'-dideoxyinosine have been generated through in vitro selection with the former compound. The polymerase regions of several of these resistant viruses shared a codon alteration at site 184 (ATG-->GTG; methionine-->valine), a mutation previously associated with low-level resistance to 2',3'-dideoxycytidine. The biological relevance of this mutation for the (-) enantiomer of 2'-deoxy-3'-thiacytidine was confirmed by site-directed mutagenesis with the HXB2-D clone of human immunodeficiency virus type 1.
Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
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Gao
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Parniak
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Cameron
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Cammack
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Boucher
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Wainberg
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D003001:Cloning, Molecular; D016049:Didanosine / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019259:Lamivudine; D008715:Methionine / Q000235:genetics; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009154:Mutation; D013237:Stereoisomerism; D014633:Valine / Q000235:genetics; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000998:Antiviral Agents; D019259:Lamivudine; D016047:Zalcitabine; D008715:Methionine; D014633:Valine; D016049:Didanosine