Mutagenesis of the Glu-89 residue in human immunodeficiency virus type 1 (HIV-1) and HIV-2 reverse transcriptases: effects on nucleoside analog resistance.
A Glu-89-->Gly alteration in the human immunodeficiency virus type 1 reverse transcriptase (RT) was previously shown to result in resistance to several dideoxynucleoside analogs and to phosphonoformic acid (PFA; foscarnet). This residue was altered to Ala, Val, Ser, Thr, Gln, Asp, Asn, or Lys, and the ddGTP and PFA sensitivities of the mutant RTs were measured. Replacements with Ala, Gly, Val, and Thr led to resistance to inhibition by ddGTP, while mutants with amino acid Ser, Gln, Asn, Asp, or Lys displayed only moderate or no resistance. A similar result was obtained with inhibition by PFA, except that the Asp-89 mutant also displayed resistance. Furthermore, the introduction of Glu-89-->Gly alteration into the RT of human immunodeficiency virus type 2 likewise rendered it resistant to both ddGTP and PFA.
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D003848:Deoxyguanine Nucleotides / Q000494:pharmacology*; D054306:Dideoxynucleotides; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics; D017245:Foscarnet / Q000494:pharmacology*; D005971:Glutamates; D018698:Glutamic Acid; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D018894:Reverse Transcriptase Inhibitors
D000998:Antiviral Agents; D003062:Codon; D003848:Deoxyguanine Nucleotides; D054306:Dideoxynucleotides; D005971:Glutamates; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D017245:Foscarnet; D018698:Glutamic Acid; C031709:2',3'-dideoxyguanosine 5'-triphosphate; C072416:reverse transcriptase, Human immunodeficiency virus 2; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase