High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase.
Passage of human immunodeficiency virus type 1 in the presence of increasing 2'-deoxy-3'-thiacytidine (3TC) concentrations results in high-level (> 100-fold) 3TC-resistant viruses. All 3TC-resistant viruses possess a substitution at the second codon (from a methionine into an isoleucine) at position 184 within the highly conserved motif (YMDD) of human immunodeficiency virus type 1 reverse transcriptase. 3TC-resistant viruses were cross-resistant to the (-) enantiomer of the fluorinated derivative of BCH-189 but remained susceptible to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine. The susceptibilities of the 3TC-resistant viruses to the (+) enantiomers of BCH-189 and the fluorinated derivative of BCH-189 demonstrate an enantiomeric specificity for viruses selected under these conditions. Introduction of an isoleucine substitution at codon 184 into a background of two known 3'-azido-3'-deoxythymidine resistance mutations (amino acids 41 and 215) restored the susceptibility of this virus to 3'-azido-3'-deoxythymidine.
Boucher
C A
CA
Antiviral Therapy Laboratory, Academic Medical Centre, Amsterdam, The Netherlands.
Cammack
N
N
Schipper
P
P
Schuurman
R
R
Rouse
P
P
Wainberg
M A
MA
Cameron
J M
JM
D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D003062:Codon / Q000235:genetics; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D019259:Lamivudine; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors; D013237:Stereoisomerism; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D003062:Codon; D018894:Reverse Transcriptase Inhibitors; D007532:Isoleucine; D019259:Lamivudine; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase