Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase.
Serial human immunodeficiency virus type-1 (HIV-1) isolates were obtained from five individuals with acquired immunodeficiency syndrome (AIDS) who changed therapy to 2',3'-dideoxyinosine (ddI) after at least 12 months of treatment with 3'-azido-3'-deoxythymidine (zidovudine, AZT). The in vitro sensitivity to ddI decreased during the 12 months following ddI initiation, whereas AZT sensitivity increased. Analysis of the reverse transcriptase coding region revealed a mutation associated with reduced sensitivity to ddI. When this mutation was present in the same genome as a mutation known to confer AZT resistance, the isolates showed increased sensitivity to AZT. Analysis of HIV-1 variants confirmed that the ddI resistance mutation alone conferred ddI and 2',3'-dideoxycytidine resistance, and suppressed the effect of the AZT resistance mutation. The use of combination therapy for HIV-1 disease may prevent drug-resistant isolates from emerging.
St Clair
M H
MH
Division of Virology, Burroughs Wellcome Co., Research Triangle Park, NC 27709.
Martin
J L
JL
Tudor-Williams
G
G
Bach
M C
MC
Vavro
C L
CL
King
D M
DM
Kellam
P
P
Kemp
S D
SD
Larder
B A
BA
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000382:microbiology; D001483:Base Sequence; D004279:DNA, Viral / Q000235:genetics*; D016049:Didanosine / Q000494:pharmacology* / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D005838:Genotype; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D012194:RNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use*
D004279:DNA, Viral; D009838:Oligodeoxyribonucleotides; D015215:Zidovudine; D012194:RNA-Directed DNA Polymerase; D016049:Didanosine