In vitro evolution of the human immunodeficiency virus type 1 gag-protease region and maintenance of reverse transcriptase resistance following prolonged drug exposure.
We studied the human immunodeficiency virus type 1 phenotypic and genotypic profiles of a dual drug-resistant isolate (isolate 14aPost-DR) selected for zidovudine (ZDV) and lamivudine (3TC) resistance and then cultured in the presence of 3TC and a protease inhibitor: indinavir (IDV), ritonavir, or KNI-272. The IDV-treated virus was highly resistant to 3TC, ZDV, and IDV and accumulated protease mutations at positions M46I and V82F. A change from alanine to valine was observed in 4 of 10 clones in the P2 position of the p7-p1 Gag-protease cleavage site, linked to position M46I in the dominant viral quasispecies. Previous 3TC resistance did not impair the development of additional mutations in the protease and Gag-protease cleavage regions.
Istituto di Malattie Infettive e Tropicali, Università di Milano, Ospedale Luigi Sacco, via GB Grassi 74, 20157 Milan, Italy.
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Rusconi
D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000235:genetics*; D015658:HIV Infections / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D019259:Lamivudine / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology
D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019469:Indinavir; D016333:HIV Protease