In vitro evolution of the human immunodeficiency virus type 1 Gag-proteaseregion 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 fo r zidovudine (ZDV) and lamivudine (3TC) resistance and then cultured in the presence of 3TC and a protease inhibitor: indinavir (IDV), ritonavir, or K NI-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 a lanine to valine was observed in 4 of 10 clones in the P2 position of the p 7-p1 Gag-protease cleavage site, linked to position M46I in the dominant vi ral quasispecies. Previous 3TC resistance did not impair the development of additional mutations in the protease and Gag-protease cleavage regions.