Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens.
Atazanavir (ATV) is a once-daily human immunodeficiency virus (HIV) protease inhibitor (PI) shown to be effective and well tolerated. ATV has a distinct resistance profile relative to other PIs, with susceptibility maintained against 86% of isolates resistant to 1-2 PIs. Clinical isolates obtained from PI-naive patients designated as experiencing virologic failure while receiving ATV-containing regimens contained a unique isoleucine-to-leucine substitution at amino acid residue 50 (I50L) of the HIV-1 protease. The I50L substitution, observed in all isolates exhibiting phenotypic resistance to ATV, emerged in a variety of different backgrounds and was most frequently accompanied by A71V, K45R, and/or G73S. Viruses containing an I50L substitution were growth impaired, displayed ATV-specific resistance, and had increased susceptibilities (</=0.4 of reference strain) to other PIs. Comparison of viruses bearing I50L with those bearing I50V revealed specific resistance to ATV and amprenavir, respectively, with no evidence of cross-resistance. The unique I50L substitution is the signature mutation for resistance to ATV.
Colonno
Richard
R
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut, USA. richard.colonno@bms.com
Rose
Ronald
R
McLaren
Colin
C
Thiry
Alexandra
A
Parkin
Neil
N
Friborg
Jacques
J
D000069446:Atazanavir Sulfate; D001483:Base Sequence; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology*; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000627:therapeutic use*; D017354:Point Mutation; D011725:Pyridines / Q000627:therapeutic use*; D016865:Reassortant Viruses / Q000235:genetics; D017422:Sequence Analysis, DNA; D014779:Virus Replication / Q000187:drug effects
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D016333:HIV Protease