Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor.
Inhibitors of the human immunodeficiency virus protease represent a promising new class of antiretroviral drugs for the treatment of AIDS. We now report the in vitro selection of viral variants with decreased sensitivity to a symmetry-based protease inhibitor, ABT-538, currently being tested in clinical trials. Molecular characterization of the variants shows that an isoleucine-to-valine substitution at position 84 results in a substantial decrease in sensitivity to the drug. Moreover, an additional mutation at position 82, valine to phenylalanine, further decreases viral susceptibility to ABT-538. Three-dimensional analysis of the protease-drug complex provides a structural explanation for the relative drug resistance induced by these two mutations. These findings emphasize the importance of closely monitoring patients receiving ABT-538 for the emergence of viral resistance and provide information that may prove useful in designing the next generation of protease inhibitors.
Markowitz
M
M
Aaron Diamond AIDS Research Center, New York University School of Medicine, New York 10016.
Mo
H
H
Kempf
D J
DJ
Norbeck
D W
DW
Bhat
T N
TN
Erickson
J W
JW
Ho
D D
DD
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D003198:Computer Simulation; D004351:Drug Resistance; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019438:Ritonavir; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D013844:Thiazoles; D016333:HIV Protease; D014633:Valine; D019438:Ritonavir