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J. Virol., Feb 1995, 701-706, Vol 69, No. 2
Copyright © 1995, American Society for Microbiology

Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor

M Markowitz, H Mo, DJ Kempf, DW Norbeck, TN Bhat, JW Erickson and DD Ho
Aaron Diamond AIDS Research Center, New York University School of Medicine, New York 10016.

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.

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