SELECTION AND ANALYSIS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-I VARIANTS WITH INCREASED RESISTANCE TO ABT-538, A NOVEL PROTEASE INHIBITOR

Inhibitors of the human immunodeficiency virus protease represent a pr omising new class of antiretroviral drugs for the treatment of AIDS. W e now report the in vitro selection of viral variants with decreased s ensitivity to a symmetry-based protease inhibitor, ABT-538, currently being tested in clinical trials. Molecular characterization of the var iants shows that an isoleucine-to-valine substitution at position 84 r esults in a substantial decrease in sensitivity to the drug. Moreover, an additional mutation at position 82, valine to phenylalanine, furth er decreases viral susceptibility to ABT-538. Three-dimensional analys is of the protease-drug complex provides a structural explanation for the relative drug resistance induced by these two mutations. These fin dings emphasize the importance of closely monitoring patients receivin g ABT-538 for the emergence of viral resistance and provide informatio n that may prove useful in designing the nest generation of protease i nhibitors.