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

We 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

M Markowitz; H Mo; D J Kempf; D W Norbeck; T N Bhat; J W Erickson; D D Ho


Scholarcy highlights

  • Inhibitors of the human immunodeficiency virus protease represent a promising new class of antiretroviral drugs for the treatment of AIDS
  • 12 of 13 clones contained an M46I mutation. This substitution on the flap of the protease was previously reported by our group for an human immunodeficiency virus type 1 variant that was resistant to a related symmetry-based protease inhibitor
  • Viral resistance to antiretroviral agents remains a critical obstacle in the path to the development of cogent strategies for treatment of HIV-1 infection
  • We demonstrated significant in vitro resistance to ABT-538, a novel inhibitor of HIV-1 protease being tested in clinical trials in the United States and Europe
  • The increased resistance to ABT-538 emerges from amino acid substitutions at positions 82 and 84 in the HIV-1 protease
  • The I84V substitution was reported by El-Farrash et al to confer resistance to RPI 312, a synthetic HIV-1 protease peptide inhibitor
  • We cannot rule out the possibility that when we introduced them singly into the NL4-3 background we could not detect a phenotypic change in viral sensitivity to ABT-538, these mutations in combination contribute to the significant resistance observed in the P22 variant

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