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Mechanism of resistance to U‐90152S and sensitization to L‐697,661 by a proline to leucine change at residue 236 of human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase
Author(s) -
Fan Naisheng,
Evans David B.,
Rank Kenneth B.,
Thomas Richard C.,
Tarpley W.Gary,
Sharma Satish K.
Publication year - 1995
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(95)00051-a
Subject(s) - reverse transcriptase , mutant , sensitization , biology , wild type , amino acid , virology , virus , leucine , mutation , proline , microbiology and biotechnology , genetics , immunology , gene , rna
Bisheteroarylpiperazines (BHAPs) are highly specific inhibitors of human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase (RT). BHAP‐resistant HIV‐1 is sensitized to other classes of nonnucleoside RT inhibitors and this has been primarily attributed to a proline‐to‐leucine substitution at amino acid 236 (P236L) of HIV‐1 RT. To understand the basis for the in vitro sensitization‐resistance phenomenon, single base pair mutations at amino acid P236 in HIV‐1 RT were introduced to obtain P236L, P236T, P236H, P236R, and P236A HIV‐1 RT mutants. Active HIV‐1 RT mutants H235W, D237T, and H235W/D237T/T240K, containing substitutions from HIV‐2 RT, were also cloned, expressed, and purified. Three BHAPs (U‐88204E, U‐87201E, and U‐90125S) and the pyridinone L‐697,661 were selected to quantitatively assess the effects of these amino acid substitutions on sensitization to L‐697,661 and resistance to the BHAPs. The HIV‐1 RT mutants bearing single (H235W; D237T) or multiple (H235W/D237T/T240K) HIV‐2 RT substitutions around the conserved P236 conferred little resistance or sensitization to these RT inhibitors. The inhibition profiles of the P236 HIV‐1 RT mutants demonstrated a direct correlation between sensitization to L‐697,661 and resistance to the BHAPs. These results suggest alterations in the shape of the binding pocket as the mechanism by which the P236L mutation confers resistance to the BHAPs and sensitization to L‐697,661.