Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors.

C K Shih; J M Rose; G L Hansen; J C Wu; A Bacolla; J A Griffin

doi:10.1073/pnas.88.21.9878

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Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors.

C K Shih·J M Rose·G L Hansen·J C Wu·A Bacolla·J A Griffin

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Abstract

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), an important therapeutic target in the treatment of AIDS, is effectively inhibited by a class of nonnucleoside analog compounds that includes nevirapine (BI-RG-587) and tetrahydroimidazo[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-one and -thione. We show that both tyrosine residues at positions 181 and 188 flanking the putative catalytic site of HIV-1 RT are required for sensitivity of the enzyme to these compounds. HIV-2 RT, which does not have tyrosines at these positions, is resistant to these nonnucleoside analog inhibitors. Substitution of the HIV-2 RT amino acid residues at position 181 or 188 into HIV-1 RT results in an enzyme that is resistant to these compounds while retaining sensitivity to 3'-azido-2',3'-dideoxythymidine triphosphate. HIV-2 RT substituted with amino acids 176-190 from HIV-1 RT acquires sensitivity to these nonnucleoside analog inhibitors.

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Affinity Labels Amino Acid Sequence Azepines Benzodiazepines Binding Sites DNA Mutational Analysis HIV-1 HIV-2 Imidazoles Molecular Sequence Data Nevirapine Pyridines RNA-Directed DNA Polymerase Recombinant Fusion Proteins Reverse Transcriptase Inhibitors Structure-Activity Relationship Tyrosine Journal Article

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C K Shih, J M Rose, G L Hansen, J C Wu, A Bacolla, J A Griffin. 1991-11-01. Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors.. https://doi.org/10.1073/pnas.88.21.9878

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