title: Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors.
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.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877.
authors.forename: C K
authors.initials: CK
authors.lastname: Shih
authors.forename: J M
authors.initials: JM
authors.lastname: Rose
authors.forename: G L
authors.initials: GL
authors.lastname: Hansen
authors.forename: J C
authors.initials: JC
authors.lastname: Wu
authors.forename: A
authors.initials: A
authors.lastname: Bacolla
authors.forename: J A
authors.initials: JA
authors.lastname: Griffin
mesh_terms: D000345:Affinity Labels; D000595:Amino Acid Sequence; D001381:Azepines / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001665:Binding Sites; D004252:DNA Mutational Analysis; D015497:HIV-1 / Q000201:enzymology*; D015498:HIV-2 / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology*; D008969:Molecular Sequence Data; D019829:Nevirapine; D011725:Pyridines / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000502:physiology
chemical_list: D000345:Affinity Labels; D001381:Azepines; D007093:Imidazoles; D011725:Pyridines; D011993:Recombinant Fusion Proteins; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; D014443:Tyrosine; C067413:R-82913; D019829:Nevirapine; D012194:RNA-Directed DNA Polymerase