HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) STRAINS SELECTED FOR RESISTANCE AGAINST THE HIV-1-SPECIFIC -OXATHIOLE-2'',2''-DIOXIDE)!-BETA-D-PENTOFURANOSYL (TSAO) NUCLEOSIDE ANALOGS RETAIN SENSITIVITY TO HIV-1-SPECIFIC NONNUCLEOSIDE INHIBITORS

We recently reported that a newly discovered class of nucleoside -oxat hiole-2'',2''-dioxide)!-beta-D-pentofuranosyl derivatives of pyrimidin es and purines (designated TSAO)-are highly specific inhibitors of hum an immunodeficiency virus type 1 (HIV-1) and targeted at the nonsubstr ate binding site of HIV-1 reverse transcriptase (RT). We now find that HIV-1 strains selected for resistance against three different TSAO nu cleoside derivatives retain sensitivity to the other HIV-1-specific no nnucleoside derivatives hydroimidazo4,5,1-jk!1,4!benzodiazepin-2(1H) -one and -thione (TIBO), 1-(2-hydroxyethoxy)methyl!-6-phenylthiothymi ne, nevirapine, and pyridinone L697,661, as well as to the nucleoside analogues 3'-azido-3'-deoxythymidine, ddI, ddC, and 9-(2-phosphonylmet hoxyethyl)adenine. Pol gene nucleotide sequence analysis of the TSAO-r esistant and -sensitive HIV-1 strains revealed a single amino acid sub stitution at position 138 (Glu --> Lys) in the RT of all TSAO-resistan t HIV-1 strains. HIV-1 RT in which the Glu-138 --> Lys substitution wa s introduced by site-directed mutagenesis and expressed in Escherichia coli could not be purified because of rapid degradation. However, HIV -1 RT containing the Glu-138 --> Arg substitution was stable. It lost its sensitivity to the TSAO nucleosides but not to the other HIV-1-spe cific RT inhibitors (i.e., TIBO and pyridinone). Our findings point to a specific interaction of the 4''-amino group on the 3'-spiro-substit uted ribose moiety of the TSAO nucleosides with the carboxylic acid gr oup of glutamic acid at position 138 of HIV-1 RT.